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Prevention and management of chronic kidney disease intype 2 diabetes
Date written: April 2009nep_1240 162..194
Final submission: April 2009Author: Chadban S, Howell M, Twigg S, Thomas M, Jerums G, Cass A, Campbell D, Nicholls K, Tong A, Mangos G,Stack A, MacIsaac RJ, Girgis S, Colagiuri R, Colagiuri S, Craig J
GUIDELINES
Blood glucose control should be optimized aiming for a general HbA1c target 27%. (Grade A*).In people with type 2 diabetes and microalbuminuria or macroalbuminuria, angiotensin receptor blocker (ARB) orangiotensin-converting enzyme inhibitor ACEi antihypertensives should be used to protect against progression ofkidney disease. (Grade A*).The blood pressure (BP) of people with type 2 diabetes should be maintained within the target range. ARB or ACEishould be considered as antihypertensive agents of first choice. Multi-drug therapy should be implemented as requiredto achieve target blood pressure. (Grade A*)People with type 2 diabetes should be informed that smoking increases the risk of chronic kidney disease (CKD) (GradeB*).
*Refer to Table A1: Definition of NHMRC grades of recommendation. Also refer to NHMRC ‘National Evidence Based Guidelines forDiagnosis, Prevention and Management of CKD in Type 2 Diabetes’ (see http://www.cari.org.au) for Levels of Evidence and EvidenceGrading which were undertaken in accordance with the NHMRC Hierarchy of Evidence procedure.
SUGGESTIONS FOR CLINICAL CARE
• The HbA1c target may need to be individualized tak-ing in to account history of hypoglycaemia andco-morbidities. (refer to NHMRC Evidence Based Guide-line for Blood Glucose Control in Type 2 Diabetes athttp://www.nhmrc.gov.au).• Systolic blood pressure (SBP) appears to be the bestindicator of the risk of CKD in type 2 diabetes. However,an optimum and safest lower limit of SBP has not beenclearly defined.• In people with type 2 diabetes antihypertensive therapywith ARB or ACEi decreases the rate of progression ofalbuminuria, promotes regression to normoalbuminuria,and may reduce the risk of decline in renal function.• Due to potential renoprotective effects, the use ofACEi or ARB should be considered for the small sub-group of people with normal BP who have type 2 diabetesand microalbuminuria.• The extent to which interventions with lipid loweringtherapy reduces the development of CKD in people withtype 2 diabetes is unclear. As there is limited evidencerelating to effects of lipid treatment on the progression ofCKD in people with type 2 diabetes, blood lipid profilesshould be managed in accordance with guidelines for pre-vention and management of cardiovascular disease (CVD).• Lifestyle modification (diet and physical activity) is anintegral component of diabetes care (refer to the NHMRC
Evidence Based Guidelines for Blood Glucose Control inType 2 Diabetes), however, there are insufficient studiesof suitable quality to enable dietary recommendations tobe made with respect to prevention and/or management ofCKD in people with type 2 diabetes.
BACKGROUND
Aim of the guideline
This guideline topic has been taken from the NHMRC‘National Evidence Based Guidelines for Diagnosis, Preven-tion and Management of CKD in Type 2 Diabetes’ whichcan be found in full at the CARI website (http://www.cari.org.au). The NHMRC guideline covers issuesrelated to the assessment and prevention of CKD in indi-viduals with established type 2 diabetes. The NHMRCguidelines do not address the care of people with diabeteswho have end-stage kidney disease or those who have afunctional renal transplant. In addition, the present guide-line does not provide recommendations regarding the man-agement of individuals with established CKD, with respectto the prevention of other (non-renal) adverse outcomes,including retinopathy, hypoglycaemia, bone disease and car-diovascular disease. It is important to note however, that inan individual with type 2 diabetes, the prevention of thesecomplications may be a more important determinant fortheir clinical care. Consequently, the recommendations
NEPHROLOGY 2010; 15, S162–S194 doi:10.1111/j.1440-1797.2010.01240.x
© 2010 The AuthorsJournal compilation © 2010 Asian Pacific Society of Nephrology
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made must be balanced against the overall managementneeds of each individual patient.
Prevention and management of CKD in type 2 diabetes
It should be noted that the best way to prevent CKDin individuals with diabetes is to prevent diabetes.NHMRC recommendations for the primary prevention oftype 2 diabetes are available elsewhere (http://www.diabetesaustralia.com.au). These guidelines specificallytarget the management of individuals with established type 2diabetes.
A risk factor analysis for kidney dysfunction in type 2diabetes following 15 years of follow up from the UKPDSstudy,1 identified systolic blood pressure; urinary albuminexcretion and plasma creatinine as common risk factors foralbuminuria and kidney impairment (creatinine clearanceand doubling of plasma creatinine). Additional independentrisk factors for kidney impairment were female gender,decreased waist circumference, age, increased insulin sensi-tivity and sensory neuropathy. A cross-sectional study of1003 Japanese hospital patients with type 2 diabetes2 identi-fied large waste circumference and elevated BP as risk factorsfor microalbuminuria while dyslipidaemia was identified as arisk factor for decreased glomerular Filtration Rate (GFR).
In contrast to type 1 diabetes, only 20% of newly diag-nosed people with type 2 diabetes are normotensive andhave a normal circadian blood pressure profile. Thereforehypertension usually precedes the onset of microalbumin-uria.3 BP control modulates the progression not only ofmicroangiopathy (diabetic kidney disease and retinopathy)but also of macroangiopathy (Coronary heart disease(CHD) and stroke).
In microalbuminuric people with type 2 diabetes, obser-vational studies have shown an association between poorglycaemic control and progression of albuminuria. Anumber of studies have identified a strong independentassociation between hyperglycaemia and the rate ofdevelopment of microvascular complications.4 The largeobservational WESDR study5 indicated an exponentialrelationship between worsening glycaemic control andthe incidence of nephropathy as well as retinopathy andneuropathy.
The UKPDS has clearly shown the importance of target-ing glycosylated haemoglobin (HbA1c) levels close tonormal (HbA1c < 7.0%) in people with type 2 diabetes. Amodest decrease in HbA1c over 10 years from 7.9 to 7.0%lowered the risk of microvascular endpoints with the onsetof microalbuminuria being reduced by 25%.6 These findingsare supported by a study of intensified glycaemic control innon-obese Japanese subjects with type 2 diabetes.7 In theUKPDS, there was no significant reduction in the risk ofprogression from microalbuminuria to proteinuria withintensive blood glucose control.8
The AusDiab study collected information on albumin-uria, measured as a spot albumin: creatinine ratio (ACR)(mg/mmol) with microalbuminuria being between 3.4 and34 mg/mmol and macroalbuminuria at >34 mg/mol.9 The
prevalence of albuminuria increased with increasing glycae-mia. People with diabetes and impaired glucose tolerancehad an increased risk for albuminuria compared with thosewith normal glucose tolerance, independent of other knownrisk factors for albuminuria (including age and sex).
Hyperglycaemia is an important determinant of the pro-gression of normoalbuminuria to microalbuminuria in diabe-tes. Strict blood glucose control has been shown to delay theprogression from normoalbuminuria to microalbuminuria orovert kidney disease6 and from normo- or microalbuminuriato overt kidney disease.7 The influence of intensive glycae-mic control is greatest in the early stages of CKD althoughsome observational studies suggest an association of glycae-mic control with the rate of progression of overt kidneydisease and even end-stage kidney disease (ESKD).10
The American Heart Association (AHA) has under-taken a review of the DCCT, UKPDS, ACCORD,ADVANCE and VA Diabetes trials and on the basis of thereview issued a Scientific Statement addressing intensiveglycaemic control in relation to cardiovascular events.11
While the AHA review is focused on cardiovascular events,the statement is relevant to the consideration of the man-agement of CKD given the strong association between CKDand CVD in people with type 2 diabetes. Consistent withthe evidence reviewed in these guidelines (refer to followingsections), the AHA note that a small but incrementalbenefit in microvascular outcomes (principally renal out-comes) is indicated with HbA1c values approachingnormal. As a consequence the AHA statement notes thaton the basis of findings from the DCCT, UKPDS andADVANCE trials some patients may benefit (in terms ofmicrovascular outcomes) from HbA1c goals lower than thegeneral goal of <7%. However, the AHA also state that lessstringent goals may be appropriate for patients with . . . ‘ahistory of hypoglycaemia, limited life expectancy, advancedmicrovascular or macrovascular complications, or extensivecomorbid conditions . . .’. Thus individualized glycaemicgoals other than the general goal of <7% HbA1c may beappropriate for some patients.11
Several studies suggest that a reduction in albuminuria aswell as treatment of elevated blood pressure by the prefer-ential use of an ACEi may lower the risk of CVD to a greaterextent than with equihypotensive doses of dihydropyridinecalcium channel blockade.12,13 One long-term study fromIsrael has shown that ACE inhibition exerts a renoprotec-tive effect in normotensive middle-aged people with type 2diabetes and microalbuminuria. In this 7-year study, GFRremained stable in the ACEi (enalapril) treated group,while both albuminuria and GFR deteriorated rapidly in theplacebo group.12,14,15 However, the study did not include athird arm treated with conventional antihypertensiveagents, and therefore it is not clear if the renoprotectiveeffect was mediated by lowering of systemic BP as opposed toan intrarenal effect of the ACEi.
Antihypertensive therapy, especially with ARB’s andACEi, has been clearly shown to reduce albumin excretionrate (AER).16,17 There are trials indicating that ACEi exertcardioprotective effects in addition to lowering of BP, evenin normotensive people.18 Renoprotection has been demon-
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strated for ARB’s in two large studies.19,20 The existence of aspecific renoprotective effect of ACE inhibition in peoplewith type 2 diabetes was not confirmed in the UKPDS8
although it is possible that both captopril and atenololexerted an equal renal protective effect, over and abovelowering of systemic BP.
The term ‘renoprotection’ is considered to denote atleast three criteria:1. Antiproteinuric effect, which has been used as a surro-gate for the subsequent rate of decline in kidney function.2. Attenuation of the rate of decline in GFR.3. Attenuation of the rate of decline of GFR when com-pared with a control group treated with other antihyperten-sive agents in equihypotensive doses.
Proteinuria is a weaker basis for identifying renoprotec-tive treatments than a reduction in the rate of decline ofGFR.21
Several studies have documented the efficacy ofantihypertensive therapy in lowering AER in bothhypertensive22–24 and normotensive25 people with type 2 dia-betes and microalbuminuria.
People with type 2 diabetes and kidney disease show abroad range of lipid abnormalities, characterized by a switchto a more atherogenic lipid profile. This becomes morepronounced with increasing proteinuria, although severalfactors such as glycaemic control, insulin administration,obesity and genetic factors may alter the degree ofdyslipidaemia.
Increased levels of triglycerides are consistently seen inpeople with type 2 diabetes and microalbuminuria or overtproteinuria.26–28 The high triglyceride levels are associatedwith an increased proportion of atherogenic small denseLDL cholesterol particles.29 The implication is that serumtriglycerides should be as low as possible to prevent athero-genic changes in LDL-cholesterol particles.30 HDL choles-terol levels in people with type 2 diabetes have beenreported to be normal in association with overt diabetickidney disease28 whereas decreased HDL-cholesterol levelshave been reported in association with microalbuminuria.27
Higher apolipoprotein (a) levels have been reported inpeople with type 2 diabetes and micro- and macroalbumin-uria than in control subjects, and also in people withmacroalbuminuria than with normoalbuminuria.31 Apolipo-protein (a) levels have been related to the rates of progres-sion of albuminuria,32 however, others have not confirmedthese findings in people with diabetes and CKD.28
There is evidence to support the hypothesis that changesin lipid profiles may play a causal role in the initiation andprogression of kidney disease, based on the finding of lipiddeposits and foam cells in the glomeruli of humans withkidney disease.33
Primary or secondary intervention with statins in hyper-cholesterolaemic people has shown similar cardioprotectiveeffects in diabetic and non-diabetic subjects.34–36 The abso-lute clinical benefit achieved by cholesterol lowering may begreater in people with CHD and diabetes than with CHDand without diabetes because people with diabetes have ahigher absolute risk of recurrent CHD events and otheratherosclerotic events.34
Observational studies have shown that dyslipidaemiainteracts with other risk factors to increase cardiovascularrisk.37,38 Microalbuminuria is a risk factor for CVD as well asovert kidney disease in people with type 2 diabetes,39,40 anddyslipidaemia is more common in microalbuminuric thannormoalbuminuric people with type 2 diabetes.27 In peoplewith type 1 or type 2 diabetes and increased AER, elevatedLDL-cholesterol and triglycerides are common, whereasHDL-cholesterol may be high, low or normal. Nearly allstudies have shown a correlation between serum cholesterolconcentration and progression of CKD.41,42 Since increasedAER and dyslipidaemia are each associated with anincreased risk of CHD, it is logical to treat dyslipidaemiaaggressively in people with increased AER. Subgroups withdiabetes in large intervention studies have confirmed thatcorrection of dyslipidaemia results in a decrease in CHD.43
However, few trials have examined the effects of treatingdyslipidaemia on kidney end-points in people with type 2diabetes and increased AER. Further studies are thereforerequired in people with microalbuminuria and macroalbu-minuria in order to assess the effects of statins and fibrateson albuminuria and kidney function. Until the results of thistype of study are known, it will not be possible to determineif correction of dyslipidaemia alone exerts renoprotectiveeffects. Furthermore, it is not known if intervention withspecific agents such as statins or fibrates exerts effectson kidney end-points over and above protection fromcardiovascular events.
Dyslipidaemia is a common finding in individuals withtype 2 diabetes, particularly those with CKD, in whom it isa significant risk factor for adverse cardiovascular out-comes27,37,38 (refer also to the NHMRC guidelines for theprevention of cardiovascular disease in type 2 diabetes).Moreover, the lowering of LDL cholesterol in individualswith type 2 diabetes leads to primary and secondary preven-tion of cardiovascular events and mortality.44 The absoluterisk benefit of lipid lowering is much larger reflecting theincreased absolute risk of adverse cardiovascular outcomes.
SEARCH STRATEGY
Databases searched: The search strategies were designed toreduce bias and ensure that most of the relevant data avail-able on type 2 diabetes were included in the present reviewand were similar to those detailed in the Cochrane Collabo-ration Reviews Handbook (Higgins JPT et al.).45 Theelectronic databases searched were Medline, EMBASE,Cochrane Library, CINAHL, HTA and DARE. Thedetailed search strategy, research terms and yields are pro-vided in Appendix 3 of the complete guideline documentthat can be found on the CARI website (http://www.cari.org.au).Date of searches:Blood Glucose – April 3, 2008BP – March 18, 2008Blood Lipids – March 27, 2008Dietary Factors – March 28, 2008Smoking Cessation – April 1, 2008.
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WHAT IS THE EVIDENCE?
Role of blood glucose control
Improving glycaemic control reduces the development andprogression of kidney disease in people with type 2 diabetes(Evidence Level I – Intervention).
The issue of the role of blood glucose control in thedevelopment and progression of kidney disease in individu-als with type 2 diabetes has been addressed by a number ofsystematic reviews and RCTs. A summary of relevant studiesis presented in Table A2 with key studies discussed in thetext below. While a number of these studies have examinedthe use of specific antihyperglycaemic agents, it is not pos-sible on the basis of the current evidence to provide recom-mendations of the use of specific agents in relation to theprogression of CKD.
The systematic review by Newman et al.4 addressed thequestion of whether improved glycaemic control reducesthe rate of development of secondary diabetic complicationsin people with either type 1 or type 2 diabetes and microal-buminuria. Five RCTs were identified in people with type 2diabetes. The review considered ESKD, estimation of theGlomerular Filtration Rate (eGFR) and clinical proteinuriawith the following outcomes:• No RCT evidence was identified to show that improvedglycaemic control has any effect on the development ofESKD. The most relevant study is the UKPDS from whichfurther information may come from long-term follow up.• Evidence from the VA Cooperative study46 indicate thatintensified glycaemic control has little if any effect on therate of GFR decline.• Three studies were identified in relation to improvedglycaemic control and the development of clinical pro-teinuria and microalbuminuria, namely the Kumamotostudy,47 UKPDS6 and the VA Cooperative study.46 Thesestudies provide some evidence that intensive treatment ofhyperglycaemia in normoalbuminuric people with type 2diabetes will, in a proportion of people, prevent developmentof microalbuminuria and provide some evidence of a reduc-tion in the rate of clinical proteinuria. However, the studiesonly included a proportion of people with microalbuminuria.The VA study examined as a sub group the effect of glycaemiccontrol in those with microalbuminuria, however, the studywas relatively small and of limited duration.
The systematic review by Richter et al.48 assessed theeffects of pioglitazone in the treatment of type 2 diabetes.The relevant outcomes for these guidelines are mortality(kidney disease) and morbidity (nephropathy). Overall theevidence for a positive patient-oriented outcome for the useof pioglitazone was considered not to be convincing. Threestudies were identified that included endpoints relevant tothe assessment of kidney disease namely, Hanefeld et al.,49
Matthews et al.50 and Schernthaner et al.51 The Hanefeldet al.49 study compared pioglitazone plus sulfonyl urea withmetformin plus sulphonyl urea over 12 months in 649people with type 2 diabetes with a history of poorly con-trolled diabetes. The pioglitazone treatment resulted in a15% reduction in the urinary ACR compared with a 2%
increase in the metformin group with both treatmentsgiving clinically equivalent glycaemic control. The Mat-thews et al.50 study compared pioglitazone plus metforminwith glicazide plus metformin in 630 people with poorlymanaged type 2 diabetes over 12 months. The pioglitazonetreatment gave a 10% reduction in the ACR compared witha 6% increase in the glicazide group with no significantdifference in HbA1c.
The Schernthaner et al.51 study included 1199 peoplewith type 2 diabetes inadequately treated by diet alone(HbA between 7.5% and 11%) and aged between35–75 years from 167 centres located across 12 Europeancountries. Pioglitazone treatment resulted in a 19% decreasein ACR compared with 1% in the metformin group. Bloodpressure was not statistically different between groups. Theresults were considered to be consistent with previousstudies that troglitazone but not metformin or glibencla-mide reduced urinary albumin excretion rate.
