management of common comorbidities in diabetes

Management of Common Comorbidities in Diabetes

1


Obesity

4

Prevalence of Obesity inType 2 Diabetes

5

61%

27%

12% Normal (BMI <25)

Overweight(BMI 25-29)

Obese(BMI ≥30)

BMI, body mass index, in kg/m2.Suh DC, et al. J Diabetes Complications. 2010;24:382-391.

NHANES 1999-2004(N=984)

T2D

M P

atie

nts

(%

)

Consequences of Obesity in Diabetes

• Increases risk of cardiovascular comorbidities– Hypertension– Dyslipidemia– Atherosclerosis

• May limit ability to engage in physical activity• Increases insulin resistance

– Worsens glucose tolerance– Necessitates higher exogenous insulin doses

• Changes neuroendocrine signaling and metabolism• Reduces quality of life

6

Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

Goal: 5% to 10% weight loss

Energy intake

Ingestion of:

Proteins

Fats

Carbohydrates

Energy expenditure

Physical activity

Diet-induced thermogenesis

Basal metabolic rate

Body Weight

Increase Decrease

Energy Homeostasis

7

Badman MK, et al. Science. 2005;307(5717):1909-1914.

GI tract

Adipose tissue

Pancreatic islets

Hypothalamus

Hindbrain

CCK

Adiponectin

Insulin

Amylin

Leptin

OXM

Ghrelin

GLP-1

PYY3-36

GIP PP

ResistinVisfatin

Vagal afferents

Multihormonal Control of Body Weight: Fat-, Gut-, and Islet-Derived Signals

8

Small Amounts of Weight Gain or Loss Have Important Effects on CHD Risk

*Patients with Low HDL-C, high cholesterol, high BMI, high systolic BP, high triglyceride, high glucose.**P <0.002 vs baseline.

Wilson PW, et al. Arch Intern Med. 1999;159:1104-1109.

Framingham Offspring Study 16-year Follow-up*

Ch

ang

e in

Ris

k F

acto

r S

um

(%

)

**

**

****

9

Abdominal Obesity and Increased Risk of Cardiovascular Events

Dagenais GR, et al. Am Heart J. 2005;149:54-60.

Waist Circumference (cm)

Men Women

Tertile 1 <95 <87

Tertile 2 95-103 87-98

Tertile 3 >103 >98

The HOPE Study

*Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-cholesterol, total-C; CVD: cardiovascular disease; MI: myocardial infarction; BMI: body mass index; DM: diabetes mellitus; HDL: high-density lipoprotein cholesterol.

10

Pulmonary diseaseAbnormal functionObstructive sleep apneaHypoventilation syndrome

Nonalcoholic fatty liver diseaseSteatohepatitisCirrhosis

Coronary heart disease Diabetes Dyslipidemia Hypertension

Gynecologic abnormalitiesAbnormal mensesInfertilityPolycystic ovary syndrome (PCOS)

Osteoarthritis

Skin

Gall bladder disease

CancerBreast, uterus, cervix, colon, esophagus, kidney, pancreas, prostate

PhlebitisVenous stasis

Gout

Idiopathic intracranial hypertension

StrokeCataracts

Severe pancreatitis

Medical Complications of Obesity

11

• Weight loss– Every kg of weight loss is

associated with 3-4 months of improved survival1

– In a prospective analysis of 5000 people with type 2 diabetes, 35% reported intentional weight loss; this subgroup experienced a 25% reduction in mortality over 12 years2

• Weight gain– A 5-kg weight gain increases

CHD risk by 30%3

Health Effects of Weight Change in T2DM

12 1. Lean ME, et al. Diabet Med. 1990;7:228-233.2. Williamson DF, et al. Diabetes Care. 2000;23:1499-1503.

3. Anderson JW, et al. J Am Coll Nutr. 2003;22:331-339.

AACE Healthful Eating Recommendations

13


Topic Recommendation

General eating habits

Regular meals and snacks; avoid fasting to lose weight Plant-based diet (high in fiber, low calories, low glycemic index, high in phytochemicals/antioxidants) Understand Nutrition Facts Label information Incorporate beliefs and culture into discussions Informal physician-patient discussions Use mild cooking techniques instead of high-heat cooking

Carbohydrate Understand health effects of the 3 types of carbohydrates: sugars, starch, and fiber Target 7-10 servings per day of healthful carbohydrates (fresh fruits and vegetables, pulses, whole

grains) Lower-glycemic index foods may facilitate glycemic control:* multigrain bread, pumpernickel bread,

whole oats, legumes, apple, lentils, chickpeas, mango, yams, brown rice

Fat Eat healthful fats: low-mercury/low-contaminant-containing nuts, avocado, certain plant oils, fish Limit saturated fats (butter, fatty red meats, tropical plant oils, fast foods) and trans fat Use no- or low-fat dairy products

