john b. buse, md, phd professor of medicine chief, division of endocrinology director, diabetes care...
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John B. Buse, MD, PhDProfessor of Medicine
Chief, Division of EndocrinologyDirector, Diabetes Care Center
University of North CarolinaChapel Hill, NC
Diabetes Management
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CVD and Glycemia
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*If A1C remains above the desired target, postprandial levels, usually measured 90–120 min after a meal, may be checked. They should be <180 mg/dl to achieve A1C levels in the target range.
†An A1C of ≥7% should serve as a call to action to initiate or change therapy with the goal of achieving an A1C level as close to the nondiabetic range as possible or, at a minimum, decreasing the A1C to 7%.
Diabetes Care 30: S4-41, 2007 (http://care.diabetesjournals.org/cgi/reprint/30/suppl_1/S4)http://www.aace.com/pub/press/releases/diabetesconsensuswhitepaper.php
Goal
Premeal plasma glucose (mg/dl)
2-h postprandial plasma glucose
HbA1c
ADA
70-130
(<180)*
<7%†
ACE
<110
<140
<6.5%
Glycemic Goals of Therapy
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Recent Glycemia CVD StudiesCharacteristic ACCORD ADVANCE VADT
N 10,251 11,140 1,791
Mean age 62 66 60
Hx CVD 35% 32% 40%
BMI 32.2 28 31.3
BL mean A1C 8.3% 7.5% 9.4%
BL meds 34% Ins/1.4 OAD 1% Ins/1.5 OAD 51% Ins/??
Statin use 62% 88% 28% 47% 58% 84%
Antiplatelet use 54.5% 75.5% 48% 62% 76% 93%
Study duration 3.4 5.0 6.0
Target A1C <6% vs 7-8% <6.5% vs “Usual” <6% vs 8-9%
Achieved mean A1C 6.5% and 7.5% 6.3% and 7.0% 6.9% and 8.4%
LDL at end 91 102 75
BP at end 127 / 67 136 / 74 127 / 69
Smokers at end 9.9% 8% 17%
Skyler J, et al. Diabetes Care. 2009; 32:187-92.
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*P=0.04
Summary: Glucose Lowering on CVD in Type 2 Diabetes
VADT ACCORD ADVANCE
Primary outcome
Non-fatal MINon-fatal stroke
CVD deathHospitalization for CHF
Revascularization
Non-fatal MINon-fatal stroke
CVD death
Non-fatal MINon-fatal stroke
CVD death
Hazard Ratio forprimary outcome
(95% CI)0.87 (0.73 – 1.04) 0.90 (0.78 – 1.04) 0.94 (0.84 – 1.06)
Hazard Ratio for mortality (95% CI)
1.07 (0.80 – 1.42) 1.22 (1.01 – 1.46)* 0.93 (0.83 – 1.06)
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ACCORD Treatment Effect onPrimary Outcome
2525
00
2020
1515
1010
55
0011 22 33 44 55
Standard therapyStandard therapy
Intensive therapyIntensive therapy
Pat
ien
ts w
ith
eve
nts
%
Pat
ien
ts w
ith
eve
nts
%
Time (yrs)Time (yrs)
HR=0.90 (0.78-HR=0.90 (0.78-1.04), P=0.161.04), P=0.16
2.29%/yr2.29%/yr2.11%/yr2.11%/yr
ACCORD Study Group ACCORD Study Group N Engl J Med N Engl J Med 358:2545-59; 2008358:2545-59; 2008
66
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Protocol Defined N Events Interaction P-value Subgroups Overall 10251 723
Primary Prevention 6643 330 0.04 Secondary Prevention 3608 393
Women 3952 212 0.74 Men 6299 511
Baseline Age<65 6779 383 0.65 Baseline Age≥65 3472 340
Baseline A1C≤8.0 4868 284 0.03 Baseline A1C>8.0 5360 438 Non-White 3647 222 0.29 White 6604 501
ACCORD: Hazard Ratios for Primary Outcome by Subgroup
0.6 1.0 1.4HR (Intensive vs. Standard)
ACCORD Study Group ACCORD Study Group N Engl J Med N Engl J Med 358:2545-59;2008.358:2545-59;2008.