The systematic review by Richter et al.52 assessed theeffects of rosiglitazone in the treatment of type 2 diabetes.The study by Lebovitz et al.53 was identified as including anoutcome measure relevant to kidney disease. The studyexamined the use of rosiglitazone as a monotherapy in 493people with type 2 diabetes over a 7 month period. Urinaryalbumin excretion was decreased significantly comparedwith the placebo. For the subgroup of people with microal-buminuria, both doses of rosiglitazone gave a reduction inACR from baseline of around 40%. Only a small percentageof patients were receiving antihypertensive therapy whichthe authors suggested indicates the effect to be a result ofimproved glycaemic control or a different effect of rosiglita-zone. The measurement of urinary ACR was a secondaryprospective outcome of the study of 203 people with type 2diabetes by Bakris et al.54 comparing rosiglitazone with gly-buride in a randomized controlled trial. RSG significantlyreduced ACR from baseline and strongly correlated withchanges in blood pressure and little relation to changes inFPG or HbA1c. Given similar levels of glucose control, themean reduction in ACR was greater for rosiglitazone thanglyburide and a greater proportion of participants in theRSG treatment group with baseline microalbuminuriaachieved normalization of the ACR by the 12 months.However, the power of the study in relation to the secondaryoutcome ACR was low and the differences in between thegroups was not statistically significant, thus the suggestedpotential benefit of RSG cannot be determined from thisstudy.
The objectives of the systematic review by Saenz et al.55
were to assess the effects of metformin monotherapy onmortality, morbidity, quality of life, glycaemic control, bodyweight, lipid levels, blood pressure, insulinaemia and albu-minuria in people with type 2 diabetes. The review identi-fied only one small trial of 51 people with type 2 diabeteswith incipient nephropathy with 3 month follow up,56
which reported some benefit for microalbuminuria withmetformin treatment. The authors concluded that microal-buminuria should be incorporated into the research out-comes and no overall conclusion has been made withrespect to effects of metformin on diabetic kidney disease.
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In addition to the studies identified by Saenz et al.,55 theHOME trial57 examined the efficacy of metformin in 345people with type 2 diabetes over a 4 month period. Met-formin was associated with a 21% increase in the UAEcompared with the placebo, the authors considered this tobe a short-term anomaly given the association of UAE withHbAc1, however, they were unable to identify the reasonfor the anomaly.
The ADVANCE trial58 was designed to assess the effectson major vascular outcomes of lowering the HbAc1 to atarget of 6.5% or less in a broad cross-section of people withtype 2 diabetes with CVD or high risk of CVD. The primaryendpoints were a composite of both macrovascular andmicrovascular events. Endpoints relevant to kidney diseaseincluded development of macroalbuminuria, doubling ofserum creatinine, and the need for renal replacementtherapy or death due to kidney disease. At baseline approxi-mately 27% of the participants had a history of microalbu-minuria and 3–4% had macroalbuminuria. At the end of thefollow up period the mean HbAc1 was significantly lower inthe intensive group (6.5%) than the standard group (7.3%).The mean SBP was on average 1.6 mm Hg lower than thestandard group.
A significant reduction (hazard ratio 0.86 CI: 0.77–0.97)in the incidence of major microvascular events occurred,while macrovascular events were not significantly differentbetween the groups. Intensive glucose control was associ-ated with a significant reduction in renal events includingnew or worsening of nephropathy (HR 0.79; CI: 0.66–0.93)predominantly due to a reduction in the development ofmacroalbuminuria and new onset microalbuminuria (0.91CI: 0.85–0.98). A trend towards a reduction in the need forrenal replacement therapy was also noted. The study con-cluded that the lack of a significant effect on major macro-vascular events may be due to inadequate power to detectsuch an effect given a lower than expected rate of macrovas-cular events. Some but not all of the overall effect on majorevents could be attributed to the small but significant1.6 mm Hg lower SBP in the intensive group.58
A significantly higher number of severe hypoglycaemicepisodes were recorded in the intensive group comparedwith the standard group (2.7% vs 1.5%). The rates were 0.7severe events per 100 people in the intensively controlledgroup and 0.4 severe events per 100 people in the stand-ard control group. The rates for minor hypoglycaemicevents were 120 per 100 people in the intensively controlledgroup compared with 90 per 100 people in the stand-ard control group. Overall the main benefit identifiedby the ADVANCE study was a one fifth reduction inkidney complications in particular the development ofmacroalbuminuria.58
A US study of Hispanic and African Americans assessedthe efficacy of rosiglitazone in a high risk (based on ethnic-ity) type 2 diabetes group.59 The urinary ACR was collectedas a secondary outcome under the general grouping of CVDmarkers. The study included 245 people with type 2 diabeteswith FPG greater than or equal to 140 mg/dL and HbA1cgreater than or equal to 7.5% who had been on a sulphonylurea monotherapy for a minimum of 2 months and were
randomized to receive glyburide (GLY) plus rosiglitazone(RSG) or glyburide (GLY) plus placebo for 6 months.The urinary ACR was reduced by 26.7% in the treatmentgroup (GLY + RSG) compared with control group(GLY + placebo). Improved insulin sensitivity and b-cellfunction with thiazolidinedione treatments was also noted.
US studies on the long-term effectiveness of miglitolhave been conducted by Johnston et al. for 385 HispanicAmericans with type 2 diabetes and 345 African Americanswith type 2 diabetes.60,61 ACR was included as an ‘efficacyparameter’ in both studies. The duration of the studies was12 months. Miglotol treatment was associated with a minorreduction in ACR in both studies.
The short-term trial of 223 mixed type 1 and type 2diabetes by,62 reported significant improvement in albumin-uria in those with micro or macroalbuminuria following a4 month high dose treatment with sulodexide. The effectwas considered to be additive to the ACE inhibitory effect.The sub analysis by diabetes type produced similar results.
The multifactorial intensive treatment of the STENO2study63 reduced the risk of nephropathy by 50%. This long-term study (mean 7.8 years) of 160 people with type 2diabetes and microalbuminuria, utilized multifactorial inter-ventions for modifiable risk factors for cardiovascular diseasewhich included intensive treatment of blood glucose. Whilea the intensive treatment group achieved a significantlylower blood glucose concentration, given the multifactorialnature of the study it is not possible to determine the rela-tive contribution that intensive blood glucose control mayhave had on the renal outcomes.
ROLE OF BP CONTROL
(a) BP as a risk factor for CKD
Arterial hypertension is a key risk factor for kidney damagein people with type 2 diabetes Evidence (Level I –Aetiology).
Several trials have clearly shown that intensive treat-ment of elevated BP lowers the risk of microvascular disease,CVD and mortality in type 2 diabetes (refer to systematicreviews of.4,16,17,64
The UKPDS has been the largest long-term study tocompare the effects of intensive versus less intensive BPcontrol in hypertensive people with type 2 diabetes. In this9-year study of 1148 people, allocated to tight BP control(n = 758) or less tight control (n = 390), mean BP wassignificantly reduced in the tight control group (144/82 mm Hg), compared with the group assigned to less tightcontrol (154/87 mm Hg) (P < 0.0001). The study showedthat microvascular endpoints, including the development ofmicroalbuminuria or overt diabetic kidney disease, werereduced by 37% in the intensive control group (P < 0.01).8
In this study, captopril and atenolol were used in equihy-potensive doses and each drug attenuated the developmentof microvascular complications to a similar degree over10 years.65
Elevated BP was identified as one of the major risk factorsassociated with a decline in kidney function and increase in
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albuminuria in a long-term non-interventional prospectivestudy of 574 people with type 2 diabetes who were normo-tensive and normoalbuminuric (based on dipstick) at thestart of the study.66 Those with elevated BP (>95 mm Hg)had an almost 10 fold increased risk of developing microal-buminuria compared with those with lower BP over theaverage 8 year follow-up period. Recent analysis of the BParm data of the ADVANCE Trial67 by Galan et al.68 hasindicated that lower achieved follow-up (median 4.3 years)systolic blood pressure levels were associated with progres-sively lower renal event rates to below 110 mm Hg.
These studies support the concept that arterial hyperten-sion plays a pivotal role in contributing to kidney damage intype 2 diabetes, across the range of albumin excretion fromnormal to micro- to macroalbuminuria. The studies alsoshow that the rate of GFR decline can be successfullylowered in people with type 2 diabetes by effective antihy-pertensive therapy, however, the systematic review by4 con-sidered that a 72% drop in clinical proteinuria noted inrelevant trials was unlikely to be caused by the small differ-ence in the BP between treatment groups and is consistentwith renoprotective effects of ACEi.
(b) BP control for prevention and management of CKD
In people with type 2 diabetes antihypertensive therapywith ARB or ACEi decreases the rate of progression ofalbuminuria, promotes regression to normoalbuminuria, andmay reduce the risk of decline in renal function (EvidenceLevel I – Intervention).
A large number of systematic reviews and trials haveexamined antihypertensive therapy using ACEi and ARBsin people with type 2 diabetes. A summary of relevantstudies is shown in Table A3 with findings of key studiesdescribed in the text below.
Systematic reviews and meta-analyses:The systematic review of RCTs up until 2002 reported by
Newman et al.4 examined three areas relevant to consider-ation of the use of antihypertensive therapy that are sum-marized below:
1. Antihypertensive therapy and development ofESKD in people with type 2 diabetes and microalbumin-uria.
Only three RCTs were identified as being of sufficient sizeand length of follow up namely ABCD, UKPDS and HOPE.Of these ABCD did not include ESKD as an endpoint.
In the UKPDS study the prevalence of ESKD was lessthan 2% with a relative risk for tight control of 0.58 (95%CI: 0.015–2.21) with similar results for death from kidneyfailure.8
The HOPE Study demonstrated that there was a non-significant relative risk reduction for the requirement forrenal dialysis among people treated with ramipril.18
As a consequence of the above two trials, Newman et al.4
concluded that there was no evidence of a beneficial effectof antihypertensive therapy on the development of ESKD.
2. Antihypertensive therapy and change in GFR inpeople with type 2 diabetes and microalbuminuria.
Three placebo controlled trials in normotensive peoplewere identified.14,25,69 Newman et al.4 considers the data areinconclusive. No appropriate trials comparing differentantihypertensive agents and intensive versus moderate BPcontrol were identified. However, later analysis of theABCD trial70 indicated a significant effect of intensivetherapy on the progression from microalbuminuria to clini-cal proteinuria, however, there was no change in creatinineclearance and no difference between ACEi and CCB.
Two placebo controlled trials in hypertensive peoplewere identified.71,72 Newman et al.4 concludes that thelimited evidence indicates kidney function to remain stablein hypertensive people with type 2 diabetes with microal-buminuria treated with ACEi compared with a decline inthe placebo group (36 month follow up). The Parvinget al.72 study also indicated a significant reduction in the rateof progression to clinical proteinuria with ARB treatmenthowever, this was not associated with a significant decline increatinine clearance.
Two trials were identified that compared intensive andmoderate BP control in hypertensive people with type 2diabetes with microalbuminuria.8,73 However, the UKPDSstudy was unable to differentiate between normoalbuminu-ric and microalbuminuric subgroups. In the large ABCDstudy no significant difference in creatinine clearance wasfound in either normoalbuminuric or microalbuminuricsubgroups.
Three appropriate trials were identified comparing differ-ent antihypertensive agents in hypertensive people withtype 2 diabetes with microalbuminuria.73–75 None of thesetrials showed significant differences in GFR or creatinineclearance.
3. Antihypertensive therapy and development ofclinical proteinuria in people with type 2 diabetes andmicroalbuminuria.
Three randomized placebo-controlled trials in normo-tensive people with type 2 diabetes with microalbuminuriawere identified.14,25,69 These three trials all used the ACEienalapril as the treatment. The overall relative risk for thedevelopment of proteinuria for the three trials was 0.28(95% CI: 0.15–0.53) with no significant heterogeneitybetween studies. No study provided information to allowassessment of regression to normoalbuminuria. The overallrisk reduction was 4.5% giving a NNT of 22 patients peryear to prevent one case of clinical proteinuria. The differ-ences in BP between treatment and placebo were small andas such consider that a 72% drop in clinical proteinuria wasunlikely to be caused by such a small difference and morelikely that ACEi have a specific renoprotective effect.4
No appropriate trials were identified comparing antihy-pertensive agents and intensive versus moderate BP controlother than the later analysis of the ABCD trial. Intensivetherapy with either enalapril or nisoldipine resulted in alower percentage of people who progressed from normoal-buminuria and microalbuminuria to clinical proteinuriawith no difference between the ACEi and CCB.73
Only one available placebo controlled study was identi-fied for hypertensive people with type 2 diabetes withmicroalbuminuria.71 The treatment involved two dose levels
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of the ARB antagonist irbesartan for 2 years. A combinedrelative risk for clinical proteinuria for the ARB treatmentswas 0.50 (95% CI: 0.0.31–0.81). This reduction in therate of progression to clinical proteinuria was independentof BP.
Only the ABCD trial was identified as being relevant forcomparing intensive versus moderate BP control in hyper-tensive people with type 2 diabetes with microalbumin-uria.73 Individuals were randomized to either ACEi enalaprilor the CCB antagonist nisoldipine. The percentage ofpeople who progressed from microalbuminuria to clinicalproteinuria was not significantly different between the treat-ment groups. Newman et al.4 noted that the results sup-ported the observations from the UKPDS of progression toclinical proteinuria among microalbuminuric and normoal-buminuric people with type 2 diabetes was not affected bythe level of BP control, however, separation of the twogroups is not possible.
Four trials were identified comparing different hyperten-sive agents in hypertensive people with type 2 diabetes withmicroalbuminuria.12,74–76 The trials all included an ACEitreatment compared with either a CCB antagonist or bblocker. The overall relative risk of development of clinicalproteinuria for ACEi versus other hypertensive therapy was0.74 (95% CI: 0.44–1.24) with no significant heterogeneity.Thus the ACEi reduced progression to clinical proteinuriaas effectively as the other therapies. These findingswere considered to be comparable with the UKPDSfindings which could not separate normoalbuminuria frommicroalbuminuria.
The two systematic reviews addressed the use of antihy-pertensive agents in people with diabetes with respect torenal outcomes.16,17 The objectives of the review by Strippoliet al.16 were to evaluate the effects of antihypertensiveagents in people with diabetes and normoalbuminuria.While the objectives of the review by Strippoli et al.17 wereto evaluate the benefits and harms of ACEi and ARBs inpreventing the progression of CKD. Both reviews includedstudies of both type 1 and type 2 diabetes and Strippoliet al.17 people with either microalbuminuria or macroalbu-minuria. While the reviews included both type 1 and type 2diabetes the majority of selected trials enrolled only peoplewith type 2 diabetes.
The overall conclusions of the two systematic reviews aresummarized below:• A significant reduction in the risk of developing microal-buminuria in normoalbuminuric patients has been demon-strated for ACEi only. This effect appears to be independentof BP and, kidney function and type of diabetes. However,there is insufficient data to be confident that these factorsare not important effects modifiers.16
• There is randomized trial evidence that ACEi versusplacebo/no treatment used at the maximum tolerable doseprevent death in people with diabetic kidney disease but notso for ARB versus placebo/no treatment. Both agentsprevent progression of nephropathy and promote regressionto a more favorable clinical pattern of normoalbuminuria.The relative effects of ACEi and ARBs are uncertain due toa lack of head to head trials.17
In relation to type 2 diabetes the following outcomes areof note:16,17
• All-cause mortality– non-significant effect of ACEi versus placebo.– comparison between ACEi and CCB – no significantdifference, however, only two studies were availablewhere relative risk could be estimated.– at less than the maximum tolerable dose for ACEiversus placebo/no treatment – no significant effect.– at the maximum tolerable dose for ACEi versusplacebo/no treatment – no significant effect in the tworelevant studies both of which were mixed type 1 andtype 2 diabetes populations.– for ARB versus placebo/no treatment – all of thestudies included people with type 2 diabetes and no sig-nificant effect was noted.
• Doubling of serum creatinine– non-significant effect of ACEi versus placebo.– comparison of ACEi and CCB – no available suitablestudies where relative risk was able to be estimated.– for ACEi versus placebo/no treatment – overall effectof marginal significance in favour of ACEi.– for ARB versus placebo/no treatment – the two studiesselected both included people with type 2 diabetes withan overall significant reduction for ARB compared withplacebo/no treatment.
• Progression to ESKD– non-significant effect of ACEi versus placebo in theone mixed type 1/type 2 diabetes study only.18
– comparison between ACEi and CCB – no availablesuitable studies where relative risk was able to beestimated.– for ACEi versus placebo/no treatment – non-significant relative risk in the two studies that includedpeople with type 2 diabetes.– for ARB versus placebo/no treatment – the two studiesselected both included people with type 2 diabetes withan overall significant reduction in progression to ESKDfor ARB compared with placebo/no treatment.
• Progression from normoalbuminuria to microalbuminuriaor macroalbuminuria
– overall significant effect of ACEi versus placebo inreducing the rate of progression.– ACEi compared with other hypertensive agents –limited to the UKPDS study which showed no significanteffect of ACEi in reducing the rate of progression.– normotensive patients – ACEi versus placebo – notrials identified with people with type 2 diabetes.– hypertensive patients – ACEi versus placebo – evi-dence for significant reduction in rate of progression withACEi treatment.– ACEi compared with CCB – significant effect of ACEiin reducing the rate of progression.
• Progression of microalbuminuria to macroalbuminuria– ACEi versus placebo/no treatment – the type 2 diabe-tes studies are weighted to a relative risk less than one(i.e. favoring ACEi) consistent with the overall assess-ment with type 2 diabetes studies accounting for approxi-mately 70% of the total number in all selected studies.
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– ARB versus placebo/no treatment – all selected studiesincluded people with type 2 diabetes and show an overallreduction in the rate of progression in favour of ARBtreatment.
• Regression from microalbuminuria to normoalbuminuria– ACEi versus placebo/no treatment – the type 2 diabe-tes studies are weighted to a relative risk greater than 1(i.e. favors ACEi) consistent with the overall assessmentof studies with type 2 diabetes being approximately 65%of the total number in all of the included studies.– ARB versus placebo/no treatment – the two trialsincluded people with type 2 diabetes and show an overallmarginal increase in the rate of regression in favor ofARB treatment.
• Comparison of effect on BP– ACEi versus placebo no trials identified that includedpeople with type 2 diabetes.– ACEi and CCB on BP – no significant effect, however,limited to one mixed type 1/type 2 diabetes study.The relevant trials comparing ACEi treatment with
ARB treatment all included people with type 2 diabetes andno significant differences on all cause mortality, progressionof microalbuminuria to macroalbuminuria or regressionfrom microalbuminuria to normoalbuminuria were noted.17
However, as noted in the overall conclusion by the authorsthe trials were limited and provide insufficient evidence forcomparison of effects.