Protein Consume protein from foods low in saturated fats (fish, egg whites, beans) Avoid or limit processed meats

Micronutrients Routine supplementation not necessary except for patients at risk of insufficiency or deficiency Chromium; vanadium; magnesium; vitamins A, C, and E; and CoQ10 not recommended for glycemic

control*Insufficient evidence to support a formal recommendation to educate patients that sugars have both positive and negative health effects

• Evaluate for contraindications and/or limitations to increased physical activity before patient begins or intensifies exercise program

• Develop exercise recommendations according to individual goals and limitations

• ≥150 minutes per week of moderate-intensity exercise – Flexibility and strength

training– Aerobic exercise (eg, brisk

walking)

• Start slowly and build up gradually

AACE Physical Activity Recommendations

14


Weight Gain/Loss Potential with Antidiabetic Agents

Class Agent(s) Weight Effect

Amylin analog Pramlintide ↓

Biguanide Metformin ↓

GLP-1 receptor agonists Exenatide, exenatide XR, liraglutide ↓

SGLT-2 inhibitor Canagliflozin ↓

-Glucosidase inhibitors Acarbose, miglitol ↔

Bile acid sequestrant Colesevelam ↔

DPP-4 inhibitors Alogliptin, linagliptin, saxagliptin, sitagliptin ↔

Dopamine-2 agonist Bromocriptine ↔

Glinides Nateglinide, repaglinide ↑

Sulfonylureas Glimepiride, glipizide, glyburide ↑

InsulinAspart, detemir, glargine, glulisine, lispro, NPH, regular ↑↑

Thiazolidinediones Pioglitazone, rosiglitazone ↑↑

15Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. Garber AJ, et al. Endocr Pract. 2013;19:327-336.

Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Stenlof K, et al. Diabetes Obes Metab 2013;15:372-382.


Dyslipidemia

16

Prevalence of Hyperlipidemia in T2DM

17 *LDL-C ≥100 mg/dL, TC≥200 mg/dL, or TG≥150 mg/dL (treatment not assessed).Fu AZ, et al. Curr Med Res Opin. 2011;27:1035-1040.

Suh DC, et al. J Diabetes Complications. 2010;24:382-391.

1%, No need for treatment

63%Receiving statin

35%Eligible for lipid-lowering therapy but untreated

Retrospective Medical Database Study, T2DM

(N=125,464)

NHANEST2DM Patients With

Hyperlipidemia*

Atherogenic Dyslipidemia

• Common in T2DM and the insulin resistance syndrome

• Features– Elevated triglycerides– Decreased HDL-C– Small, dense LDL particles– Postprandial increase in triglyceride-rich

lipoproteins

18HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein.

Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78.

Dyslipidemia Treatment Options

ClassMOA

Efficacy

Main LimitationsLDL-C HDL-C Triglycerides

HMG CoA reductase inhibitors (statins)Slow cholesterol synthesis in liver by inhibiting rate-limiting step

21-55% 2-10% 6-30%

Risk of myopathy, increased liver transaminasesContraindicated in liver diseaseLiver enzyme monitoring requiredRisk of new-onset diabetes

Fibric acid derivativesStimulate lipoprotein lipase activity

VLDL-C LDL-C 20-25% (fibrinogen only)

6-18% 20-35%

GI symptoms, possible cholelithiasisGemfribrozil may LDL-CMyopathy risk increased when used with statins

Niacin/nicotinic acidReduce hepatic synthesis ofLDL-C and VLDL-C

10-25% 10-35% 20-30%Skin flushing, pruritis, GI symptoms, potential increases in blood glucose and uric acid

Bile acid sequestrantsBind bile acids in the intestine

15-25% — —GI symptomsMay triglycerides

Cholesterol absorption inhibitorsInhibit intestinal absorption of cholesterol

10-18%(as monotherapy)

— — Risk of myopathy

19HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein.


Benefits of Aggressive LDL-C Lowering in Diabetes

Shepherd J, et al. Diabetes Care. 2006;29:1220-1226. Sever PS, et al. Diabetes Care. 2005;28:1151-1157.Colhoun HM, et al. Lancet. 2004;364:685-696. HPS Collaborative Group. Lancet. 2003;361:2005-2016.

Difference in LDL-C

(mg/dL)

Aggressive lipid-lowering better

Aggressive lipid-lowering worse

0.026

0.036

0.001

<0.0001

0.0003

Primary event rate (%)

17.9

11.9

9.0

12.6

13.5

Control

13.8

9.2

5.8

9.4

9.3

Treatment

0.63

0.67

0.73

P

TNT Diabetes, CHD

ASCOT-LLA Diabetes, HTN

CARDS Diabetes, no CVD

HPS All diabetes

Diabetes, no CVD

*Atorvastatin 10 vs 80 mg/day†Statin vs placebo Relative riskRelative risk

0.7 0.9 10.5 1.7

0.77

22*

35†

46†

39†

39†

0.75

20

Patients with Diabetes(N=18,686; 14 RCTs)

Cholesterol Treatment Trialists’ Collaborators. Lancet. 2008;371:117-125.

Randomized Trials of Statins: A Meta-Analysis of CV Events

21

Risk Reduction in Major Vascular Events per mmol/L Decrease in LDL-C

Treat Patients With the Greatest Absolute Risk the Most Aggressively

Robinson JG, et al. Am J Cardiol. 2006;98:1405-1408.

22

Residual Cardiovascular Risk in Major Statin Trials

LIPID Study Group. N Engl J Med. 1998;339:1349-1357. Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.HPS Collaborative Group. Lancet. 2002;360:7-22. Colhoun HM, et al. Lancet. 2004:364:685-696.

Secondary Primary

CHD events still occur in patients treated with statins

N = 9014 4159 20,536 2841 LDL-C -25% -28% -29% -40%

23

Tota

lP

op

ula

tio

n(%

)

Pat

ien

ts w

ith

D

iab

etes

(%)

N = 782 586 5963 2841

LIPID CARE HPS CARDS

Lipid Effects of Adding a Fenofibrate to a Statin in Patients With T2DM

ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.

24

Action to Control Cardiovascular Risk in Diabetes(N=5518)

Effects of Adding a Fenofibrate to a Statin on CV Events in Patients With T2DM


25


Adding a Fenofibrate to a Statin in Patients With T2DM: Subgroup Analyses



*P=0.02 vs placeboDiabetes Atherosclerosis Intervention Study. Lancet. 2001;357:905-910.

Diabetes Atherosclerosis Intervention Study

Effect of Fenofibrate on Progression of Coronary Atherosclerosis in Patients With

Type 2 Diabetes

*

Cha

nge

in S

teno

sis

(%)

(n=207) (n=211)

27

Fenofibrate Placebo

Triglycerides (mmol/L)

Baseline 2.59 2.42

Endpoint -29% +1%

HDL-C (mmol/L)

Baseline 1.01 1.05

Endpoint +7% +2%

Coronary Drug Project:15-Year Follow-up

Canner PL, et al. J Am Coll Cardiol. 1986;8:1245-1255. Canner PL, et al. J Am Coll Cardiol. 2005;95:254-257.

Eve

nt

Rat

e (%

)

12% ReductionP <0.05

11% ReductionP =0.0004

28

Dyslipidemia Summary

• Patients with diabetes and insulin resistance syndrome have atherogenic dyslipidemia and an increased risk for CVD

• Although statin therapy is effective in lowering LDL-C, residual CVD risk remains after statin therapy

• To reduce residual CVD risk, lipid abnormalities beyond LDL-C (non–HDL-C, triglycerides,HDL-C) should be intensively treated

29CVD, cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.



Hypertension

30

BPLTTC. BMJ. 2008;336:1121-1123.

Meta-Regression Analysis of Major CV Events and BP Reduction

-15 -12 - 9 -6 -3 0 36

Rel

ativ

e R

isk

Reduction in risk per 5 mm Hg reduction in SBP

Age <65: 11.9% (5.3% to 18.0%)Age >65: 9.1% (3.6% to 14.3%)

P for heterogeneity of slopes = 0.38

Difference in reduction in systolic BP (mm Hg)

2.0

1.0

0.5

0.25

31

DBP, diastolic blood pressure, in mmHg.Hansson L, et al. Lancet. 1998;351:1755-1762.

BP Reduction and Effect on CV Mortality at 4 Years

Hypertension Optimal Treatment Trial

Eve

nts

per

1000

Pat

ien

t-ye

ars

n=18,790n=1501

67%

32

The lower the target BP in patients with diabetes,the lower the rates of CV events and CV deaths

P=0.016

P=0.49

CV Deaths

Eve

nts

per

1000

Pat

ien

t-ye

ars

n=18,790n=1501

51%

P=0.005

P=0.50

Major CV Events

DBP ≤ 90

DBP ≤85

DBP ≤ 80

Adler Al, et al. BMJ. 2000;321:412-419.