The objectives of the systematic review was to assess theRCT evidence for the effects of different therapeutic BPgoals and interventions in the normotensive range on thedecline of glomerular function.64 The search strategy waslimited to studies of people with 2 years duration of type 1 ortype 2 diabetes with incipient or overt nephropathy with orwithout elevated BP. The intervention was required to betreatment with one or more hypertensive agents. Thereview identified 5 RCTs meeting the search criteria. All ofthese studies have been identified and assessed.4,16,17 Onlytwo studies that considered the effect of BP targets withinthe normotensive range in people with type 2 diabetes wereidentified.70,73
Kaiser et al.64 considered GFR as surrogate endpoint inthe absence of a renal failure endpoint such as need fordialysis and/or transplantation. The authors noted that notrial demonstrated any beneficial effect of lower target BPvalues on the progression of kidney failure. In shortdecreases in albuminuria were not accompanied by adecrease in the rate of decline in GFR. They conclude thatthe available evidence does not support a beneficial effect ofBP lowering within the normotensive range on progressionof diabetic nephropathy as assessed by the change in GFR.
The systematic review and meta analysis pooled analysesfrom the number of small studies comparing combinationtreatment of ACEi + ARB with ACEi alone.77 A total of tenstudies covering both type 1 and type 2 diabetes wereincluded in the meta-analysis. The majority of the studieswere of people with type 2 diabetes. The authors concludedthat the meta-analysis suggests that combined ACEi + ARBreduces 24 h proteinuria to a greater extent than ACEialone and that this benefit is associated with small effects on
GFR. However, analysis also concludes that the availablestudies were heterogeneous and mostly of short duration(only one study greater than 12 weeks) and the few longerterm studies have not demonstrated a benefit.
Hamilton et al.78 conducted a meta-analysis of RCTsevaluating the efficacy of ACEi in the treatment of nephr-opathy in individuals with type 2 diabetes. Specifically themeta-analysis addressed the reduction in albuminuria orproteinuria and thus included only those studies that pro-vided either geometric or arithmetic means of albuminuria.Studies reporting geometric means and arithmetic meanswere analysed separately. The results of the meta-analysisindicated that treatment with ACEi produced significantreductions in albuminuria in people with type 2 diabetes instudies where geometric means were used to normalize databut less clear where data is reported as arithmetic means(presumed to reflect the skewing of the albuminuria data).While studies were stratified on the basis of the degree ofalbuminuria and study duration, no distinction betweennormotensive or hypertensive patients have been made.
Studies with ARB’s in people with type 2 diabetes andovert kidney disease have shown that angiotensin receptorblockade with irbesartan attenuates the rate of doubling ofserum creatinine by 20–30% over 2.7 years when comparedwith placebo or amlodipine, used in equihypotensivedoses.19 A study of angiotensin receptor blockade with irbe-sartan in hypertensive, microalbuminuric people with type 2diabetes showed a 70% decrease in AER over 2 years.72
However, preservation of GFR over and above the effects ofBP lowering was not demonstrated in this relatively short-term study.
Studies not covered by Systematic Reviews
The ADVANCE study is a multinational randomizedcontrol trial undertaken by 215 centres across 20 countrieswhich, in addition to intensive blood glucose treatment,included a BP treatment study arm.67 Participants were ran-domized to either fixed combined perindopril indapamide orplacebo. Additional antihypertensive agents were allowedfor both groups as required with the exception that thiazidediuretics were not allowed and the only open labelled ACEiallowed was perindopril to a maximum dose of 4 mg a daythereby ensuring that the active treatment group did notexceed the maximum recommended dose. The active treat-ment resulted in a mean reduction after 4.3 years (median)in SBP and DBP of 5.6 and 2.2 mm Hg, respectively, com-pared with placebo. The relative risk of a major micro-vascular event was 7.9% in the active treatment groupcompared with 8.6% in the placebo group, however, this wasnot significant. Active treatment was associated with a bor-derline significant reduction in macroalbuminuria and a sig-nificant reduction in the development of microalbuminuriawith a relative risk reduction of 21% (95% CI: 15–30).Further detailed analysis of the ADVANCE trial data hasindicated that lower achieved follow-up systolic BP levelswere associated with progressively lower renal event rates tobelow 110 mm Hg.68 Renoprotective effects of blood pres-
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suring lowering with perindopril indapamide treated werenoted even among the sub group with baseline BP below120/70 mm Hg.
An open label parallel prospective randomized trial pro-vides a comparison of the effects of a ARB (losartan) and aCCB (amlidopine) on the UAE and ACR of 87 hyperten-sive type 2 diabetes Japanese patients with persistent mac-roalbuminuria.79 The ARB and CCB treatments providedsimilar BP control (no significant difference). The ARBtreatment resulted in a 30% drop in the UAE after 6 monthstreatment and a 16% drop in the ACR. There was nosignificant change in both the UAE and the ACR in theCCB treatment.
In relation to ACEi, a number of additional trials havebeen identified, the details and findings of which are sum-marized in Table A3.80–83 While the study summarized inTable A10 has examined both ACEi and ARBs either aloneof in combination.84 A number of studies have specificallyassessed the ARB valsartan.85–90 The details and findings ofthese studies are summarized in Table A3 below. Overall,the studies are consistent with the renoprotective effect ofARBs, however, they do not provide additional data allow-ing a direct comparison with ACEi.
The BENDICT Trial was a long-term (median43 months) prospective multicentre RCT of 1204 peoplewith type 2 diabetes, elevated BP and normoalbumin-uria.91,92 The trial was aimed at assessing the efficacy of ACEiand CCB alone and in combination. Additional agents werepermitted to achieve appropriate BP control. Trandolaprilplus verapamil and trandolapril alone decreased the inci-dence of microalbuminuria to similar extent. Verapamilalone was found to be no different to the placebo.
The comparative effects of HCT, ACEi and ARB onUAE (as a secondary outcome) were assessed in 70 peoplewith type 2 diabetes in the Netherlands.93 The people withtype 2 diabetes were Caucasian with an average age inthe randomized treatment groups of 60–63, hypertensiveand either normoalbuminuric or early microalbuminuric(UAE < 100 mg/day). The trial was of 12 months durationafter a 1 month run in and a 4–6 month BP titration period.All three agents achieved the aggressive BP goals equallywell in the three treatment groups. The UAE was reducedby around 35% over 12 months and there was no significantdifference between the three treatments. The authors notethat this outcome may reflect the relatively small samplesize. This additional ACEi/ARB comparative study fromthose reported does not provide additional evidence for theefficacy of ARB compared with ACEi in achieving regres-sion of microalbuminuria.17
The multicentric CENTRO trial of 129 Italians withtype 2 diabetes compared the ARB candesartan with theACEi enalapril with albumin excretion rate as a secondaryoutcome. After 6 months treatment the ARB treatmentgroup had a reduced albumin excretion rate and ACR, whilethe ACEi was higher.94 However, the baseline conditionsdiffered between treatment groups and the majority ofindividuals were normoalbuminuric thus the relevance ofthe outcomes for individuals with microalbuminuria isquestionable.
The GEMINI trial involved 1235 people with type 2diabetes with elevated BP under either an ACEi or ARBhypertension treatment randomized for treatment with twodifferent b-blockers (carvedilol and metoprolol).95 A posthoc analysis of differential effects of the b-blockers on theprogression of albuminuria indicated a greater reduction inmicroalbuminuria for carvedilol compared with metoprolol.In those with normoalbuminuria fewer progressed tomicroalbuminuria on carvedilol. These effects were notrelated to BP. Multivariate analysis demonstrated only base-line urine ACR and treatment were significant predictors ofchanges in albuminuria. In a separate analysis the presenceof metabolic syndrome at baseline corresponded with an ORof 2.68 (95% CI: 1.36–5.30) over the duration of the study.
The DETAIL study involved 250 people with type 2diabetes with mild to moderate hypertension andeGFR 3 70 mL/min per 1.73 m2 from 6 European coun-tries.96 The study compared an ARB and an ACEi treatmentover 5-years. After 5 years the difference in eGFR betweenthe ARB and the ACEi was -3.1 mL/min per 1.73 m2 andwas insignificant. The mean annual declines in eGFR were3.7 mL/min per 1.73 m2 for the ARB and 3.3 mL/min per1.73 m2 for the ACEi. These results were considered by theauthors to be similar to eGFR decline reported in the IRMA2, IDNT, and RENAAL studies and compare to an expecteduntreated type 2 diabetes annual decline in the order of10 mL/min per 1.73 m2. Telmisartan was concluded to benot inferior to enalapril in providing long-term renoprotec-tion. However, the results do not necessarily apply to moreadvanced nephropathy but support clinical equivalence ofARB and ACEi in persons with conditions that place themat high risk for CV events.
The large ONTARGET trial comparing ARB and ACEiof in excess of 25 000 participants included a large propor-tion with diabetes and microalbuminuria.97 Relevant sec-ondary outcomes are kidney impairment and kidney failurerequiring dialysis. The only significant differences betweentreatments (ACEi, ARB and ACEi + ARB) were forincreased kidney impairment in the combination therapycompared with the ACEi. Further analysis of renal out-comes,98 indicated a significantly higher increase in ACR inthe ACEi treatment group compared with the ARB andACEi + ARB (31% vs 24% and 21%). The risk of develop-ing new microalbuminuria was not different between ACEiand ARB treatment groups, but was significantly lower inthe combination treatment group. However, in contrast toalbuminuria a greater rate of decline in eGFR was noted forthe combination treatment group, thus the authorsconcluded that there was no evidence for a renal benefitwith combination therapy even though proteinuria wasimproved. No subgroup analysis has been undertaken withrespect to diabetes or albuminuria.
The short-term (6 month) study examined the renopro-tective effects in people with type 2 diabetes with albumin-uria of treatment with a direct renin inhibitor (aliskiren) inaddition to maximal treatment with an ARB (losartan).99
Treatment with 300 mg of aliskiren was demonstrated toreduce the ACR by 18% compared with the placebo groupand to increase the number of people with an albuminuria
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reduction of greater than 50% over the treatment period.These effects were independent of changes in BP and there-fore considered to indicate renoprotective effects of thetreatment. The rationale behind the trial was provision offurther benefit by use of a direct renin inhibitor in additionto maximal use of a angiotensin II receptor antagonist.
Table A3 provides a summary of studies that provideevidence in relation to use of antihypertensive agents inpeople with type 2 diabetes and the progression of CKD.Included are details of a number of studies conducted priorto 2000 that have not been discussed above that are pro-vided as an overview of the collective evidence in relationto the role of BP control in the progression of CKD.100–103
(iii) Role of blood lipid modification
The extent to which interventions with lipid loweringtherapy reduces the development of CKD is unclear (Evi-dence Level I – Intervention).
As detailed below there are some trials that show that,over and above the cardio-protective actions, lipid-loweringmay also exert beneficial effects on the development andprogression of kidney disease in individuals with type 2diabetes, as determined by albuminuria and/or GFR.However, there are no RCT studies in which renal outcomesincluding ESKD or doubling of serum creatinine have beenused. It is unlikely that these studies will ever be performedgiven the overwhelming benefit of lipid lowering in terms ofcardio-protection. Clinical trials in cardiovascular diseasestudying agents targeting dyslipidaemia have commonlyexcluded subjects with late stage CKD. Moreover, the sig-nificant cardiovascular benefits of these agents could con-found associations between lipid effects and renal functionoutcomes. Consequently, conclusions regarding their poten-tial as reno-protective agents must be limited by relianceon early, surrogate markers of kidney disease and itsprogression.
An overall summary of relevant studies is provided inTable A4 with findings from key studies described in thetext below.
Systematic reviews and meta-analyses
Sandhu et al.104 conducted a systematic review and meta-analysis to determine the effect of statins on the rate ofkidney function loss and proteinuria in individuals withCKD (with and without diabetes). They included 27 eli-gible studies with 39 704 participants (21 with data foreGFR and 20 for proteinuria or albuminuria). Overall, thechange in the eGFR was slower in statin recipients (byapproximately 1.2 mL/min per year). In addition, treatmentwith statins resulted in a significant reduction in baselinealbuminuria and/or proteinuria. However, the magnitude ofcholesterol reduction from baseline was not significantlyassociated with the described renal benefit of statins inmeta-regression. In the smaller studies specifically per-formed in people with type 2 diabetes and kidney disease(n = 3) the change in eGFR was unaffected by statins,
although the modest magnitude of the effect observed in theother (larger) trials, if translated to these smaller studies,would mean the latter were underpowered to detect aneGFR difference.
Keating & Croom105 specifically addressed the pharma-cological properties and efficacy of the fibric acid derivative,fenofibrate, in the treatment of dyslipidaemia in individualswith type 2 diabetes. The review included consideration ofeffects on albuminuria in the two major RCTs (FIELD andDAIS, see below). In both trials fenofibrate, reduced therate of progression from normoalbuminuria to microalbu-minuria and microalbuminuria to macroalbuminuria andincreased the rate of regression, when compared with treat-ment with placebo. This effect was modest in size. Forexample, the proportion of people developing microalbu-minuria was significantly reduced in the FIELD trial (10%compared with 11%) and in the DAIS trial (8% comparedwith 18%).
Strippoli et al.106 examined data on 50 trials (30 144people), 15 of which evaluated the potential renoprotectiveeffect of statins. Most of these studies enrolled people withearly or late stages of CKD and with a history of coronaryheart disease. These studies did not include people withmoderate CKD but without known cardiovascular disease.In the small number of studies reporting urinary proteinexcretion (g/24 h) in individuals with CKD (6 randomizedcontrolled trials, 311 people), statins modestly reducedalbuminuria and/or proteinuria. However, in contrast tofindings of other meta-analyses, no significant effect wasobserved on creatinine clearance (11 randomized controlledtrials, 548 people). This review was unable to distinguish aspecific response in individuals with diabetes.
Fried et al.107 conducted a meta-analysis of trials of effectsof lipid lowering therapy on nephropathy. A total 12 trialswere included following systematic review, with all but onebeing a RCT. Of the 12 trials, the cause of kidney diseasewas stated as being due to diabetes (no distinction betweentype 1 or type 2 diabetes) in 7 of the 12 trials. Meta-analysisindicated that lipid reduction had a beneficial effect on thedecline in GFR. The reduction in GFR from lipid-loweringtherapy was 1.9 mL/min per year. There was no significantheterogeneity and no indication of publication bias. Regres-sion analysis showed no relationship between effect of treat-ment and age, gender, cause of kidney disease and the typeof lipid lowering therapy. No clear conclusions were possiblewith respect to the effect of lipid lowering therapy on pro-teinuria due to significant heterogeneity. Overall theauthors concluded that meta-analysis suggests that lipidlowering therapy may help slow the rate of kidney diseaseprogression. However, the applicability to type 2 diabetes isless clear as no sub group analysis was conducted.
Randomized clinical trials using statins
Statins are the most widely used class of drug for lipid low-ering in individuals with type 2 diabetes. Currently in Aus-tralian practice at least two thirds of patients seeing theirGP are receiving a statin. This reflects the clear and incon-
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trovertible evidence that lowering of LDL cholesterol inindividuals with type 2 diabetes is associated with reducedcardiovascular events and mortality.44 Moreover, whenresults were adjusted for baseline risk, people with diabetesbenefited more in both primary and secondary prevention.In addition, a number of studies have looked at the effects ofstatins on renal parameters, including GFR, creatinineclearance and urinary albumin excretion. However, notrials report endpoints such as end stage kidney diseaseor doubling of creatinine as an outcome. The followingtrials provide evidence in relation to the use of statins inpeople with type 2 diabetes and that also include renaloutcomes.
A number of major statin trials have been conducted,which have included individuals with type 2 diabetes. Inpost hoc analyses of these large studies, beneficial effects onrenal functional parameters have been examined in thesubgroup of participants with diabetes.• In the MRC/BHF heart protection study108 subgroupanalysis for participants with diabetes, allocation to simvas-tatin (40 mg/day) significantly decreased the rise in SCrvalues. Subjects were excluded from entering the trial iftheir serum creatinine was above 200 mmol/L, reflectingthat those with late stage CKD were not studied.• In the Greek atorvastatin and coronary heart diseaseevaluation (GREACE) treatment with atorvastatin wasassociated with a significant decrease in urinary albuminexcretion, however, the study did not include separateanalysis for type 2 diabetes.109
• The Aggressive Lipid-Lowering Initiation Abates NewCardiac Events (ALLIANCE) showed beneficial effects onGFR in individuals with type diabetes, however, the studydid not separately identify or assess type 2 diabetes.110
There have also been a number of studies examining theeffects of statins on albuminuria and or creatinine clearancein individuals with type 2 diabetes, however, most of theseare small (i.e. less than 50). The following two studies havebeen identified:• A multicentric double blind parallel group RCT of type 2diabetes Swedish patients with dyslipidaemia (fasting LDL-C > 3.3 mmol/L) compared two statin treatments (rosuvas-tatin and atorvastatin) over a 16 week treatment period.111
The primary endpoints were UAE and GFR which weremeasured/calculated at baseline and at 8 and 16 weeks intothe treatment period. The treatment goal (achieved bytitration) was an LDL-C <3.0 mmol/L. As noted by theauthors, the short duration of the study allows only conclu-sions to be made with respect to ‘acute or subacute changes’in UAE and estimated GFR. The overall conclusion of thetrial was that both drugs were well tolerated and ‘show noevidence of short-term detriment on the renal endpoints ofUAE and GFR over a 4 month treatment period.’ Anabsence of clinically important changes in albuminuria wasnoted for both treatments.• Nakamura et al.112 studied the effect of cerivastatin onurinary albumin excretion in people with type 2 diabetes,microalbuminuria and dyslipidaemia. Sixty participantswere enrolled in a double-blind study for 6 months, receiv-ing either cerivastatin (0.15 mg/day) or placebo. At the
endpoint, cerivastatin treatment resulted in a significantdecrease in UAE (P < 0.01).