Blood Pressure and Diabetic Complications

12% Decrease per 10 mmHg reduction in SBP

Updated Mean A1C

Myo

card

ial I

nfa

rcti

on

Haz

ard

Rat

io

0.5

1

10

110 120 130 150 160 170140

P<0.0001

13% Decrease per 10 mmHg reduction in SBP

Updated Mean A1C

Mic

rova

scu

lar

Co

mp

licat

ion

sH

azar

d R

atio

0.5

1

10

110 120 130 150 160 170140

P<0.0001

United Kingdom Prospective Diabetes Study

33

BP Reductions and Risk of Micro- and Macrovascular Complications in T2DM

UKPDS Group. BMJ. 1998;317:703-713.

United Kingdom Prospective Diabetes StudyBenefits of 144/82 vs. 154/87 mm Hg (N=1148)

Ris

k R

edu

ctio

n (

%)

Myocardial infarction

Any diabetes-related

endpoint

Diabetes-related death Stroke

Heart failure

Renal failure Retinopathy

Vision deterior-

ation

P=0.013

P=0.004

P=0.004

P=0.004

P=0.13P=0.005

P=0.019

P=0.29

34

Effect of Intensive Blood-Pressure Control on CV Outcomes and Death in T2DM



35

Good BP control must be continued if benefits are to be maintained

Holman RR, et al. N Engl J Med. 2008;359;1565-1576.

• BP became similar within 2 years of trial termination (mainly due to increased BP in tight control group)

• Relative risk reductions achieved with tight BP control during the trial were not sustained for: – Any diabetes-related end point– Diabetes-related death– Microvascular disease– Stroke

• Peripheral vascular disease risk reduction became significant during the follow-up (P = 0.02)

Long-Term Follow-up After Tight Control of Blood Pressure in T2DM

UKPDS Post-monitoring Study

Any Diabetes-related Endpoint

36

Intensive Blood Pressure Control in T2DM


37


Multiple Antihypertensive Agents Are Usually Required to Achieve BP Control

38

ABCD, Appropriate Blood pressure Control in Diabetes trial; DBP, diastolic blood pressure, in mm Hg; HOT, Hypertension Optimal Treatment trial; IDNT, Irbesartan in Diabetic Nephropathy trial; IRMA-2, Irbesartan Microalbuminuria Type 2

Diabetes in Hypertensive Patients trial; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study; UKPDS, United Kingdom Prospective Diabetes Study.

Bakris G, et al. Am J Kidney Dis. 2000;36:646-661.

Compelling Indication

Recommended Drugs

Clinical Trial BasisDiuretic BB ACEI ARB CCBAldoANT

Heart failure • • • • •

ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES, CHARM

Post-myocardial infarction

• • •ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS

High coronary disease risk

• • • •ALLHAT, HOPE, ANBP2, LIFE, CONVINCE, EUROPA, INVEST

Diabetes • • • • •NKF-ADA Guideline, UKPDS, ALLHAT

Chronic kidneydisease

• •NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK

Recurrent stroke prevention

• • PROGRESS

Compelling Indications for Individual Drug Classes

Aldo ANT = aldosterone antagonist.

Chobanian AV, et al. Hypertension. 2003;42:1206-1252.

39

The Renin Angiotensin System: ACE Inhibition

Unger T, et al. Am J Cardiol. 2007;100:25J-31J.

AT2AT1

Angiotensin I

Angiotensin II

B2 NO, PGI2

Vasodilation, etc

NOVasodilation

Tissue protection

Vasoconstriction

Proliferation

Aldosterone

Sympathetic NS

NaCl retention

Inflammation

Apoptosis

ACEI

Antiproliferation

Differentiation

Regeneration

Anti-inflammation

Apoptosis?

ACE-independentformation of ANG II

BradykininACE

40

The Renin Angiotensin System: AT1 Blockade

Unger T, et al. Am J Cardiol. 2007;100:25J-31J.

ARB

AT2AT1

Angiotensin I

Angiotensin II

B2 NO, PGI2

Vasodilation, etc

NOVasodilation

Tissue protection

Vasoconstriction

Proliferation

Aldosterone

Sympathetic NS

NaCl retention

Inflammation

Apoptosis

Antiproliferation

Differentiation

Regeneration

Anti-inflammation

Apoptosis?

ACE

41

EventsARBs ACEIs Odds Ratio

ARB vs ACEI

ELITE 1997 4/352 4/370 0.79 (0.17,3.54)

ELITE II 2000 31/1578 28/1574 1.11 (0.66,1.85)OPTIMAAL 2002 384/2744 379/2733 1.01 (0.87,1.18)DETAIL 2004 9/120 6/130 1.68 (0.58,4.86)VALIANT (val) 2003 796/4909 798/4909 1.00 (0.90,1.11)ONTARGET (tel) 2008 440/8542 413/8576 1.07 (0.94,1.23)

Fixed effect model (I2=0.0%, p=0.884) 1663/18,245 1628/18,292 1.03 (0.95, 1.10)

Random effect model 1.03 (0.95,1.10)ARB + ACEI vs ACEI

VALIANT (val + cap) 2003 756/4885 798/4909 0.94 (0.85,1.05)

ONTARGET (tel+ram) 2008 438/8502 413/8576 1.07 (0.94,1.23)

Fixed effect model (I2=0.0%, p=0.148) 1194/13,387 1211/13,485 0.99 (0.91,1.08)

Random effect model 1.00 (0.88,1.13)

Overall Effect

Fixed effect model (I2=0.0%, p=0.759)

2857/31,632 2839/31,777 1.01 (0.96,1.07)

Random effect model 1.01 (0.96,1.07)

Heterogeneity between groups p=0.555

Volpe M, et al. J Hypertension. 2009;27:941-946.

0.5 1.0 2.0

Odds Ratiofavors 1st listed favors 2nd listed

MI Risk With ACEIs and ARBs

42

Hypertension Summary

• In T2DM, blood pressure lowering has the greatest and most immediate effect on morbidity and morality

• The recommended BP target for patients with diabetes is 130/80 mm Hg

• Multiple agents are usually required to achieve target BP

• BP treatment must be continued for benefits to be maintained

• An ACE inhibitor or ARB should be included in the BP-control regimens of patients with diabetes because of beneficial effects on the renin-angiotensin system

43

Torre JJ, et al. Endocr Pract. 2006;12:193-222.


Chronic Kidney Disease

44

Reducing A1C Reduces Nephropathy Risk in T2DM

45

UKPDS ADVANCE ACCORD

A1C reduction (%)* 0.9 0.8 1.3

Nephropathy risk reduction (%)* 30 21 21

Newonset

microalbuminuria(P=0.033)

New orworsening

nephropathy(P=0.006)

Newmicroalbuminuria

(P=0.0005)

*Intensive vs standard glucose control.UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.Ismail-Beigi F, et al. Lancet. 2010;376:419-430.

Prevalence of CKD in Diagnosed Diabetes

*Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.ESRD, end-stage renal disease; GFR, glomerular filtration rate (mL/min/1.73 m2); NKF, National Kidney Foundation.

CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Plantinga LC, et al. Clin J Am Soc Nephrol. 2010;5:673-682.

NKF Stage

Description GFR

1Kidney damage* with normal or GFR

≥90

2Kidney damage* with mild GFR

60-89

3 Moderate GFR 30-59

4 Severe GFR 15-29

5Kidney failure or ESRD

<15 or dialysis

Diabetic Kidney Disease Is the Leading Cause of Kidney Failure in the United States

46

Cardiovascular Outcomes Worsen With CKD Progression

*23% of patients had diabetes.†P<0.001 vs GFR ≥75 by Cox model.

CHF, congestive heart failure; CV, cardiovascular.Anavekar NS, et al. N Engl J Med. 2004;351:1285-1295.

75

60-74

45-59

<45

eGFR (mL/min/1.73 m2)

47

Valsartan in Acute Myocardial Infarction Trial(N=14,527*)

†

†

†

†

†

†

CV Risk Increases With Comorbid Diabetes and CKD

CHF, congestive heart failure; AMI, acute myocardial infarction; CVA/TIA, cerebrovascular accident/transient ischemic attack; PVD, peripheral vascular disease; ASVD, atherosclerotic vascular disease.

*ASVD was defined as the first occurrence of AMI, CVA/TIA, or PVD.Foley RN, et al. J Am Soc Nephrol. 2005;16:489-495.

x 2.8

x 2.3

x 1.7x 2.1

x 2.0

x 2.5

48

Appropriate Staging and Management of CKD

CKD, chronic kidney disease.*Includes actions from preceding stages.

†Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.National Kidney Foundation. Am J Kidney Dis. 2002;49(suppl 1):S1-S266.