Randomized clinical trials using fibrates
Fibrates are effective in raising HDL cholesterol levels inindividuals with type 2 diabetes and in improving LDLcholesterol quality. Two recent large studies have examinedthe effect of fenofibrate on renal outcomes in individualswith type 2 diabetes. The efficacy of this drug class has notbeen tested in individuals with renal impairment. There isalso an increased potential for side-effects in this subgroup.• A subgroup analysis of the Diabetes AtherosclerosisIntervention Study (DAIS), examined the effects of fenofi-brate treatment (vs placebo) in 314 people with type 2diabetes (Canada and Europe) with mild to moderate lipidabnormalities and normo to microalbuminuria.113 The studylength was a minimum of 3 years. Regression of albuminuria(defined as micro to normoalbuminuria or macro to microal-buminuria) was significantly higher in the treatment group(13%) compared with the placebo group (11%), while pro-gression of albuminuria was significantly lower in the treat-ment group (8%) compared with the placebo group (18%).Significantly more people showed no change in albuminuriain the treatment group (79%) compared with the placebogroup (71%). The use of ACEi and ARBs increased duringthe course of the study; however, the use at the end of thetrial was not significantly different between the groups atthe end of the trial. The differences between groups in theprogression and regression of albuminuria remained signifi-cant after controlling for baseline BP and HbA1c. The finalurinary albumin was significantly correlated with eitherHbA1c level or BP. A significant correlation was observedbetween urinary albumin and baseline fasting triglyceride(TG) levels. After fenofibrate treatment urinary albuminlevels correlated significantly with HDL-C levels but notwith changes in TG. The study was not able to assess thepersistence of the reduction to microalbuminuria after ces-sation of treatment.
Keech et al.114 and Radermecker & Scheen115 report thelarge (9795) multinational Fenofibrate Intervention andevent Lowering in Diabetes (FIELD) study, which includedassessment of progression and regression of albuminuria.Fenofibrate was associated with a significantly lower pro-gression and significantly higher regression of albuminuria,however, the overall differences were relatively small (in theorder of 2%). Albuminuria was a secondary outcome of thestudy.
In the only study to compare statins and fibrates, head tohead, in 71 individuals with type 2 diabetes both benzafi-brate and pravastatin prevented increase in the urinaryalbumin excretion rate over 4 years, with no differenceobserved between drug classes.116
Randomized clinical trials using other lipidlowering agents
A number of other agents have clinically useful effects ondyslipidaemia in individuals with type 2 diabetes, including
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probucol and glitazones. However, their other primaryactions, on oxidative stress and glucose lowering make itimpossible to gauge the contribution of lipid lowering totheir efficacy. Currently available glitazones do vary in theirimpact on lipid profiles, indicating sub-class variations ineffect. Nonetheless, both agents appear to have effects onthe development and progression of kidney disease in indi-viduals with type 2 diabetes.
The effects of probucol treatment on the progression ofdiabetic nephropathy was evaluated in a randomized openstudy of 102 people with type 2 diabetes with clinical albu-minuria (UAE > 300 mg/g Cr).117 The mean follow upperiod was 28.5 months for all patients and 18.6 monthsfor advanced patients (defined as those having serumCr > 2.0 mg/dL). The mean interval to initiation of haemo-dialysis was significantly longer in probucol patients. Inadvanced cases treated with probucol, increases in serumcreatinine and urinary protein were significantly suppressedand the haemodialysis-free rate was significantly higher. Thestudy concluded that probucol may suppress the progressionof diabetic nephropathy as a consequence of the anti-oxidative effect of the drug.
The multifactorial intensive treatment of the STENO2reduced the risk of nephropathy by 50%.63 This long-termstudy (mean 7.8 years) of 160 people with type 2 diabetesand microalbuminuria, utilized multifactorial interventionsfor modifiable risk factors for cardiovascular disease whichincluded blood lipid control with statins and fibrates. Whilethe intensive treatment group achieved a significantly lowerblood glucose concentration, given the multifactorialnature of the study it is not possible to determine the rela-tive contribution of the intensive lipid treatment may havehad.
(iv) Role of diet modification
There are insufficient studies of suitable quality to enabledietary recommendations to be made with respect toCKD in people with type 2 diabetes (Evidence Level II –Intervention).
Lifestyle modification (diet and physical activity) is anintegral component of diabetes care (refer to the guidelinesfor Blood Glucose Control in type 2 diabetes). However,there are few studies that have specifically addressed kidneyrelated outcomes in type 2 diabetes and as such it is notpossible to currently make recommendations specific to themanagement of CKD. The following sections summarize thecurrent evidence in relation to alternate diets, proteinrestriction, and salt.
Role of dietary fats
The Diabetes and Nutrition Clinical Trial (DCNT) is apopulation based prospective, observational multicentrestudy designed to evaluate the nutritional pattern of peoplewith diabetes in Spain and associations with diabetic com-plications.118 The study (total 192) included a mix of peoplewith type 2 diabetes (99) and type 1 diabetes (93). Nephr-
opathy progression was indicated by change from normoal-buminuria to microalbuminuria and microalbuminuria tomacroalbuminuria. Regression was indicated by changefrom microalbuminuria to normoalbuminuria. The nutri-tional pattern of people with nephropathy regression wascharacterized by greater polyunsaturated fatty acid (PUFA)and smaller saturated fatty acid (SFA) than those withnephropathy, whereas the PUFA to SFA and monounsat-urated fatty acid (MUFA) to SFA ratios were greater.An opposite pattern was observed for progression ofnephropathy.
The authors note that the findings of the study are con-sistent with CVD studies and the role that SFAs may play ininsulin sensitivity and other factors affecting diabetescontrol. Nonetheless, the authors consider that control ofBP and blood glucose and cessation of smoking shouldremain the therapeutic objectives for modifiable risk factors.When these objectives are obtained, other measures such asencouraging PUFA and MIFA over SFA may help preventmicro and macroalbuminuria.118
Table A5 presents a summary of the relevant studiesfound by the search strategy in relation to dietary fat. Withthe exception of the study by Cardenas et al.118 discussedabove, the studies are either of short duration and thusprovide little useful evidence for the role of dietary fat in theprogression of CKD. Relevant details of the studies are pro-vided in Table A12. In summary, there are insufficient reli-able studies to support a recommendation in relation to theprevention and management of CKD in people with type 2diabetes.
Protein restriction
Intake of protein in the usual range does not appear to beassociated with the development of CKD. However, long-term effects of consuming >20% of energy as protein ondevelopment of CKD has not been determined. Althoughdiets high in protein and low in carbohydrate may produceshort-term weight loss and improved glycaemic control, ithas not been established that weight loss is maintained inthe long term. There have been few prospective controlledstudies of low protein diets in people with type 2 diabetesand kidney disease. The studies that have been performedhave generally been deficient in experimental design, inmethods for measuring kidney function and/or in durationof follow-up. Furthermore, the level of compliance with alow protein diet has not always been assessed objectively byurinary urea nitrogen excretion. A particular criticism isthat changes in the creatinine pool and creatinine intakeseen in low protein diet studies render measurements ofcreatinine clearance or the reciprocal of serum creatinineunreliable for the assessment of GFR.119
The objective of the systematic review was to assess theeffects of dietary protein restriction on the progression ofdiabetic nephropathy in people with diabetes (type 1 andtype 2 diabetes).120 The review identified 11 studies (9 RCTsand 2 before and after trials) where diet modifications werefollowed for at least 4 months. Before and after trials were
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included as it was considered that people could act as theirown controls. Of these studies 8 were of people with type 1diabetes, one type 2 diabetes and two included both type 1and type 2 diabetes. Overall the total number of participantsin the trials was 585 with 263 being people with type 2diabetes. Protein modified diets of all types lasting aminimum of 4 months were considered with protein intakeranging from 0.3 to 0.8 g/kg per day.
Overall protein restriction appeared to slow progressionof CKD, but not by much on average. Individual variabilitysuggests some may benefit more than others. Results of metaanalysis imply that patients can delay dialysis by, on averagearound one or 2 months. Positive but non-significant corre-lation between improvement in GFR and level of proteinrestriction is evident. There were insufficient studies to rec-ommend a level of protein intake. Furthermore, problems ofnon-compliance remain a significant issue. The review alsoconsidered different sources of protein (e.g. red meat,chicken, fish, vegetarian); however, relevant studies are ofshort duration only. The authors consider that the availableinformation supports further research in this area. Thenumber of studies that include people with type 2 diabetesare limited.
The study by Dussol et al.121 was the only other RCTidentified that was not reviewed by Robertson et al.120 This2 year single centre RCT of type 1 and type 2 diabetesindicated that the low-protein diet did not alter the courseof GFR or of AER in people with diabetes with incipient orovert nephropathy.
Table A6 includes a summary of studies identified by thesearch strategy. The studies are characterized by being smalland of short duration. Relevant details are provided below;however, as for dietary fat, there are insufficient reliablestudies that provide evidence to support a recommendationin relation protein restriction in the prevention and man-agement of CKD in people with type 2 diabetes.
Restricted salt intake
When considering the evidence related to salt intake andCKD in people with type 2 diabetes, the following pointsmade based on a literature review for preparation of aCochrane Protocol are noteworthy:122
• Dietary salt is important in BP control in both hyperten-sives and normotensives (supported by meta-analyses) andtherefore expect that this could be protective in the devel-opment and progression of CKD.• High dietary salt suppresses the renin-angiotensin system(RAS). Salt sensitivity in people with diabetes may beincreased due to less responsive RAS. Low salt intakeenhances and high salt intake reduces the antiproteinuriceffect of ACE inhibition.• Urinary albumin excretion is reduced by lowering dietarysalt.• Changes in dietary salt may have a beneficial influenceon TGF b production, affecting the progression of CKD.
Table A7 presents a summary of studies identified by thesearch strategy in relation to the assessment of the role of
restricted salt intake. As for protein restriction the studiesare small and of short duration. Details of the studies areincluded in Table A7; however, it is concluded that thereare insufficient reliable studies that provide evidence tosupport a recommendation in relation to restriction ofdietary salt and the prevention and management of CKD inpeople with type 2 diabetes.
(v) Role of smoking cessation
Smoking increases the risk of the development and progres-sion of CKD in people with type 2 diabetes (Evidence LevelII – Aetiology).
Interventional studies to assess the effects of smokingcessation have not been performed, but it has been calcu-lated from the cause-specific 10-year mortality data of thesubjects screened for the Multiple Risk Factor InterventionTrial (MRFIT), that stopping smoking is the most (cost-)effective risk factor intervention in people with diabetes.Smoking cessation would prolong life by a mean of 4 yearsin a 45-year old man and by 3 years in a diabetic man,whereas aspirin and antihypertensive treatment wouldprovide approximately 1 year of additional life expect-ancy.123,124 The following cohort studies summarized in thetext below and in Table A15 have included assessment ofrenal outcomes.
Smoking has been found to be an independent risk factorfor progression of AER in people with type 2 diabetes. In aprospective 9-year follow-up study of 108 people with type 2diabetes and normal AER after a duration of diabetes of9 years, there was an over-representation of smokers (55% vs27%; P = 0.01) in people who progressed to micro- or mac-roalbuminuria versus those who did not progress.125
A number of prospective cohort studies were identifiedby the search strategy that have considered smoking inpeople with type 2 diabetes in relation to kidney function.Relevant details of these studies are summarized inTable A15. All of these studies showed an associationbetween smoking and albuminuria. Only one cohort studywas found which included an assessment of smoking as a riskfactor for eGFR.126 Of the 7 prospective cohort studies iden-tified only one small study reported no significant associa-tion between smoking and the progress of albuminuria.127
Chuahirun & Wesson128 prospectively sought predictorsof renal function decline in 33 people with type 2 dia-betes, successfully targeting a mean BP goal of 92 mm Hg(about 125/75 mm Hg) with antihypertensives includingACEi. Initial plasma creatinine was <1.4 mg/dL, follow-up 64.0 1 1.1 months. Regression analysis showed thatsmoking was the only examined parameter that signifi-cantly predicted renal function decline. In the 13 smokers,serum Cr increased from 1.05 +/ to 0.08 mg/dL to1.78 1 0.20 mg/dL although MAP was the same. The 20non-smokers had a lesser Cr rise at 1.08 1 0.03 mg/dL to1.32 1 0.04 mg/dL.
The 6 month prospective cohort studies concluded thatcigarette smoking exacerbates renal injury despite adequateBP control with ACEi.129 Smoking cessation by those with
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microalbuminuria was associated with amelioration of theprogressive renal injury caused by continual smoking. Thesmaller but long-term study concluded that smoking andincreased UAE are interrelated predictors of nephropathyprogression and that smoking increases UAE in patientsdespite improved BP control and ACE inhibition.130
The prospective cohort study included 6513 people withtype 2 diabetes with 5 year follow up period.131 Smoking wasidentified as an independent risk factor for establishedmicroalbuminuria and for the development of microalbu-minuria. Similarly the retrospective cohort study,126 usedlogistic to show that smoking was the most important riskfactor for progression of nephropathy. The authors con-cluded that quitting smoking should be part of the preven-tion therapy. The OR for smoking and development ofmicroalbuminuria in a prospective cohort study of 930people with type 2 diabetes and high cholesterol was 3.19(95% CI: 1.02–9.96).132
The large cohort study of people with type 2 diabetesreceiving dialysis treatment, concluded that dialysis pati-ents with a history of smoking had the highest all causemortality.133
In addition to the prospective cohort studies, a numberof cross sectional studies were identified by the search strat-egy. These provide a lower level of evidence for the assess-ment of smoking as a risk factor for CKD. A total of 11 crosssectional studies have been identified the details of whichare summarized in Table A8. All of the studies identifiedsmoking to be associated with or to be an independent riskfactor indicators of CKD.
SUMMARY OF THE EVIDENCE
• Given the strong association between type 2 diabetes andESKD, strategies aimed at prevention of type 2 diabetes arealso relevant to the prevention of CKD.• Effective control of blood glucose has been shown toreduce the progression of CKD in people with type 2 diabe-tes. There is some evidence to suggest that HbA1c targetsbelow that recommended for the management of type 2diabetes may have beneficial outcomes with respect toCKD. However, the same evidence suggests that lowertargets may have adverse outcomes or at best no effect oncardiovascular events, which are a key focus in the manage-ment of type 2 diabetes. Furthermore, lower blood glucosetargets are also associated with an increase in serioushypoglycaemic events.• Elevated BP is strongly associated with the developmentof albuminuria in people with type 2 diabetes. Managementof elevated BP has been shown to influence the rate ofprogression of CKD as well as CVD and is thus a major focusof both prevention and management.• There is evidence to indicate that antihypertensiveagents that act on the renin-angiotensin system (i.e. ACEiand ARB) have a renoprotective effect over and above thatresulting from the effect on BP. As a consequence use ofthese agents is favored in the treatment of elevated BP intype 2 diabetes and has also lead to their use in normoten-sive people with type 2 diabetes.
• Abnormal blood lipid profiles are strongly associated withthe progression and severity of CKD in people with type 2diabetes. Given the strong association between dyslipi-daemia and CVD, management of blood lipid in type 2diabetes is recommended irrespective of the presence ofindicators of CKD. There is no evidence to suggest alternatemanagement strategies are required for management ofCKD. Nor is there evidence to show that lipid loweringprevents development or rate of progression of CKD inindividuals with type 2 diabetes.• There is limited evidence demonstrating a long-termeffect of dietary interventions on the progress of CKD intype 2 diabetes. There is some evidence to suggest thatprotein restriction may affect the rate of progress of CKD,however, the clinical application of these interventions arequestionable. Diet and lifestyle are, however, important forthe management of type 2 diabetes and CVD risk and thuslikely to form a component of the overall management of anindividuals risk profile irrespective of CKD.• In observational studies, smoking has been identified as aindependent risk factor in the progression of CKD, andgiven the role of smoking as a strong risk factor in a range ofother outcomes, including CVD, an individuals smokingcessation is an important recommendation irrespective ofCKD.
WHAT DO THE OTHER GUIDELINES SAY?
KDOQI: Clinical Practice Guidelines and Clinical PracticeRecommendations for Diabetes and Chronic KidneyDisease, AJKD, Suppl 2. 49(2):S46, February 2007. (Notecovers both type 1 and type 2 diabetes)• Hyperglycemia, the defining feature of diabetes, is a fun-damental cause of vascular target-organ complications,including kidney disease. Intensive treatment of hypergly-cemia prevents DKD and may slow progression of estab-lished kidney disease.• Target HbA1c for people with diabetes should be <7.0%,irrespective of the presence or absence of CKD.• Clinicians should encourage the adoption of a healthylifestyle in their patients; this includes sound nutrition,weight control, exercise and smoking cessation.• In patients with type 2 diabetes, therapeutic lifestylechanges (diet, exercise, and weight loss, when appropriate)should be the initial interventions for hyperglycemia.• Most people with diabetes and CKD have hypertension.Treatment of hypertension slows the progression of CKD.• Hypertensive people with diabetes and CKD stages 1–4should be treated with an ACE inhibitor or an ARB, usuallyin combination with a diuretic.• Target BP in diabetes and CKD stages 1–4 should be<130/80 mm Hg.• Normotensive people with diabetes and macroalbumin-uria should be treated with an ACE inhibitor or an ARB.• Treatment with an ACE inhibitor or an ARB may beconsidered in normotensive people with diabetes andmicroalbuminuria.• Albuminuria reduction may be considered a treatmenttarget in DKD.
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• Dyslipidemia is common in people with diabetes andCKD. The risk of CVD is greatly increased in this popula-tion. People with diabetes and CKD should be treatedaccording to current guidelines for high-risk groups.• Target low-density lipoprotein cholesterol (LDL-C) inpeople with diabetes and CKD stages 1–4 should be<100 mg/dL; <70 mg/dL is a therapeutic option.• People with diabetes, CKD stages 1–4, and LDL-C>100 mg/dL should be treated with a statin.• Target dietary protein intake for people with diabetes andCKD stages 1–4 should be the recommended daily allow-ance (RDA) of 0.8 g/kg body weight per day.UK Renal Association: No recommendation.Canadian Society of Nephrology: No recommendation.European Best Practice Guidelines: No recommendation.NICE Guidelines: National Collaborating Centre forChronic Conditions. type 2 diabetes: national clinicalguideline for management in primary and secondary care(update). London: Royal College of Physicians, 2008.• Start ACE inhibitors with the usual precautions andtitrate to full dose in all individuals with confirmed raisedalbumin excretion rate (>2.5 mg/mmol for men, >3.5 mg/mmol for women).• Substitute an angiotensin II-receptor antagonist for anACE inhibitor for a person with an abnormal albumin-: creatinine ratio if an ACE inhibitor is poorly tolerated.• For a person with an abnormal albumin : creatinine ratio,maintain BP below 130/80 mm Hg.American Diabetes Association: Standards of MedicalCare in Diabetes – 2008. Diabetes Care: 31, S1 JANUARY2008. (Note covers both type 1 and type 2 diabetes)• To reduce the risk or slow the progression of nephropathy,optimize glucose control.• To reduce the risk or slow the progression of nephropathy,optimize BP control.• In the treatment of the nonpregnant patient with micro-or macroalbuminuria, either ACE inhibitors or ARBsshould be used.• In patients with type 2 diabetes, hypertension, andmicroalbuminuria, both ACE inhibitors and ARBs havebeen shown to delay the progression to macroalbuminuria.• In patients with type 2 diabetes, hypertension, macro-albuminuria, and renal insufficiency (serum creatinine –1.5 mg/dL), ARBs have been shown to delay the progressionof nephropathy.• If one class is not tolerated, the other should besubstituted.