Stage Description GFR(mL/min/1.73 m2)

Action*

1Kidney damage† with normal or GFR ≥90

Diagnose and treat CKD, slow progression of CKD, treat comorbid conditions, reduce CVD risk factors

2Kidney damage† with mild GFR 60-89 Estimate progression

3 Moderate GFR 30-59 Evaluate and treat complications

4 Severe GFR 15-29 Prepare for kidney replacement therapy

5

Kidney failure <15 or dialysis

Kidney replacement, if uremia present

ESRD Renal replacement therapy

49

KDIGO CKD Classification by Relative Risk

50

Albuminuria stages (mg/g)

A1 A2 A3

Optimal and high

normalHigh

Very high and nephrotic

<10 10-29 30-299 300-1999 ≥2000

GFR stages(mL/min per 1.73 m2 body surface area)

G1High and optimal

≥105Very low Very low Low Moderate Very high

90-104

G2 Mild75-89

Very low Very low Low Moderate Very high60-74

G3aMild to moderate

45-59 Low Low Moderate High Very high

G3bModerate to severe

30-44 Moderate Moderate High High Very high

G4 Severe 15-29 High High High High Very high

G5Kidney failure

<15 Very high Very high Very high Very high Very high

Levey AS, et al. Kidney Int. 2011;80:17-28.

DKD Risk Factor Management

Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.

Risk Factor Goal Management Recommendation

Hyperglycemia

Individualized A1C goals

≤6.5% for most (AACE)

<7.0% (NKF)

Avoid biguanide in moderate to severe CKD

Consider need for dose reductions and/or risk of hypoglycemia and other renal-related AEs with other antidiabetic agents

Hypertension BP <130/80 mmHgUse ACE inhibitor or ARB in combination with other antihypertensive agents as needed

Proteinuria Use ACE inhibitor or ARB as directed

DyslipidemiaLDL-C <100 mg/dL,<70 mg/dL an option for high risk

Statin therapy recommended

Fibrate dose reduction may be required

51

Dietary Guidelines for DKD

CKD Stage

Macronutrient 1-2 1-4 3-4

Sodium, g/d <2.3

Total fat, % calories* <30

Saturated fat, % calories <10

Cholesterol, mg/day <200

Carbohydrate, % calories 50-60

Protein, g/kg/day (% calories) 0.8 (~10) 0.6-0.8 (~8–10)

Phosphorus 1.7 0.8-1.0

Potassium >4 2.4

*Adjust so total calories from protein, fat, and carbohydrate are 100%.

Emphasize such whole-food sources as fresh vegetables, whole grains, nuts, legumes, low-fat or nonfat dairy products, canola oil, olive oil, cold-water fish, and poultry.

Tailor dietary counseling to cultural food preferences.

Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.

52

Use of Noninsulin Antidiabetic Therapies in Patients With Kidney Disease

Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.

Class Agent(s) Kidney Disease Recommendation

Amylin analog Pramlintide No dosage adjustment

Thiazolidinediones Pioglitazone, rosiglitazone No dosage adjustment

Bile acid sequestrant Colesevelam No dosage adjustment

DPP-4 inhibitors Linagliptin, saxagliptin, sitagliptinReduce dosage for saxagliptin and

sitagliptin if CrCl <50 mg/dL

Dopamine-2 agonist Bromocriptine Use with caution

Glinides Nateglinide, repaglinideUse lowest effective dose of nateglinide

for stage ≥3 CKD

InsulinAspart, detemir, glargine, glulisine, lispro, NPH, regular

Dosage reduction needed instage 4-5 CKD

Sulfonylureas Glimepiride, glipizide, glyburideGlimepiride preferred, use lowest effective dose; avoid other SUs

GLP-1 receptor agonists Exenatide, exenatide XR, liraglutideUse with caution in stage 3 CKD;

avoid in stage 4-5 CKD

-Glucosidase inhibitors Acarbose, miglitolNot recommended if SCr >2 mg/dL;

avoid in dialysis

Biguanide MetforminContraindicated if SCr >1.5 in men or

1.4 in women

53


Cardiovascular Disease

54

Coincidence of CV Comorbidities in T2DM

55

NHANES 1999-2004(N=984)

5.0%

16.9%

7.4%

Hyperlipidemia(LDL-C ≥100 mg/dL,TC ≥200 mg/dL, orTG ≥150 mg/dL)

Obesity(BMI ≥30 kg/m2)

Hypertension(BP ≥140/90 mm Hg or taking antihypertensive medication)

5.9%

20.6%

17.7% 12.2%

Suh DC, et al. J Diabetes Complications. 2010;24:382-391.

Cardiovascular Disease Risk Factors

Major Additional Nontraditional

• Advancing age

• Features of dyslipidemia

• High total serum cholesterol level

• High non–HDL-C

• High LDL-C

• Low HDL-C

• Diabetes mellitus

• Hypertension

• Cigarette smoking

• Family history of CAD

• Obesity or abdominal obesity

• PCOS

• Family history of hyperlipidemia


• Small, dense LDL-C

• Increased Apo B

• Increased LDL particle number

• Fasting/postprandial hypertriglyceridemia

• Dyslipidemic triad*

• Elevated clotting factors

• Inflammation markers (hsCRP; Lp-PLA2)

• Hyperhomocysteinemia

• Elevated uric acid


• Apo E4 isoform

• Elevated lipoprotein (a)

*Hypertriglyceridemia; low HDL-C; and small, dense LDL-C.

56Apo, apolipoprotein; CAD, coronary artery disease; HDL-C, high-density lipoprotein cholesterol;

hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol;Lp-PLA2, lipoprotein-associated phospholipase A2; PCOS, polycystic ovary syndrome.


Coronary Artery Disease Risk Categories

Risk Category Risk Determinant

Very high Established or recent hospitalization for coronary, carotid, and peripheral vascular disease

– or –Diabetes plus 1 or more additional risk factor(s)

High ≥2 risk factors and 10-year risk* >20%– or –

CHD risk equivalent• Diabetes ± other risk factors• Noncoronary atherosclerotic disease

• Peripheral arterial disease• Abdominal aortic aneurysm• Carotid artery disease

Moderately high ≥2 risk factors and 10-year risk 10% to 20%

Moderate ≥2 risk factors and 10-year risk <10%

Low ≤1 risk factor

*Framingham Risk Score57

CHD, coronary heart disease.Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78.

Diabetes Is a Cardiovascular Disease Risk Equivalent

7-Y

ear

Inci

den

ce o

f M

I (%

)

Diabetic(n=1059)

Prior MINo prior MIPrior MINo prior MI

Nondiabetic(n=1373)

MI, myocardial infarction.Grundy SM, et al. Circulation. 2004;110:227-239.

Haffner SM, et al. N Engl J Med. 1998;339:229-234.

58

P<0.001

P<0.001

CVD Risk Factors:AACE Targets

Risk Factor Recommended Goal

Anticoagulant therapy Use aspirin for primary and secondary prevention of CVD events

Weight Reduce by 5% to 10%; avoid weight gain

Lipids

Total cholesterol, mg/dL <200

LDL-C, mg/dL <70 very high risk; <100 all other risk categories

Non-HDL-C, mg/dL 30 above LDL-C goal

ApoB, mg/dL <80 very high risk; <90 high risk

HDL-C, mg/dL ≥40 in both men and women

Triglycerides, mg/dL <150

Blood pressure

Systolic, mm Hg <130

Diastolic, mm Hg <80

59Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.



Depression

60

Prevalence of Comorbid Depression and Diabetes

61

Major Depressive

Disorder

Likely Depression

% P

op

ula

tio

n

Diagnostic Interview

Self-report Scale

1.9 OR 2.1

P=0.5

% P

op

ula

tio

n

Diverse, Community Sample Meta-analysis

Fisher L, et al. Diabetes Care. 2007;30:542-548; Anderson RJ, et al. Diabetes Care. 2001;24:1069-1078

Depression and Adherence to Diabetes Self-management

Generaldiet

Foot care

P<0.001

Carbo-hydrates

Exercise Glucose monitoring

Fruitsand

vegetables

High fat foods

P<0.001

P<0.001

P=0.001P=0.006

P=0.241

P=0.348

Mea

n A

dh

eren

t D

ays/

Wee

k

HANDS, Harvard Department of Psychiatry/National Depression Screening Day Scale.Gonzales JS, et al. Diabetes Care. 2007;30:2222-2227.

2.3-Fold increased risk of missing 1 or more prescribed medications over previous week with major depression

(HANDS score <9) (HANDS score ≥9)

62

Mental Health Referral for Patients With Diabetes

• Establish emotional well-being as a part of diabetes management

• Include psychological assessment and treatment in routine care– Do not wait for deterioration in psychological status– Utilize patient-provider relationship as a foundation for psychological

management

• Indications for referral– Gross noncompliance with medical regimen– Depression with the possibility of self-harm– Debilitating anxiety (alone or with depression)– Eating disorder– Cognitive functioning that significantly impairs judgment

• Always refer to mental health specialist familiar with diabetes management

Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. ADA. Diabetes Care. 2012;34(suppl 1):S11-S61.