IMPLEMENTATION AND AUDIT
No recommendation.
SUGGESTIONS FOR FUTURE RESEARCH
No recommendation.
CONFLICT OF INTEREST
Non-identified.
ACKNOWLEDGEMENT
The Type 2 Diabetes Guidelines project was funded by theDepartment of Health and Ageing under a contract withDiabetes Australia. The development of the ‘National Evi-dence Based Guidelines for Diagnosis, Prevention and Man-agement of Chronic Kidney Disease in Type 2 Diabetes’ wasundertaken by CARI in collaboration with The DiabetesUnit, Menzies Centre for Health Policy at the University ofSydney.
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APPENDIX
Table A1 Definition of NHMRC grades of recommendation
Grade ofrecommendation Description
A Body of evidence can be trusted to guide practice.B Body of evidence can be trusted to guide practice in most situations.C Body of evidence provides some support for recommendations(s) but care should be taken in its application.D Body of evidence is weak and recommendation must be applied with caution
Type 2 Diabetes: Kidney Disease S181
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Tab
leA
2Su
mm
ary
ofst
udie
sre
leva
ntto
the
asse
ssm
ent
ofth
ero
leof
gluc
ose
cont
roli
nC
KD
inin
divi
dual
sw
ith
type
2di
abet
es
Stud
yID
Stud
yde
scri
ptio
nIn
terv
enti
onO
utco
me
(rel
evan
tto
CK
D)
Follo
wup
(mon
ths)
Com
men
ts/c
oncl
usio
ns
AD
VA
NC
E(2
008)
58R
CT
Mul
tice
ntre
(215
acro
ss20
coun
trie
s)Ty
pe2
diab
etes
diag
nose
dat
30ye
ars
orol
der.
Age3
55ye
ars
atth
est
art
ofth
est
udy.
His
tory
ofm
ajor
vasc
ular
orm
icro
vasc
ular
dise
ase
orat
leas
ton
eot
her
risk
fact
orfo
rva
scul
ardi
seas
e.n
=11
000
Inte
nsiv
ebl
ood
gluc
ose
cont
rol(
targ
et<6
.5%
HbA
c1).
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ieve
dus
ing
glic
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dot
her
drug
sas
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vsSt
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rdbl
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seni
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phro
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oubl
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men
tth
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deat
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kidn
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seas
e
60(m
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vera
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ain
bene
fitid
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byth
eA
DV
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fifth
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the
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tth
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dof
the
follo
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HbA
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lylo
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inth
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grou
p(6
.5%
)th
anth
est
anda
rdgr
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(7.3
%).
The
mea
nsy
stol
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pres
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was
onav
erag
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6m
mH
glo
wer
than
the
stan
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grou
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tens
ive
cont
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soci
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wit
ha
sign
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nale
vent
sin
clud
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ofne
phro
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R0.
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66–
0.93
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tly
due
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lopm
ent
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acro
albu
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new
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tm
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85–
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).A
tren
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norm
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GLB
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ma
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wit
hno
neof
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inre
nalh
aem
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ris
etal
.(2
003)
54R
CT,
open
labe
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rdia
csa
fety
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tice
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,US
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AC
EiA
RB
beta
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CC
Bn
=20
3
RSG
vsG
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CR
12R
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dA
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base
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Stro
ngly
corr
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ith
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b.SB
P,D
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and
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inFP
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iven
sim
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leve
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the
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RSG
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hedi
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low
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.Sug
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ntia
lbe
nefit
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(200
7)59
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blin
d,pl
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tice
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(GLY
+R
SG)
com
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dw
ith
cont
rolg
roup
(GLY
+pl
aceb
o).I
mpr
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insu
linse
nsit
ivit
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db-
cell
func
tion
wit
hth
iazo
lidin
edio
netr
eatm
ents
.
De
Jage
ret
al.
(200
5)H
OM
E57
RC
TN
ethe
rlan
ds–
3ce
ntre
sTy
pe2
diab
etes
n=
345
Met
form
inpl
usin
sulin
vsPl
aceb
opl
usin
sulin
UA
E4
Met
form
intr
eatm
ent
was
asso
ciat
edw
ith
a21
%in
crea
sein
UA
Eco
mpa
red
wit
hth
epl
aceb
o.H
owev
erco
nsid
ered
ash
ort
anom
aly
asU
AE
show
nto
beas
soci
ated
wit
hH
bAc1
.
Gae
deet
al.
(200
3)St
eno2
63R
CT
Type
2di
abet
es,m
icro
albu
min
uria
n=
160
Mul
tifa
ctor
iali
nten
sive
trea
tmen
tvs
Stan
dard
trea
tmen
tU
AE
94(m
ean)
Targ
etdr
iven
long
-ter
min
tens
ified
trea
tmen
tai
med
atm
ulti
ple
risk
fact
ors
redu
ced
neph
ropa
thy
byab
out
50%
.
The CARI GuidelinesS182
This G
uideli
ne in
OUT O
F DATE &
has b
een A
RCHIVED
Gam
baro
etal
.(2
002)
62R
CT,
doub
lebl
ind,
plac
ebo
Mul
tice
ntre
Type
1di
abet
esan
dty
pe2
diab
etes
,m
icro
orm
acro
albu
min
uric
n=
223
Sulo
exid
evs
Plac
ebo
UA
E4
Sign
ifica
ntly
redu
ced
albu
min
uria
inpe
ople
wit
hbo
thty
pe1
and
type
2di
abet
es.
Han
efel
det
al.
(200
4)49
RC
T,do
uble
blin
dM
ulti
cent
reTy
pe2
diab
etes
,ina
dequ
atel
ym
anag
edn
=64
9
Piog
litaz
one
plus
SUvs
Met
form
inpl
usSU
AC
R12
Clin
ical
lyeq
uiva
lent
impr
ovem
ents
ingl
ycae
mic
cont
rol.
Piog
litaz
one
plus
SUre
sult
edin
are
duct
ion
ofA
CR
.Ove
rall
diffe
renc
esfr
omba
selin
eA
CR
smal
l(i.e
.<15
%).
John
ston
etal
.(1
998)
60R
CT
Type
2di
abet
es,H
ispa
nic
n=
385
Mig
litol
vsPl
aceb
oA
CR
.12
Mig
litol
had
‘just
non-
sign
ifica
nt’r
educ
tion
ofA
CR
.
John
ston
etal
.(1
998)
61R
CT
Type
2di
abet
es,A
fric
an-A
mer
ican
n=
345
Mig
litol
vsPl
aceb
oA
CR
12M
inor
redu
ctio
nin
AC
Rw
ith
mig
litol
.
Lebo
vitz
etal
.(2
001)
53R
CT
Mul
tice
ntre
(42)
,US,
mix
edra
ce.
Type
2di
abet
es,3
6–81
year
s,FP
G(7
.8–1
6.7
mm
ol/L
),B
MI
betw
een
22–3
8kg
/m2 ,n
ore
nali
mpa
irm
ent
orD
N.
n=
493
Ros
igla
tzon
e(2
or4
mg/
day)
vsPl
aceb
oU
AE,
AC
R7
AC
Rde
crea
sed
sign
ifica
ntly
inbo
th2
and
4m
g/da
yR
SG.C
ompa
red
wit
han
insi
gnifi
cant
incr
ease
from
base
line
ofth
epl
aceb
o.Fo
rsu
bgro
upw
ith
mic
roal
bum
inur
ia,b
oth
dose
sof
RSG
gave
redu
ctio
nin
AC
Rfr
omba
selin
eof
arou
nd40
%.
Onl
ya
smal
lper
cent
age
ofpa
tien
tsw
ere
rece
ivin
gan
tihy
pert
ensi
veth
erap
y–
sugg
ests
effe
ctis
are
sult
ofim
prov
edgl
ycae
mic
cont
rolo
ra
diffe
rent
effe
ctof
RSG
.
Levi
net
al.
(200
0)46
RC
TTy
pe2
diab
etes
(mea
nag
e60
,mea
ndu
rati
onof
diab
etes
8ye
ars)
n=
153
Inte
nsiv
e(H
bA1c
goal
7.1%
)vs
Stan
dard
(HbA
1cgo
al9.
1%)
UA
E,A
CR
24In
tens
ive
glyc
aem
icco
ntro
lret
arde
dm
icro
albu
min
uria
,but
may
not
less
enth
epr
ogre
ssiv
ede
teri
orat
ion
ofgl
omer
ular
func
tion
.
Mat
thew
set
al.
(200
5)50
RC
T,do
uble
blin
dTy
pe2
diab
etes
,poo
rly
man
aged
n=
630
Met
form
inpl
uspi
oglit
azon
evs
Met
form
inpl
usgl
icla
zide
AC
R12
Mea
nA
CR
redu
ced
by10
%in
met
plus
piog
grou
p.Po
tent
ialb
enefi
tsar
ein
dica
ted.
Ohk
ubo
etal
.(1
995)
7R
CT
Japa
nTy
pe2
diab
etes
,div
ided
into
prim
ary
prev
enti
onan
dse
cond
ary
inte
rven
tion
coho
rts
onth
eba
sis
ofal
bum
inur
iaan
dre
tino
path
y.n
=11
0
Mul
tipl
eIn
sulin
Trea
tmen
t(M
IT)
vsC
onve
ntio
nalI
nsul
inTr
eatm
ent
(CIT
)
UA
E60
Inte
nsiv
egl
ycae
mic
cont
rolc
ande
lay
the
onse
tan
dpr
ogre
ssio
nof
neph
ropa
thy.
The
cum
ulat
ive
perc
enta
ges
ofth
ede
velo
pmen
tan
dth
epr
ogre
ssio
nin
neph
ropa
thy
afte
r6
year
sw
ere
7.7%
for
the
MIT
grou
pan
d28
.0%
for
the
CIT
grou
pin
the
prim
ary-
prev
enti
onco
hort
(P=
0.03
2).
Sche
rnth
aner
etal
.(2
004)
51R
CT,
doub
le-b
lind
Mul
tice
ntre
,167
cent
res
acro
ss12
Euro
pean
coun
trie
sTy
pe2
diab
etes
inad
equa
tely
trea
ted
bydi
etal
one
(HbA
betw
een
7.5%
and
11%
),35
–75
year
sn
=11
99
Piog
litaz
one
vsM
etfo
rmin
AC
R12
Piog
litaz
one
–19
%de
crea
sein
AC
Rco
mpa
red
wit
h1%
inm
etfo
rmin
grou
p.B
Pno
tst
atis
tica
llydi
ffere
ntbe
twee
ngr
oups
.Con
sist
ent
wit
hpr
evio
usst
udie
sth
attr
oglit
azon
ebu
tno
tm
etfo
rmin
orgl
iben
clam
ide
redu
ced
urin
ary
albu
min
excr
etio
nra
te.
Shic
hiri
etal
.(2
000)
47
Kun
amot
oSt
udy
RC
Tn
=11
0M
ITvs
CIT
Alb
umin
uria
96In
tens
ive
glyc
aem
icco
ntro
l(M
IT)
–cu
mul
ativ
epe
rcen
tage
sof
wor
seni
ngin
neph
ropa
thy
wer
esi
gnifi
cant
lylo
wer
.
Type 2 Diabetes: Kidney Disease S183
This G
uideli
ne in
OUT O
F DATE &
has b
een A
RCHIVED
Tab
leA
3Su
mm
ary
ofst
udie
sre
leva
ntto
the
asse
ssm
ent
ofth
ero
leof
bloo
dpr
essu
reco
ntro
land
anti
hype
rten
sive
agen
tsin
CK
Dan
din
divi
dual
sw
ith
type
2di
abet
es.
Stud
yID
Stud
yde
scri
ptio
nIn
terv
enti
onO
utco
me
rele
vant
toC
KD
Follo
wup
(mon
ths)
Com
men
ts
AD
VA
NC
E(2
007)
67
and
deG
alan
(200
9)68
RC
TM
ulti
cent
re(2
15ac
ross
20co
untr
ies)
Type
2di
abet
esdi
agno
sed
at30
year
sor
olde
r.A
ge3
55ye
ars
atth
est
art
ofth
est
udy.
His
tory
ofm
ajor
vasc
ular
orm
icro
vasc
ular
dise
ase
orat
leas
ton
eot
her
risk
fact
orfo
rva
scul
ardi
seas
e.n
=11
000
Peri
ndop
rilp
lus
inda
pam
ide
vspl
aceb
o
Wor
seni
ngne
phro
path
yi.e
.dev
elop
men
tof
mac
roal
bum
inur
ia,d
oubl
ing
ofse
rum
crea
tini
ne,n
eed
for
rena
lrep
lace
men
tth
erap
yor
deat
hdu
eto
kidn
eydi
seas
e.
52(m
edia
n)A
ctiv
etr
eatm
ent
mea
nre
duct
ion
inSB
Pan
dD
BP
of5.
6an
d2.
2m
mH
gre
spec
tive
ly,c
ompa
red
wit
hpl
aceb
o.T
here
lati
veri
skof
am
ajor
mic
rova
scul
arev
ent
was
7.9%
inth
eac
tive
trea
tmen
tgr
oup
com
pare
dw
ith
8.6%
inth
epl
aceb
ogr
oup
(non
-sig
nific
ant)
.A
ctiv
etr
eatm
ent
was
asso
ciat
edw
ith
abo
rder
line
sign
ifica
ntre
duct
ion
inm
acro
albu
min
uria
and
asi
gnifi
cant
redu
ctio
nin
the
deve
lopm
ent
ofm
icro
albu
min
uria
wit
ha
rela
tive
risk
redu
ctio
nof
21%
(95%
CI:
15–3
0).
Aga
rdh
etal
.(1
996)
74R
CT,
doub
lebl
ind
Mul
tice
ntre
,mul
tina
tion
alTy
pe2
diab
etes
,mic
roal
bum
inur
ia,
earl
ydi
abet
icne
urop
athy
,hy
pert
ensi
ve23
9m
ales
96fe
mal
es
Lisi
nopr
ilvs
Nife
dipi
neU
AE,
crea
tini
necl
eara
nce
12Si
gnifi
cant
lym
ore
bene
ficia
leffe
cton
UA
E,ho
wev
ercr
eati
nine
clea
ranc
edi
dno
tch
ange
sign
ifica
ntly
wit
hei
ther
trea
tmen
t.
Ahm
adet
al.
(199
7)25
RC
Tsi
ngle
blin
dIn
dia
Type
2di
abet
esN
orm
oten
sive
n=
103
AC
Eivs
Plac
ebo
AER
60A
fter
5ye
ars
AC
Eitr
eate
dpa
tien
tsex
peri
ence
dsi
gnifi
cant
lyle
sspr
ogre
ssio
nof
mic
roal
bum
inur
iato
clin
ical
albu
min
uria
.
Bab
a&
MIN
DSt
udy
Gro
up(2
001)
82R
CT
–in
tent
totr
eat
anal
ysis
Mul
tice
ntre
Japa
nTy
pe2
diab
etes
Nor
moa
lbum
inur
iaM
icro
albu
min
uria
n=
486
AC
Eivs
CC
BU
AE
24C
CB
and
AC
Eiha
da
sim
ilar
effe
cton
neph
ropa
thy
inhy
pert
ensi
vepe
ople
wit
hty
pe2
diab
etes
wit
hout
over
tpr
otei
nuri
a.
Bak
ris
etal
.(2
005)
95R
CT
Type
2di
abet
es,h
yper
tens
ion,
AC
Eior
AR
Bas
part
ofth
etr
eatm
ent
regi
me
prio
rto
com
men
cem
ent
ofth
est
udy.
n=
1235
Met
opro
lol(
mai
ntai
nA
CEi
/AR
B)
vsC
arve
dilo
l(m
aint
ain
AC
Ei/A
RB
)
Alb
umin
uria
(spo
tA
CR
)5
afte
rre
achi
ngta
rget
BP
Pre
spec
ified
and
post
hoc
anal
yses
ofth
eG
EMIN
Itr
ial.
Gre
ater
redu
ctio
nin
mic
roal
bum
inur
iaw
asob
serv
edfo
rca
rved
ilol.
Tho
sew
ith
norm
oalb
umin
uria
few
erpr
ogre
ssed
tom
icro
onca
rved
ilol.
Thi
sef
fect
was
not
rela
ted
toB
P.M
ulti
vari
ate
anal
ysis
inal
bum
inur
iach
ange
dem
onst
rate
don
lyba
selin
eur
ine
AC
Ran
dtr
eatm
ent
wer
esi
gnifi
cant
pred
icto
rs.I
na
sepa
rate
anal
ysis
–th
epr
esen
ceof
met
abol
icsy
ndro
me
atba
selin
eco
rres
pond
edw
ith
anO
Rof
2.68
(95%
CI:
1.36
–5.3
0)ov
erth
edu
rati
onof
the
stud
y.
Bar
nett
etal
.(2
004)
96R
CT,
doub
lebl
ind.
Mul
tice
ntre
(39)
,6Eu
rope
anco
untr
ies
Type
2di
abet
es,m
ildto
mod
erat
ehy
pert
ensi
on,a
llha
dto
have
been
trea
ted
byan
AC
Eito
elim
inat
ein
tole
ranc
e,G
FR>7
0m
L/m
inpe
r1.
73m
2 ,m
ostl
yw
hite
and
mal
e.n
=25
0
AR
B(t
elis
arta
n–
40m
g/da
yup
to80
mg/
day
for
BP
cont
rol)
AC
Ei(e
nala
pril
–10
mg/
day
upto
20m
g/da
yfo
rB
Pco
ntro
l)(A
ddit
iona
lhyp
erte
nsiv
eal
low
edas
requ
ired
)
GFR
(cal
cula
ted
from
seru
mcr
eati
nine
),U
AE
60T
hedi
ffere
nce
inG
FRbe
twee
nth
eA
RB
and
the
AC
Eiw
as-3
.1m
L/m
inpe
r1.
73m
2an
dw
asin
sign
ifica
nt.T
hem
ean
annu
alde
clin
esin
GFR
wer
e3.
7m
L/m
inpe
r1.
73m
2fo
rth
eA
RB
and
3.3
mL/
min
per
1.73
m2
for
the
AC
Ei.T
hese
resu
lts
sim
ilar
toG
FRde
clin
ere
port
edin
IRM
A2,
IDN
T,an
dR
ENA
AL
stud
ies.
Com
pare
toun
trea
ted
type
2di
abet
esan
nual
decl
ine
of10
mL/
min
per
1.73
m2 .
Telm
isar
tan
isno
tin
feri
orto
enal
apri
lin
prov
idin
glo
ng-t
erm
reno
prot
ecti
on.D
oes
not
nece
ssar
ilyap
ply
tom
ore
adva
nced
neph
ropa
thy
–bu
tsu
ppor
tcl
inic
aleq
uiva
lenc
eof
AR
Ban
dA
CEi
inpe
rson
sw
ith
cond
itio
nsth
atpl
ace
them
athi
ghri
skfo
rC
Vev
ents
.
The CARI GuidelinesS184
This G
uideli
ne in
OUT O
F DATE &
has b
een A
RCHIVED
Cha
net
al.
(200
0)76
RC
TTy
pe2
diab
etes
Hyp
erte
nsiv
en
=10
2
AC
Eivs
CC
BU
AE,
CC
rIn
itia
lly12
then
54(m
ean)
Trea
tmen
tw
ith
AC
Eias
soci
ated
wit
hgr
eate
rre
duct
ion
inal
bum
inur
iath
anw
ith
CC
Bin
the
enti
repa
tien
tgr
oup
and
espe
cial
lyin
thos
ew
ith
mic
roal
bum
inur
ia.I
nm
acro
albu
min
uria
,rat
eof
dete
rior
atio
nin
rena
lfun
ctio
nw
asal
soat
tenu
ated
wit
hA
CEi
.
Esta
cio
(200
6)85
RC
Tty
pe2
diab
etes
norm
oten
sive
n=
129
Inte
nsiv
eB
Pco
ntro
l(v
alsa
rtan
+ot
her
asre
quir
ed)
vsM
oder
ate
BP
cont
rol(
plac
ebo
plus
othe
rsas
requ
ired
)
UA
E,se
rum
crea
tini
ne,
crea
tini
necl
eara
nce
23(m
edia
n)In
tB
P–
1181
10.9
/751
5.7
Mod
BP
–12
41
109/
801
6.5
UA
E–
sign
ifica
nttr
eatm
ent
diffe
renc
eat
2ye
ars.
AB
CD
Esta
cio
etal
.(2
000)
73
Esta
cio
&Sc
hrie
r(1
998)
12
Schr
ier
etal
.(2
002)
70
RC
Tpr
ospe
ctiv
eTy
pe2
diab
etes
Nor
mot
ensi
ve(D
BP
betw
een
80an
d89
mm
/Hg,
not
rece
ivin
gan
tihy
pert
ensi
ves)
n=
470
AC
Ei,e
nalp
ril
vsC
CB
,nis
oldi
pine
vsPl
aceb
o
Cre
atin
ine
clea
ranc
e,U
AE
64B
lood
pres
sure
cont
rolo
f138
/86
or13
8/78
mm
/Hg
wit
hei
ther
AC
Eior
CC
Bas
the
init
ialh
yper
tens
ive
agen
tap
pear
edto
stab
ilize
rena
lfun
ctio
nin
hype
rten
sive
peop
lew
ith
type
2di
abet
esw
itho
utov
ert
albu
min
uria
over
a5
year
peri
od.M
ore
inte
nsiv
eB
Pco
ntro
ldec
reas
edal
lcau
sem
orta
lity.
Inte
nsiv
eB
Pco
ntro
lin
norm
oten
sive
type
2di
abet
essl
owed
prog
ress
ion
toin
cipi
ent
and
over
tne
phro
path
y,de
crea
sed
prog
ress
ion
ofre
tino
path
yan
ddi
min
ishe
dth
ein
cide
nce
ofst
roke
.Stu
dyin
dica
tes
BP
cont
rola
sbe
ing
the
impo
rtan
tfa
ctor
rath
erth
anA
CEi
vsC
CB
.
Foga
riet
al.
(200
0)83
RC
TTy
pe2
diab
etes
(wel
lcon
trol
led)
,60
to75
year
s,hy
pert
ensi
ven
=14
7
AC
Eivs
CC
BU
AE,
crea
tini
necl
eara
nce
24A
t24
mon
ths
UA
Esi
gnifi
cant
lyde
crea
sed
inbo
thtr
eatm
ents
.Cre
atin
ine
clea
ranc
eun
affe
cted
byA
CEi
,but
incr
ease
dby
CC
B
Gal
leet
al.
(200
8)86
RC
TM
ulti
cent
ric
Type
2di
abet
esw
ith
hype
rten
sion
,pr
otei
nuri
aan
dse
rum
crea
tini
ne2
3.0
mg/
dL)
n=
885
Telm
isar
tan
vsva
lsar
tan.
(add
itio
naln
on-A
CEi
/AR
Ban
tihy
pert
ensi
ves
perm
itte
das
nece
ssar
y)
24h
prot
einu
ria,
eGFR
12M
ean
redu
ctio
nin
prot
einu
ria
33%
(sam
efo
rbo
thtr
eatm
ents
).G
reat
erre
nopr
otec
tion
seen
amon
gpa
tien
tsw
ith
bett
erbl
ood
pres
sure
cont
rol.
Hol
lenb
erg
etal
.(2
007)
87R
CT
Mul
tice
ntri
cTy
pe2
diab
etes
wit
hhy
pert
ensi
onan
dal
bum
inur
ia(A
ER20
–700
mg/m
in)
n=
391
vals
arta
n16
0m
g/da
yvs
320
mg/
day
vs64
0m
g/da
y(a
ddon
med
icat
ions
for
BP
cont
rola
sre
quir
ed)
AER
,ser
umcr
eati
nine
7.5
Hig
hdo
seva
lsar
tan
abov
e16
0m
g/da
y–
grea
ter
redu
ctio
nfr
omba
selin
eA
ERw
ith
grea
ter
num
ber
(12%
)re
gres
sing
tono
rmoa
lbum
inur
ia.
Jeru
ms
etal
.(2
004)
80R
CT
pros
pect
ive
open
,blin
ded
endp
oint
Type
2di
abet
esn
=77
AC
EiC
CB
vsPl
aceb
oG
FR,a
lbum
inur
ia66
(med
ian)
Long
-ter
mco
ntro
lofb
lood
pres
sure
wit
hA
CEi
orC
CB
stab
ilize
sA
ERan
dat
tenu
ates
GFR
decl
ine
inpr
opor
tion
toM
AP
inno
n-hy
pert
ensi
vepe
ople
wit
hty
pe2
diab
etes
and
mic
roal
bum
inur
ia.
Laco
urci
ere
etal
.(1
993)
75R
CT
doub
lebl
ind
Cau
casi
an(4
5to
75ye
ars)
Type
2di
abet
esM
ildto
mod
erat
ehy
pert
ensi
onn
=10
9
AC
Eivs
conv
enti
onal
ther
apy
UA
E36
Trea
tmen
tw
ith
capt
opri
ldec
reas
edal
bum
inur
iaan
dre
duce
dth
ede
velo
pmen
tof
mac
roal
bum
inur
iain
thos
ew
ith
pers
iste
ntm
icro
albu
min
uria
.
Type 2 Diabetes: Kidney Disease S185
This G
uideli
ne in
OUT O
F DATE &
has b
een A
RCHIVED
Tab
leA
3C
ontin
ued
Stud
yID
Stud
yde
scri
ptio
nIn
terv
enti
onO
utco
me
rele
vant
toC
KD
Follo
wup
(mon
ths)
Com
men
ts
Laco
urci
ere
etal
.(2
000)
84R
CT
pros
pect
ive
Mul
tice
ntre
Can
ada
Type
2di
abet
esH
yper
tens
ive
Earl
yne
phro
path
yn
=92
AC
Eivs
AR
BR
enal
bioi
ndic
ator
s12
Trea
tmen
tw
ith
eith
erA
CEi
orA
RB
sign
ifica
ntly
redu
ced
UA
E.R
educ
tion
inU
AE
wit
hea
chtr
eatm
ent
was
sim
ilarl
yre
late
dto
decr
emen
tsin
AB
P.R
ate
ofde
clin
ein
GFR
was
sim
ilar
inbo
thtr
eatm
ent
grou
ps.
Lebo
vitz
etal
.(1
994)
71R
CT,
doub
lebl
ind
Type
2di
abet
esH
yper
tens
ive
n=
121
AC
Eivs
Plac
ebo
UA
E,pr
otei
n,ur
ea,
nitr
ogen
,cre
atin
ine,
GFR
36A
CEi
pres
erve
dG
FRbe
tter
inpa
tien
tsw
ith
sub-
clin
ical
prot
einu
ria
atba
selin
ebe
tter
than
othe
ran
tihy
pert
ensi
ves
wit
hout
AC
Ei.S
mal
ler
perc
enta
gepr
ocee
ded
tocl
inic
alal
bum
inur
ia.
Mar
reet
al.
(200
4)81
RC
Tdo
uble
blin
d,pa
ralle
lgro
upM
ulti
cent
re,p
rim
ary
care
,16
Euro
pean
and
Nor
thA
fric
anTy
pe2
diab
etes
>50
year
sPe
rsis
tent
mic
roal
bum
inur
iaor
prot
einu
ria
n=
4912
AC
Ei(o
nto
pof
usua
ltr
eatm
ent)
vsPl
aceb
oES
KD
Seco
ndar
y–
UA
E,ur
inar
ypr
otei
n
72(m
edia
n)Lo
wdo
sera
mip
rilo
nce
daily
has
noef
fect
onC
VD
and
kidn
eyou
tcom
es(t
ype
2di
abet
esan
dal
bum
inur
ia)
desp
ite
slig
htde
crea
sein
bloo
dpr
essu
rean
dU
AE.
Mui
rhea
det
al.
(199
9)10
0R
CT,
doub
lebl
ind,
plac
ebo
Mul
tice
ntre
,Cau
casi
anTy
pe2
diab
etes
,nor
mot
ensi
ve,
mic
roal
bum
inur
ian
=12
2
AC
EiA
RB
vsPl
aceb
oU
AE
12T
heA
RB
slow
edpr
ogre
ssiv
eri
seof
UA
Eco
mpa
red
wit
hth
eA
CEi
.
Nak
amur
aet
al.
(200
2)13
4R
CT,
Type
2di
abet
es,
norm
oten
sive
,mic
roal
bum
inur
ian
=60
AC
EiA
RB
AC
Ei+
AR
Bvs
Plac
ebo
UA
E18
Dat
asu
gges
tth
eco
mbi
nati
onof
AR
B/A
CEi
has
anad
diti
veef
fect
.On
the
redu
ctio
nof
mic
roal
bum
inur
ia.
ON
TAR
GET
(200
8)97
and
Man
net
al.
(200
8)98
RC
TH
eart
dise
ase,
incl
uded
38%
wit
hdi
abet
es(t
ype
1an
dty
pe2)
and
13%
wit
hm
icro
albu
min
uria
n=
2500
0
AC
Ei(R
amip
ril)
vsA
RB
(Tel
mis
arta
n)vs
Com
bina
tion
eGFR
,UA
ESe
cond
ary-
Ren
alim
pair
men
t(b
ased
oncl
inic
alin
vest
igat
ors
repo
rt)
Ren
alfa
ilure
requ
irin
gdi
alys
is.
56(m
edia
n)N
osu
bgro
upan
alys
isha
sbe
enpr
esen
ted
incl
udin
gdi
abet
esan
dm
icro
albu
min
uria
.The
refo
reno
tge
nera
lisea
ble
toty
pe2
diab
etes
.Ove
rall,
nosi
gnifi
cant
diffe
renc
esno
ted
betw
een
trea
tmen
tsex
cept
for
rena
lim
pair
men
t.C
ombi
nati
ontr
eatm
ent
resu
lted
inlo
wer
AC
Ran
dlo
wer
onse
tof
new
mic
roal
bum
inur
iaat
the
end
ofth
efo
llow
uppe
riod
,how
ever
gree
ter
rate
ofde
clin
ein
eGFR
.
Parv
ing
etal
.(2
001)
72
and
Bre
nner
etal
.(2
001)
19
RC
T,do
uble
blin
dM
ulti
cent
re,m
ulti
nati
onal
Type
2di
abet
esn
=15
13
AR
B15
0m
g/da
yA
RB
300
mg/
day
vsPl
aceb
o(a
ndco
nven
tion
alhy
pert
ensi
vetr
eatm
ent)
Seru
mcr
eati
nine
doub
ling,
ESK
D,d
eath
,pro
tein
uria
,pr
ogre
ssio
nof
kidn
eydi
seas
e
40(m
ean)
Losa
rtan
conf
erre
dsi
gnifi
cant
rena
lben
efits
inty
pe2
diab
etes
wit
hne
urop
athy
and
was
gene
rally
wel
lto
lera
ted.
Parv
ing
etal
.(2
008)
99R
CT,
doub
lebl
ind,
plac
ebo
cont
rolle
dM
ulti
cent
ric,
mul
tina
tion
alTy
pe2
diab
etes
,nep
hrop
athy
.Ex
clud
ed–
know
nno
n-di
abet
icne
phro
path
y,A
CR
>350
0m
g/g,
eGFR
<30
mL/
min
,chr
onic
UT
I,se
vere
hype
rten
sion
,car
diov
ascu
lar
dise
ase
wit
hin
the
prev
ious
6m
onth
s.n
=59
9
Alis
kire
n(d
irec
tre
nin
inhi
bito
r)15
0m
gfo
r3
mon
ths
300
mg
for
3m
onth
s.vs
plac
ebo
Bot
h–
max
imal
losa
rtan
(100
mg)
plus
addi
tion
alhy
pert
ensi
veto
achi
eve
opti
mal
BP
(i.e
.tar
get
of13
0/80
mm
Hg)
.
Uri
nary
AC
R,e
GFR
.6
Aft
erad
just
men
tfo
rch
ange
sfr
omba
selin
ein
syst
olic
BP,
the
alis
kire
ntr
eatm
ent
redu
ced
the
mea
nur
inar
yA
CR
by18
%co
mpa
red
wit
hth
epl
aceb
o.T
hetr
eatm
ent
grou
pha
da
grea
ter
num
ber
ofpa
tien
tsw
here
albu
min
uria
redu
ctio
nw
asgr
eate
rth
an50
%(2
4.7%
vs12
.5%
).T
hebe
nefit
ofal
iski
ren
appe
ared
tobe
inde
pend
ent
ofdi
ffere
nces
(sm
all)
inbl
ood
pres
sure
.
The CARI GuidelinesS186
This G
uideli
ne in
OUT O
F DATE &
has b
een A
RCHIVED
Rav
idet
al.
(199
3)14
RC
T–
doub
lebl
ind
fist
phas
ean
dop
ense
cond
phas
e.Is
rael
,Mul
tice
ntre
Type
2di
abet
esN
orm
oten
sive
Mic
roal
bum
inur
ian
=94
AC
Eivs
Plac
ebo
AER
60–
ontr
eatm
ent
24–
choi
cefo
rtr
eatm
ent
AC
Eiof
fers
long
term
prot
ecti
onag
ains
tth
ede
velo
pmen
tof
neph
ropa
thy
inno
rmot
ensi
vew
ith
mic
roal
bum
inur
ia,a
ndit
stab
ilize
sre
nalf
unct
ion
inpr
evio
usly
untr
eate
dpa
tien
tsw
ith
impa
ired
rena
lfu
ncti
on.D
isco
ntin
uati
onof
trea
tmen
tre
sult
sin
rene
wed
prog
ress
ion
ofne
phro
path
y.
Rav
idet
al.
(199
8)66
RC
Tdo
uble
blin
dM
ulti
cent
reTy
pe2
diab
etes
Nor
mot
ensi
veN
orm
oalb
umin
uria
n=
156
AC
Eivs
Plac
ebo
UA
E,cr
eati
nine
clea
ranc
e70
AC
Eiat
tenu
ated
the
decl
ine
inre
nalf
unct
ion
and
redu
ced
the
exte
ntof
albu
min
uria
inno
rmot
ensi
ve,
norm
oalb
umin
uric
peop
lew
ith
type
2di
abet
es.
Ros
eiet
al.
(200
5)94
RC
TM
ulti
cent
reTy
pe2
diab
etes
Mild
hype
rten
sion
,eit
her
prev
ious
lyun
trea
ted
for
hype
rten
sion
orun
succ
essf
ully
trea
ted.
n=
129
AC
Ei–
enal
apri
l(20
mg/
day)
vsA
RB
–ca
ndes
arta
n(1
6m
g/da
y)(H
CT
used
for
addi
tion
altr
eatm
ent
asre
quir
ed.)
UA
E6
Can
dest
arta
nan
den
alap
rils
how
edsi
mila
ref
fect
son
BP
and
circ
ulat
ing
adhe
sion
mol
ecul
es.U
AE
was
redu
ced
sign
ifica
ntly
mor
eby
cand
esta
rtan
.How
ever
,the
maj
orit
yof
pati
ents
had
norm
alpr
otei
nex
cret
ion
and
ther
efor
edi
fficu
ltto
extr
apol
ate
the
resu
lts
obta
ined
.
Rug
gene
ntie
tal
.(1
998)
91al
soR
emuz
ziet
al.
(200
6)92
BEN
EDIC
T
RC
TM
ulti
cent
reTy
pe2
diab
etes
Hyp
erte
nsio
nN
orm
oalb
umin
uria
n=
1204
–V
erap
amil
–24
0m
g/da
y–
Trad
olap
ril–
2m
g/da
y–
Ver
apam
ilpl
ustr
ando
lapr
ilvs
Plac
ebo
UA
E43
.2A
ddit
iona
lage
nts
perm
itte
dto
achi
eve
BP
cont
rol.
Tran
dola
pril
plus
vera
pam
ilan
dtr
ando
lapr
ilal
one
decr
ease
din
cide
nce
ofm
icro
albu
min
uria
tosi
mila
rex
tent
.Ver
apam
ilal
one
nodi
ffere
ntto
plac
ebo.
Sano
etal
.(1
996)
69R
CT
pros
pect
ive
Japa
nTy
pe2
diab
etes
Nor
mot
ensi
veM
icro
albu
min
uria
n=
62
AC
Eivs
No
trea
tmen
tU
AE,
crea
tini
necl
eara
nce
48U
AE
intr
eate
dgr
oup
decr
ease
dan
din
crea
sed
slow
lyin
untr
eate
dgr
oup.
Schr
amet
al.
(200
5)93
RC
T,do
uble
blin
d,do
uble
dum
my
Mul
ti-c
entr
e,T
heN
ethe
rlan
ds,
Cau
casi
an.