63


Sleep Apnea

64

Obstructive• Caused by relaxation of

muscles supporting palate• Risk factors

– Obesity– Hypertension– Male gender– Neck circumference >44 cm– Narrowed airway– Age– Family history– Alcohol, sedative use– Smoking

Central• Caused by neural signaling

failure between brain and muscles surrounding lungs

• Risk factors– CHF– Atrial fibrillation– Cerebrovascular disease– Brain tumor

Sleep Apnea

65 Epstein LJ, et al. J Clin Sleep Med. 2009;5:263-276.

NHLBI Working Group on Sleep Apnea. Am Fam Physician. 1996;53:247-253.

Obstructive Sleep Apnea and Insulin Resistance

66

Vgontzas AN, et al. J Intern Med. 2003;254:32-44 .

Visceral fatInsulin resistance

Inflammatory cytokines

EDS fatigueSleep apnea

Sleep fragmentationSleep debt

Stress hormonesInterleukin-6

Depression of ventilation

Diaphragm mobility

Soft tissue edema

Prevalence of Sleep Apneain T2DM

67OSA, obstructive sleep apnea.

Foster GD, et al. Diabetes Care. 2009;32:1017-1019.

Sleep AHEAD StudyObese Patients With T2DM

(N=305)

Obstructive Sleep Apnea• Continuous positive airway pressure

(CPAP)• Adjustable airway pressure devices• Oral appliances• Surgery

– Uvulopalatopharyngoplasty (UPPP)– Maxillomandibular advancement– Tracheostomy

Central and Mixed Sleep Apnea• Optimize therapy for associated

conditions• Supplemental oxygen• CPAP• Bilevel positive airway pressure (BiPAP)• Adaptive servo-ventilation (ASV)

Treatment for Sleep Apnea

68Aurora RN, et al. Sleep. 2012;35:17-40.

Epstein LJ, et al. J Clin Sleep Med. 2009;5:263-276.


Cancer

69

• Diabetes (especially T2DM) may:– ↑ Cancer risk

• Liver• Pancreas• Endometrium• Colon and rectum• Breast• Bladder

– ↓ Cancer risk: prostate

• Hyperinsulinemia, hyperglycemia, and inflammation may directly increase cancer risk

• Shared risk factors– Aging– Obesity– Diet– Physical inactivity

Diabetes and Cancer Risk

70

Giovannucci E, et al. Diabetes Care. 2010;33:1674-1685.

Insulin and Cancer Risk

71Gerstein HC, et al. N Engl J Med. 2012;367:319-328. Kirkman MS, et al. Presented at the American Diabetes

Association 72nd Scientific Sessions. June 11, 2012. Session CT-SY13. Philadelphia, PA.

Study Hazard Ratio (95% CI)

Outcome Reduction With an Initial Glargine Intervention (ORIGIN)N=12,537; prospective RCTMedian follow-up: 6.2 years

Any cancer: 1.00 (0.88-1.13); P=0.97Death from cancer: 0.94 (0.77-1.15); P=0.52

Northern European Database StudyN=447,821; observationalMean follow-up:

Glargine users: 3.1 yearsOther insulin users: 3.5 years

Breast cancer (women): 1.12 (0.99-1.27)Prostate cancer (men): 1.11 (1.00-1.24)Colorectal cancer (men and women): 0.86 (0.76-0.98)

Kaiser-Permanente CollaborationN=115,000; observationalMedian follow-up:

Glargine users: 1.2 yearsNPH users: 1.4 years

Breast cancer (women): 1.0 (0.9-1.3)Prostate cancer (men): 0.7 (0.6-0.9)Colorectal cancer (men and women): 1.00 (0.8-1.2)All cancers (men and women): 0.9 (0.9-1.0)

MedAssurant Database StudyN=52,453; observationalMean follow-up:

Glargine users: 1.2 yearsNPH users: 1.1 years

No increased risk for breast cancer

Diabetes and Cancer Risk Management

• Conduct cancer screenings as recommended for age and sex

• Encourage healthful diet, physical activity, and weight management

• Evidence is inconclusive on effects of specific drugs on cancer risk due to limited data and confounding factors

• Cancer risk should not be a major factor in the choice of antidiabetic agent unless the patient has a very high risk of cancer occurrence or recurrence

72

Giovannucci E, et al. Diabetes Care. 2010;33:1674-1685.

management of common comorbidities in diabetes

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