Type
2di
abet
es,H
yper
tens
ive,
mea
nag
ein
trea
tmen
ts60
to63
,UA
E<1
00m
g/d
(nor
mo
and
mic
roal
bum
inur
ic)
n=
70
HC
T–
12.5
mg/
dA
CEi
–10
mg/
dA
RB
–8
mg/
dvs
Dum
my
plac
ebos
used
tom
aint
ain
doub
lebl
ind.
UA
E(s
econ
dary
outc
ome)
1ru
nin
4to
6ti
trat
ion
peri
od12
stud
y
The
rew
asno
sign
ifica
ntdi
ffere
nce
inth
eU
AE
betw
een
the
trea
tmen
tgr
oups
,whi
chm
aybe
aco
nseq
uenc
eof
the
smal
lsam
ple
size
.A
ggre
ssiv
ean
tihy
pert
ensi
veth
erap
yca
nim
prov
eU
AE
inhy
pert
ensi
vepe
ople
wit
hty
pe2
diab
etes
rega
rdle
ssof
the
type
ofth
erap
yus
ed.
SMA
RT
Gro
up(2
007)
88R
CT
Type
2di
abet
esw
ith
mic
roal
bum
inur
ian
=34
1
Val
sart
anvs
mlo
dipi
neA
CR
3V
alsa
rtan
–A
CR
68%
ofba
selin
eA
mlo
dipi
ne–
AC
R11
8%of
base
line
Rem
issi
on–
23vs
11%
Reg
ress
ion
–34
vs16
%
Tan
etal
.(2
002)
89R
CT
doub
lebl
ind
Type
2di
abet
esM
icro
albu
min
uria
n=
80
AR
Bvs
Plac
ebo
UA
E6
Peop
lew
ith
type
2di
abet
esan
dm
icro
albu
min
uria
have
impa
ired
endo
thel
ium
-dep
ende
ntan
d–i
ndep
ende
ntva
sodi
lata
tion
.Tre
atm
ent
wit
hlo
wdo
selo
sart
anis
suffi
cien
tto
redu
cem
icro
albu
min
uria
wit
hout
alte
rati
onin
endo
thel
ialf
unct
ion
and
syst
emic
bloo
dpr
essu
re.
Type 2 Diabetes: Kidney Disease S187
This G
uideli
ne in
OUT O
F DATE &
has b
een A
RCHIVED
Tab
leA
3C
ontin
ued
Stud
yID
Stud
yde
scri
ptio
nIn
terv
enti
onO
utco
me
rele
vant
toC
KD
Follo
wup
(mon
ths)
Com
men
ts
The
HO
PESt
udy
Gro
up(2
000)
18R
CT
Mul
tice
ntre
CV
Dor
diab
etes
plus
high
CV
Dri
sk.
(98%
type
2di
abet
es)
n=
3577
Ram
ipri
lvs
Plac
ebo
Alb
umin
uria
(sec
onda
ryou
tcom
e)54
Sign
ifica
ntre
duct
ion
inri
skof
over
tne
phro
path
yin
ram
ipri
ltre
atm
ent
grou
p.N
odi
ffere
nce
inri
skof
new
mic
roal
bum
inur
ia.
Trev
isan
&Ti
engo
(199
5)10
3R
CT
doub
lebl
ind
Ital
y–
mul
tice
ntre
Type
2di
abet
esM
icro
albu
min
uria
Nor
mal
orm
ildhy
pert
ensi
onn
=12
2
AC
Eivs
Plac
ebo
AER
6Lo
wdo
seA
CEi
can
arre
stth
epr
ogre
ssiv
eri
sein
albu
min
uria
inty
pe2
diab
etes
wit
hpe
rsis
tent
mic
roal
bum
inur
ia.
UK
PDS
(199
8)65
RC
TM
ulti
cent
reU
K20
hosp
ital
clin
ics
Type
2di
abet
esH
yper
tens
ive
n=
1148
AC
Eivs
Bet
abl
ocke
rU
AE
100
(med
ian)
BP
low
erin
gw
ith
capt
opri
lwas
sim
ilarl
yef
fect
ive
inre
duci
ngth
ein
cide
nce
ofdi
abet
icco
mpl
icat
ions
.
UK
PDS
(199
8)8
RC
TM
ulti
cent
reU
K20
hosp
ital
clin
ics
Type
2di
abet
esH
yper
tens
ive
n=
1148
AC
Eivs
Bet
abl
ocke
rD
iabe
tes
rela
ted
deat
hsan
dal
lcau
sem
orta
lity.
UA
E
100
(med
ian)
Tigh
tbl
ood
pres
sure
cont
roli
npa
tien
tsw
ith
hype
rten
sion
and
type
2di
abet
esac
hiev
esa
clin
ical
lyim
port
ant
redu
ctio
nin
the
risk
ofde
aths
rela
ted
todi
abet
es,c
ompl
icat
ions
rela
ted
todi
abet
es,p
rogr
essi
onof
diab
etic
reti
nopa
thy,
and
dete
rior
atio
nin
visu
alac
uity
Vib
erti
(200
2)90
RC
TTy
pe2
diab
etes
wit
hm
icro
albu
min
uria
n=
332
Val
sart
anvs
amlo
dipi
ne(a
ddit
iona
lage
nts
used
tom
eet
BP
targ
etof
135/
80m
m/H
g)
AER
6M
ore
pati
ents
reve
rted
tono
rmoa
lbum
inur
iaw
ith
losa
rtan
29.9
%vs
14.5
%).
BP
redu
ctio
nsw
ere
sim
ilar.
Yasu
daet
al.
(200
5)79
Ope
n-la
belp
aral
lelp
rosp
ecti
veR
CT
Japa
nTy
pe2
diab
etes
,Ove
rtne
phro
path
y(U
AE
betw
een
300
and
3000
mg/
day)
,31
and
80ye
ars
(ave
rage
44),
hype
rten
sive
n=
87
AR
B–
losa
rtan
25up
to10
0m
g/d
CC
B–
amlo
dipi
ne2.
5up
to10
mg/
d
UA
E,A
CR
6A
RB
–U
AE
redu
ced
from
810
mg/
day
to57
0m
g/da
y(P
<0.
001)
.CC
Bno
drop
.Sim
ilar
for
AC
Rsi
gnifi
cant
drop
for
AR
Bns
for
CC
B.N
oco
rrel
atio
nbe
twee
nB
Pan
dU
AE
orA
CR
.Bot
hA
RB
and
CC
Bde
crea
sed
BP
toth
esa
me
degr
ee.
Res
ults
sugg
est
that
regu
lati
ng24
hbl
ood
pres
sure
alon
eis
inad
equa
teto
redu
cem
acro
albu
min
uria
and
addi
tion
alef
fect
sof
AR
B(l
osar
tan)
are
cruc
ialf
oran
tipr
otei
nuri
cac
tion
.
The CARI GuidelinesS188
This G
uideli
ne in
OUT O
F DATE &
has b
een A
RCHIVED
Tab
leA
4Su
mm
ary
ofst
udie
sre
leva
ntto
the
role
ofbl
ood
lipid
profi
les
inC
KD
inin
divi
dual
sw
ith
type
2di
abet
es
Stud
yID
Stud
yde
scri
ptio
nIn
terv
enti
onO
utco
me
(rel
evan
tto
CK
D)
Follo
wup
(mon
ths)
Com
men
ts/c
oncl
usio
ns
Ans
quer
etal
.(2
005)
113
RC
T11
Cen
tres
loca
ted
inC
anad
a,Fi
nlan
d,Fr
ance
and
Swed
enTy
pe2
diab
etes
(40
to65
year
s),n
orm
oor
mic
roal
bum
inur
ia,a
dequ
ate
gluc
ose
cont
rol,
mild
tom
oder
ate
lipid
abno
rmal
itie
s.n
=31
4
Feno
fibra
tevs
Plac
ebo
UA
E(s
econ
dary
tom
ain
stud
y)38
(ave
rage
)Im
prov
emen
tin
lipid
profi
les
was
asso
ciat
edw
ith
redu
ced
prog
ress
ion
from
norm
alto
mic
roal
bum
inur
ia,h
ighe
rre
gres
sion
and
larg
ernu
mbe
rof
pati
ents
wit
hun
chan
ged
albu
min
uria
.The
pers
iste
nce
ofef
fect
afte
rtr
eatm
ent
was
not
asse
ssed
.
Endo
etal
.(2
006)
117
RC
T,op
enst
udy,
Sing
lece
ntre
,Jap
anTy
pe2
diab
etes
,clin
ical
albu
min
uria
(UA
E>3
00m
g/g
Cr)
.102
defin
edas
adva
nced
pati
ents
onth
eba
sis
ofse
rum
Cr
>2.0
mg/
dL.
n=
102
Prob
ucol
(500
mg/
day)
.Pro
tein
rest
rict
ion
diet
.Blo
odgl
ucos
eco
ntro
lto
HbA
1c(<
6.5%
).B
lood
pres
sure
cont
rolw
ith
CC
Bor
a-bl
ocke
r.vs
No
trea
tmen
tPr
otei
nre
stri
ctio
ndi
et.B
lood
gluc
ose
cont
rolt
oH
bA1c
(<6.
5%).
Blo
odpr
essu
reco
ntro
lwit
hC
CB
ora-
bloc
ker.
UA
E36
(max
)28
.5(m
ean
all)
18.6
(mea
nfo
rad
vanc
edca
ses)
Mea
nin
terv
alto
init
iati
onof
haem
odia
lysi
sw
assi
gnifi
cant
lylo
nger
inpr
obuc
olpa
tien
ts.I
nad
vanc
edca
ses
incr
ease
sin
seru
mcr
eati
nine
and
urin
ary
prot
ein
wer
esi
gnifi
cant
ly.
supp
ress
ed.I
nad
vanc
edca
ses
the
haem
odia
lysi
s-fr
eera
tew
assi
gnifi
cant
lyhi
gher
inpr
obuc
olgr
oup.
Sugg
est
prop
ucol
may
supp
ress
the
prog
ress
ion
ofdi
abet
icne
phro
path
y.
Gae
deet
al.
(200
3)63
RC
TTy
pe2
diab
etes
,mic
roal
bum
inur
ian
=16
0
Mul
tifa
ctor
iali
nten
sive
trea
tmen
tvs
Stan
dard
trea
tmen
tU
AE
94(m
ean)
Targ
etdr
iven
long
-ter
min
tens
ified
trea
tmen
tai
med
atm
ulti
ple
risk
fact
ors
redu
ced
neph
ropa
thy
byab
out
50%
.
Kee
chet
al.
(200
5)11
4
Rad
erm
ecke
r&
Sche
en(2
005)
115
RC
TM
ulti
cent
re,m
ulti
coun
try
Type
2di
abet
es,n
otta
king
stat
inth
erap
y.n
=9
795
Feno
fibra
tevs
Plac
ebo
UA
E60
(ave
rage
)R
ate
ofpr
ogre
ssio
nto
albu
min
uria
was
sign
ifica
ntly
redu
ced
byfe
nofib
rate
and
rate
ofre
gres
sion
was
sign
ifica
ntly
incr
ease
d.H
owev
er,
the
diffe
renc
esin
term
sof
num
bers
ofpa
tien
tsw
assm
all(
inth
eor
der
of2%
).
Nag
aiet
al.
(200
0)11
6R
CT
Type
2di
abet
esn
=71
Ben
zafib
rate
vsPr
avas
tati
nU
AE
48U
AE
–no
sign
ifica
ntch
ange
over
the
48m
onth
sw
ith
eith
erdr
ug.C
oncl
ude
usef
ulin
prev
enta
tive
trea
tmen
tof
albu
min
uria
and
lipid
low
erin
g.
Nak
amur
aet
al.
(200
1)11
2R
CT,
doub
lebl
ind
Type
2di
abet
es,m
icro
albu
min
uria
,dy
slip
idae
mia
n=
60
Cer
ivas
tati
nvs
Plac
ebo
UA
E6
BP,
HbA
c1no
tsi
gnifi
cant
lyaf
fect
ed.T
otal
chl
and
LDL
chlr
educ
edan
dco
ncom
itan
tde
crea
sein
UA
E.
Nis
him
ura
etal
.(2
001)
135
RC
TM
ulti
cent
re,J
apan
Type
2di
abet
es,n
orm
oan
dm
icro
albu
min
uric
n=
168
AC
EiPr
obuc
olvs
Plac
ebo
UA
E24
AC
Eiha
sa
bene
ficia
leffe
ctan
dpr
obuc
olm
ayha
vea
bene
ficia
leffe
ctin
prev
enti
ngth
epr
ogre
ssio
nof
earl
ydi
abet
icne
phro
path
y.
Soro
fet
al.
(200
6)11
1R
CT,
doub
lebl
ind,
para
llelg
roup
Mul
tice
ntre
,Sw
eden
Type
2di
abet
es,d
yslip
idae
mia
(fas
ting
LDL-
C>3
.3m
mol
/L)
>18
year
s(a
ctua
l65
year
sav
erag
e),e
xclu
sion
sin
clud
ed–
neph
roti
csy
ndro
me,
seve
rere
nal
dysf
unct
ion,
unco
ntro
lled
hype
rten
sion
.n
=34
4
Ros
uvas
tati
n–
10m
gw
ith
titr
atio
nup
to40
mg
vsA
torv
asta
tin
–10
mg
wit
hpo
ssib
leti
trat
ion
to80
mg
UA
E,G
FR6
wee
ksru
nin
4m
onth
trea
tmen
t.N
och
ange
from
base
line
UA
Efo
rei
ther
trea
tmen
tgr
oup,
nosi
gnifi
cant
chan
gein
GFR
for
eith
ertr
eatm
ent
grou
p.
The
Hea
rtPr
otec
tion
Stud
y(2
003)
108
RC
TM
ulti
cent
re,U
KTy
pe1
diab
etes
(10%
)an
dty
pe2
diab
etes
(90%
)59
63–
Dia
bete
s11
307
–N
odi
abet
es
Sim
vast
atin
(40
mg/
day)
vsPl
aceb
oPl
asm
acr
eati
nine
,eG
FR(r
etro
spec
tive
ly)
60A
lloca
tion
tosi
mva
stat
inw
asas
soci
ated
wit
ha
sign
ifica
ntly
smal
ler
fall
ineG
FRov
erth
etr
ial
peri
od(5
.9m
L/m
invs
6.7
mL/
min
)an
dw
assl
ight
lyla
rger
amon
gth
ose
wit
hdi
abet
es.
Type 2 Diabetes: Kidney Disease S189
This G
uideli
ne in
OUT O
F DATE &
has b
een A
RCHIVED
Tab
leA
5Su
mm
ary
ofst
udie
sre
leva
ntto
the
asse
ssm
ent
ofth
ero
leof
diet
ary
fat
Stud
yID
Stud
yde
scri
ptio
nIn
terv
enti
onO
utco
me
(rel
evan
tto
CK
D)
Follo
wup
(mon
ths)
Com
men
ts/c
oncl
usio
ns
Bar
nard
etal
.(2
006)
136
RC
TTy
pe2
diab
etes
n=
99
Low
Fat
Veg
anvs
AD
Adi
etU
AE
5U
AE
grea
ter
redu
ctio
nin
vega
ndi
et.A
lso
impr
oved
glyc
aem
ican
dlip
idco
ntro
l.
Car
dena
set
al.
(200
4)11
8Pr
ospe
ctiv
eco
hort
Popu
lati
onba
sed,
mul
tice
ntre
Type
1di
abet
es,t
ype
2di
abet
esn
=19
2
AC
R84
Nor
moa
lbum
inur
iaan
dne
phro
path
yre
gres
sion
inw
ell-
cont
rolle
ddi
abet
esin
peop
lew
ith
long
term
diab
etes
dura
tion
are
asso
ciat
edw
ith
grea
ter
PUFA
cons
umpt
ion
and
less
erSF
Aco
nsum
ptio
n,sp
ecifi
cally
high
erPU
FA/S
FAan
dM
UFA
/SFA
rati
os–
the
oppo
site
patt
ern
isas
soci
ated
wit
hpr
ogre
ssio
nof
neur
opat
hy.
Nic
hols
onet
al.
(199
9)13
7R
CT
Type
2di
abet
esn
=11
Low
fat
vega
nvs
Con
vent
iona
llow
fat
UA
E3
No
sign
ifica
ntef
fect
onU
AE.
Nie
lsen
etal
.(1
995)
138
Bef
ore
and
afte
rcr
oss
over
.Pse
udo
rand
omiz
edtr
ial.
Type
2di
abet
es,p
ersi
sten
tm
icro
albu
min
uria
n=
10
Die
tri
chin
MU
Fvs
Rec
omm
ende
dhi
ghca
rboh
ydra
tedi
et
UA
E3
wee
ksN
oef
fect
onU
AE.
How
ever
apo
tent
ialb
enefi
cial
effe
cton
LDL/
HD
Lra
tio
was
dete
cted
.
Shim
izu
etal
.(1
995)
139
Bef
ore
and
afte
rno
n-ra
ndom
ized
tria
l.C
ompa
rati
vest
udy
usin
gpa
tien
tsgr
oupe
dac
cord
ing
toal
bum
inur
icst
atus
.Ty
pe2
diab
etes
n=
115
Eico
sape
ntae
noic
acid
ethy
l(EP
A-E
)(p
rese
ntin
cod
liver
oil)
AC
R12
Impr
oved
incr
ease
dal
bum
inex
cret
ion
inty
pe2
diab
etes
wit
hne
phro
path
yan
dth
eef
fect
sw
ere
sust
aine
dat
leas
t12
mon
ths
afte
rth
est
art
oftr
eatm
ent.
The CARI GuidelinesS190
This G
uideli
ne in
OUT O
F DATE &
has b
een A
RCHIVED
Tab
leA
6Su
mm
ary
ofst
udie
sre
leva
ntto
the
asse
ssm
ent
ofth
ero
leof
prot
ein
rest
rict
ion
Stud
yID
Stud
yde
sign
Inte
rven
tion
Out
com
e(r
elev
ant
toC
KD
)Fo
llow
up(m
onth
s)C
omm
ents
/con
clus
ions
Bar
sott
iet
al.
(199
8)14
0R
CT
Type
1di
abet
es,t
ype
2di
abet
esw
ith
chro
nic
rena
lfai
lure
n=
32
Low
prot
ein
diet
vsFr
eeR
esid
ualr
enal
func
tion
62.4
(med
ian)
Stud
yco
nfirm
sth
epr
otec
tive
effe
ctof
low
prot
ein
diet
son
neph
ropa
thy
inth
eab
senc
eof
any
sign
ofpr
otei
nm
alnu
trit
ion.
deM
ello
etal
.(2
006)
141
Bef
ore
and
afte
r–
rand
omor
der
ofdi
etC
ross
over
Type
2di
abet
es,m
acro
albu
min
uric
n=
17
Chi
cken
(CD
)La
ctov
eget
aria
nLo
wPr
otei
n(L
PD)
vsU
sual
(UD
)
GFR
,UA
E4
wk
for
each
diet
Wit
hdra
win
gre
dm
eat
from
diet
redu
ces
UA
Era
te.
Dus
sole
tal
.(2
005)
121
RC
T(u
nblin
ded)
Sing
lece
ntre
Type
1di
abet
esan
dty
pe2
diab
etes
Inci
pien
tor
over
tne
phro
path
yan
dm
ildre
nalf
ailu
re,S
tric
tB
Pco
ntro
lus
ing
AC
Eior
AR
Bn
=63
Low
prot
ein
vsU
sual
prot
ein
(pro
vide
dno
tgr
eate
rth
an1.
2g/
kgpe
rda
y)
GFR
,UA
E24
The
low
prot
ein
diet
did
not
alte
rth
eco
urse
ofG
FRor
UA
E.T
heim
pact
ofa
low
prot
ein
diet
inpr
even
ting
the
prog
ress
ion
ofdi
abet
icne
phro
path
y,if
any,
issm
all.
Gro
sset
al.
(200
2)14
2R
CT,
cros
sov
erTy
pe2
diab
etes
,nor
mo
orm
icro
albu
min
uric
n=
28
Low
prot
ein
Chi
cken
(no
red
mea
t)vs
Usu
aldi
et
GFR
,UA
E1/
1w
ith
1w
asho
utbe
twee
nN
orm
oalb
umin
uric
–bo
thLP
and
chic
ken
redu
ced
UA
Eco
mpa
red
wit
hno
rmal
diet
.M
icro
albu
min
uric
–on
lych
icke
nre
duce
dU
AE
com
pare
dw
ith
norm
aldi
et.
Mel
onie
tal
.(2
004)
143
RC
T,pr
ospe
ctiv
eN
ephr
olog
you
tpa
tien
ts,8
0w
ith
DK
D(2
4ty
pe1
diab
etes
,56
type
2di
abet
es)
n=
169
Low
prot
ein
diet
vsFr
eepr
otei
ndi
etR
enal
func
tion
12Si
gnifi
cant
slow
ing
ofth
epr
ogre
ssio
nof
kidn
eyda
mag
ew
ason
lyob
serv
edin
non-
diab
etic
s.
Pijls
etal
.(1
999)
144
RC
TTy
pe2
diab
etes
,mic
roal
bum
inur
ian
=12
1
Cou
nsel
ling
onpr
otei
nre
stri
ctio
nvs
Usu
alad
vice
UA
E6
and
12A
t6
mon
ths
expe
rim
enta
lgro
upha
dsi
gnifi
cant
ly.L
ower
prot
ein
inta
kean
dsi
gnifi
cant
ly.L
ower
UA
E.A
t12
mon
ths
diffe
renc
esbe
twee
ngr
oups
had
decr
ease
d.
Pijls
etal
.(2
002)
145
RC
TTy
pe2
diab
etes
,mic
roal
bum
inur
ian
=13
1
Die
tary
coun
selli
ng–
prot
ein
rest
rict
ion
vsU
sual
diet
ary
advi
ce
GFR
,UA
E281
7Pr
otei
nin
take
betw
een
grou
psat
follo
wat
6m
onth
sdi
ffere
dby
only
0.08
g/kg
per
day.
No
diffe
renc
esby
end
oftr
ial.
Wit
hin
the
inte
rven
tion
grou
pin
divi
dual
sw
ith
redu
ctio
nof
atle
ast
0.2
mg/
kgpe
rda
ypr
otei
nco
mpa
red
wit
hco
ntro
lsw
ith
noch
ange
–sh
owed
non-
sign
ifica
ntly
diffe
renc
ein
GFR
.Con
clud
eth
atpr
otei
nre
stri
ctio
nis
neit
her
feas
ible
oref
ficac
ious
.
Pom
erle
auet
al.
(199
3)14
6R
CT,
cros
sov
erTy
pe2
diab
etes
,nor
mot
ensi
ven
=12
3w
eek
mod
erat
epr
otei
nvs
3w
eek
high
prot
ein
UA
E,G
FR,c
reat
inin
ecl
eara
nce
3w
eeks
/3w
eeks
Mod
erat
edi
etre
duce
dth
eU
AE,
GFR
,pr
otei
nuri
aan
dcr
eati
nine
clea
ranc
ew
itho
utad
vers
ely
affe
ctin
ggl
ycae
mic
cont
rol.
Hig
hpr
otei
ndi
etin
duce
dsm
allc
hang
esin
rena
lfu
ncti
on.
Teix
eira
etal
.(2
004)
147
Bef
ore
and
afte
rcr
oss
over
.R
ando
mor
der
ofin
terv
enti
ons
Type
2di
abet
esn
=14
Isol
ated
soy
prot
ein
vsC
asei
nU
AE
2/2
wit
h1
lead
inan
dw
ash
out
UA
Esi
gnifi
cant
lyre
duce
din
ISP
com
pare
dw
ith
case
in.
Whe
eler
etal
.(2
002)
148
RC
T,cr
oss
over
Type
2di
abet
es,m
icro
albu
min
uric
n=
17
Plan
tba
sed
prot
ein
vsA
nim
alba
sed
prot
ein
GFR
,UA
E1.
5/1.
5N
osi
gnifi
cant
diffe
renc
ebe
twee
nG
FRan
dU
AE.
Type 2 Diabetes: Kidney Disease S191
This G
uideli
ne in
OUT O
F DATE &
has b
een A
RCHIVED
Tab
leA
7Su
mm
ary
ofst
udie
sre
leva
ntto
the
asse
ssm
ent
ofth
ero
leof
rest
rict
edsa
ltin
take
Stud
yID
Stud
yde
sign
Inte
rven
tion
Out
com
e(r
elev
ant
toC
KD
)Fo
llow
up(m
onth
s)C
omm
ents
/con
clus
ions
Hou
lihan
etal
.(2
000)
149
RC
T–
w.r.
tlo
sart
anan
dpl
aceb
oTy
pe2
diab
etes
,hyp
erte
nsiv
e,m
icro
albu
min
uric
n=
17
Low
sodi
umvs
Nor
mal
sodi
umU
AE
1/1
Low
salt
ampl
ified
both
anti
-hyp
erte
nsiv
ean
dan
ti-p
rote
inur
icef
fect
sof
losa
rtan
and
nosi
gnifi
cant
effe
ctin
the
plac
ebo.
Hou
lihan
etal
.(2
002)
150
RC
TTy
pe2
diab
etes
,UA
E10
–200
mg/d
ay,h
yper
tens
ion
n=
21
Losa
rtan
+lo
wan
dhi
ghsa
ltvs
Plac
ebo
+lo
wan
dhi
ghsa
lt
TG
F-be
ta(u
rine
),U
AE
1/1
The
AR
Bno
tso
dium
rest
rict
ion
redu
ced
urin
ary
TG
F-be
ta.
Hou
lihan
etal
.(2
002)
151
RC
TTy
pe2
diab
etes
,UA
E10
–200
mg/d
ayn
=20
Losa
rtan
+lo
wan
dhi
ghsa
ltvs
Plac
ebo
+lo
wan
dhi
ghsa
lt
AC
R1/
1A
CR
inlo
sart
angr
oup
decr
ease
dsi
gnifi
cant
lyw
ith
low
salt
.No
sign
ifica
ntly
chan
ges
inpl
aceb
ogr
oup.
Dem
onst
rate
da
low
-sod
ium
diet
pote
ntia
tes
the
anti
hype
rten
sive
and
anti
prot
einu
ric
effe
cts
oflo
sart
an.
Iman
ishi
etal
.(2
001)
152
Bef
ore
and
afte
rcr
oss
over
Type
2di
abet
es–
norm
oto
mac
roal
bum
inur
ia,n
orm
alle
vels
ofse
rum
crea
tini
nen
=32
Sodi
umre
stri
cted
diet
vsN
orm
also
dium
diet
.U
AE
1w
eek/
1w
eek
Sodi
umse
nsit
ivit
yof
bloo
dpr
essu
reap
pear
sbe
fore
hype
rten
sion
and
isre
late
dto
albu
min
uria
.
Ved
ovat
oet
al.
(200
4)15
3B
efor
ean
daf
ter
Type
2di
abet
esC
ase
–m
icro
albu
min
uria
Con
trol
–no
rmoa
lbum
inur
ian
=42
Red
uced
salt
vsH
igh
salt
UA
E1
wee
kH
igh
salt
incr
ease
dB
Pan
dU
AE.
Yosh
ioka
etal
.(1
998)
154
Cro
ssov
erra
ndom
izat
ion
islim
ited
toth
eor
der
ofdi
etTy
pe2
diab
etes
,nor
mo
tom
acro
albu
min
uria
.n
=19
Sodi
umre
stri
cted
diet
vsN
orm
also
dium
diet
.C
alcu
late
dIg
Gan
dal
bum
infr
acti
onal
clea
ranc
es.
1w
eek/
1w
eek
Cha
rge
sele
ctiv
ity
islo
stbe
fore
size
sele
ctiv
ity
asdi
abet
icne
phro
path
ypr
ogre
sses
.
The CARI GuidelinesS192
This G
uideli
ne in
OUT O
F DATE &
has b
een A
RCHIVED
Tab
leA
8Su
mm
ary
tabl
esof
stud
ies
ofsm
okin
gas
risk
fact
orfo
rth
ede
velo
pmen
tan
dpr
ogre
ssio
nof
CK
Din
peop
lew
ith
type
2di
abet
es
Stud
yID
Stud
yde
sign
Out
com
e(r
elev
ant
toC
KD
)Fo
llow
up(m
onth
s)C
omm
ents
/con
clus
ions
Ana
net
al.
(200
7)15
5C
ross
sect
iona
l.Ty
pe2
diab
etes
prem
enop
ausa
lw
omen
,n
=20
/35
(Sm
oker
s/no
n-sm
oker
s)
UA
EU
AE
was
inde
pend
entl
yas
soci
ated
wit
hcu
rren
tsm
okin
gsu
gges
ting
smok
ing
asa
risk
fact
orfo
rde
velo
pmen
tof
incr
ease
dU
AE.
Bag
gio
etal
.(2
002)
156
Cro
ssse
ctio
nal
Type
2di
abet
esw
ith
abno
rmal
AER
n=
96
UA
E,G
FR,G
BM
wid
thSm
okin
gaf
fect
sgl
omer
ular
stru
ctur
ean
dfu
ncti
onin
type
2di
abet
esan
dm
aybe
anim
port
ant
fact
orfo
rth
eon
set
and
prog
ress
ion
ofdi
abet
icne
phro
path
y.
Bia
rnes
etal
.(2
005)
132
Pros
pect
ive
coho
rtTy
pe2
diab
etes
,hig
hch
oles
tero
ln
=93
0
Alb
umin
uria
24O
Rfo
rsm
oker
and
deve
lopm
ent
ofm
icro
albu
min
uria
3.19
(1.0
2–9.
96).
Bru
noet
al.
(199
6)26
Cro
ssse
ctio
nal
Type
2di
abet
esn
=15
74
UA
ESm
okin
gha
bits
are
inde
pend
entl
yre
late
dto
both
mic
roan
dm
acro
albu
min
uria
.
Ced
erho
lmet
al.
(200
5)13
1Pr
ospe
ctiv
eco
hort
Type
2di
abet
esan
dty
pe1
diab
etes
4097
(typ
e1
diab
etes
)65
13(t
ype
2di
abet
es)
Alb
umin
uria
60Sm
okin
gid
enti
fied
asan
inde
pend
ent
risk
fact
orfo
res
tabl
ishe
dm
icro
albu
min
uria
and
for
the
deve
lopm
ent
ofm
icro
albu
min
uria
.
Chu
ahir
unet
al.
(200
3)13
0Pr
ospe
ctiv
eco
hort
Type
2di
abet
esun
derg
oing
BP
cont
rol
n=
84
Plas
ma
crea
tini
ne,
UA
E64
Smok
ing
and
incr
ease
dU
AE
are
inte
rrel
ated
pred
icto
rsof
neph
ropa
thy
prog
ress
ion
and
smok
ing
incr
ease
sU
AE
inpa
tien
tsde
spit
eim
prov
edB
Pco
ntro
land
AC
Ein
hibi
tion
.
Chu
ahir
unet
al.
(200
4)12
9Pr
ospe
ctiv
eco
hort
Type
2di
abet
esw
ith
and
wit
hout
mac
roal
bum
inur
ia.S
mok
ing
cess
atio
nin
type
2di
abet
esm
icro
albu
min
uria
n=
237
Uri
neex
cret
ion
ofT
GFb
etaV
,UA
E6
Cig
aret
tesm
okin
gex
acer
bate
sre
nal
inju
ryde
spit
eB
Pco
ntro
land
AC
Ei–
cess
atio
nby
thos
ew
ith
mic
roal
bum
inur
iaam
elio
rate
sth
epr
ogre
ssiv
ere
nali
njur
yca
used
byco
ntin
uals
mok
ing.
Cor
radi
etal
.(1
993)
157
Cro
ssse
ctio
nal
Type
2di
abet
es,h
yper
tens
ive,
mal
esn
=90
UA
ET
hede
term
inan
tsof
ade
crea
sein
UA
Eaf
ter
lisin
opri
ltre
atm
ent
wer
eth
edu
rati
onof
hype
rten
sion
inno
n-sm
oker
san
dda
ilyto
bacc
oco
nsum
ptio
nan
ddu
rati
onof
smok
ing
insm
oker
s.Sm
okin
gm
aybe
anin
depe
nden
tde
term
inan
tof
mic
roal
bum
inur
iain
hype
rten
sive
indi
vidu
als.
Dea
net
al.
(199
4)15
8C
ross
sect
iona
lTy
pe2
diab
etes
,nor
mot
ensi
ven
=87
UA
ER
elat
ions
hip
ifan
ybe
twee
nsm
okin
gan
dU
AE
not
stat
edin
abst
ract
.
Type 2 Diabetes: Kidney Disease S193
This G
uideli
ne in
OUT O
F DATE &
has b
een A
RCHIVED
Tab
leA
8C
ontin
ued
Stud
yID
Stud
yde
sign
Out
com
e(r
elev
ant
toC
KD
)Fo
llow
up(m
onth
s)C
omm
ents
/con
clus
ions
Fors
blom
etal
.(1
998)
125
Ret
rosp
ecti
veco
hort
Type
2di
abet
esn-
134
UA
E10
8T
here
was
anov
er-r
epre
sent
atio
nof
smok
ers
(55%
vs27
%;P
=0.
01)
inpe
ople
who
prog
ress
edto
mic
ro-
orm
acro
albu
min
uria
vsth
ose
who
did
not
prog
ress
.
Gam
baro
etal
.(2
001)
126
Ret
rosp
ecti
veco
hort
Ital
yTy
pe2
diab
etes
n=
273
AER
,ser
umcr
eati
nine
.36
Logi
stic
regr
essi
on–
smok
ing
was
the
mos
tim
port
ant
risk
fact
orfo
rpr
ogre
ssio
nof
neph
ropa
thy.
Qui
ttin
gsm
okin
gsh
ould
bepa
rtof
the
prev
enti
onth
erap
y.
Gat
ling
etal
.(1
988)
159
Cro
ssse
ctio
nal
Type
2di
abet
esn
=84
2
UA
E,A
CR
Sign
ifica
ntas
soci
atio
nfo
und
betw
een
UA
Ean
dsm
okin
gca
tego
ry.
Iked
aet
al.
(199
7)16
0C
ross
sect
iona
lTy
pe2
diab
etes
–m
enn
=14
8
AC
RO
Rfo
rth
epr
eval
ence
ofm
icro
/mac
roal
bum
inur
iaw
assi
gnifi
cant
lyhi
gher
for
smok
ers
than
exsm
oker
s.
Nils
son
etal
.(2
004)
161
Cro
ssse
ctio
nal
Type
1di
abet
esan
dty
pe2
diab
etes
Hos
pita
ls,p
rim
ary
heal
thca
ren3
1700
0ty
pe2
diab
etes
Alb
umin
uria
Smok
ing
was
asso
ciat
edw
ith
poor
glyc
aem
icco
ntro
land
mic
roal
bum
inur
ia.
Pijls
etal
.(2
001)
162
Cro
ssse
ctio
nal
Type
2di
abet
es–
prim
ary
care
pati
ents
n=
335
AC
RSm
okin
gin
depe
nden
tly
asso
ciat
edw
ith
AC
R.
Sava
geet
al.
(199
5)16
3C
ross
sect
iona
lTy
pe2
diab
etes
wit
hap
prop
riat
eB
Pco
ntro
ln
=93
3
UA
ET
hem
ost
sign
ifica
ntpr
edic
tors
ofm
icro
and
mac
roal
bum
inur
iaw
ere
syst
olic
hype
rten
sion
,BM
I,H
DL,
insu
linus
ean
dsm
okin
gpa
ckye
ars.
Smul
ders
etal
.(1
997)
127
Pros
pect
ive
coho
rtTy
pe2
diab
etes
wit
hm
icro
albu
min
uria
n=
58
AC
R24
Smok
ing
was
not
asi
gnifi
cant
pred
icto
rof
the
prog
ress
ofal
bum
inur
ia.
Tho
mas
etal
.(2
006)
164
Cro
ssse
ctio
nTy
pe2
diab
etes
Chi
nese
mal
esn
=49
6
AC
RA
CR
elev
ated
insm
oker
s.Sm
okin
gw
asas
soci
ated
wit
ha
mor
ead
vers
em
etab
olic
profi
lean
dpe
riph
eral
vasc
ular
dise
ase.
Mal
esm
oker
sco
mpa
red
wit
hne
ver
smok
ers
had
low
erH
DL-
chol
este
roll
evel
s(1
.121
0.31
vs1.
201
0.30
mm
ol/L
,P
=0.
006)
,and
elev
ated
albu
min
-to
-cre
atin
ine
rati
o(3
.57
(2.6
8–4.
75)
vs2.
47(1
.99–
3.05
)m
g/m
mol
,P
=0.
040)
.
The CARI GuidelinesS194
This G
uideli
ne in
OUT O
F DATE &
has b
een A
RCHIVED