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A1C
(%
)
YearDCCT
11
10
9
8
7
6
091 2 3 4 5 6 7 8 1 2 3 4 5 6 7DCC
T end EDIC
Conventional group encouraged to switch to intensive treatment
Adapted from: N Engl J Med 329:977–86,1993; EDIC: JAMA 287: 2563–9;2002
A1C During DCCT and Follow-Up
Intensive
Conventional
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Cumulative Incidence of the First of Any Predefined CVD Outcomes
Years since entry
Cumulative Cumulative incidence incidence
of any CVD of any CVD outcomeoutcome
Conventional treatment
Intensive treatment
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Risk reduction 42%, CI - 9,63
Log-rank p = 0.016
nonfatal MI, stoke, death from cardiovascular disease, confirmed angina, or the need for coronary-artery revascularization
Fatal MI, CVA, or CVD death ↓57%DCCT/EDIC Study Research Group, N Engl J Med 2005; 353:2643-53.
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After median 8.8 years post-trial follow-up
Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040
Microvascular disease RRR: 25% 24% P: 0.009 0.001
Myocardial infarction RRR: 16% 15% P: 0.052 0.014
All-cause mortality RRR: 6% 13% P: 0.44 0.007
UKPDS: “Legacy Effect”of Insulin/Sulfonylurea Therapy
RRR = Relative Risk Reduction P = Log Rank
Holman RR, et al. New England Journal of Medicine 2008; 359:1577-1589
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6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
TIME (yrs since diagnosis)
A1C (%)
Drive the risk for complications
Drive the risk for complications
Build up “bad” metabolic memory
Build up “bad” metabolic memory
The “Natural History” of Type 2 Diabetes
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• Lowering A1C to below or around 7% has been shown
to reduce microvascular and neuropathic complications
of type 1 and type 2 diabetes. Therefore, for
microvascular disease prevention, the A1C goal for non-
pregnant adults in general is <7%. (A)
ADA – AHA – ACCRevised Glycemic Control Recommendations
ADA/AHA/ACC. Diabetes Care. 2009; 32:187-92.
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ADA – AHA – ACCRevised Glycemic Control Recommendations
• In type 1 and type 2 diabetes, randomized controlled trials of intensive vs. standard glycemic control have not shown a significant reduction in CVD outcomes during the randomized portion of the trials. Long-term follow-up of the DCCT and UKPDS cohorts suggests that treatment to A1C targets below or around 7% in the years soon after the diagnosis of diabetes is associated with long-term reduction in risk of macrovascular disease. Until more evidence becomes available, the general goal of <7% appears reasonable for many adults for macrovascular risk reduction. (B)
ADA/AHA/ACC. Diabetes Care. 2009; 32:187-92.
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• Subgroup analyses of clinical trials such as the DCCT and UKPDS, and the microvascular evidence from the ADVANCE trial, suggest a small but incremental benefit in microvascular outcomes with A1C values closer to normal. Therefore, for selected individual patients, providers might reasonably suggest even lower A1C goals than the general goal of <7%, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Such patients might include those with short duration of diabetes, long life expectancy, and no significant cardiovascular disease. (B)
ADA – AHA – ACCRevised Glycemic Control Recommendations
ADA/AHA/ACC. Diabetes Care. 2009; 32:187-92.
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• Conversely, less stringent A1C goals than the general goal of <7% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose lowering agents including insulin. (C)
ADA – AHA – ACCRevised Glycemic Control Recommendations
ADA/AHA/ACC. Diabetes Care. 2009; 32:187-92.
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Risk of Death over a Range of Average A1c
Average A1c %
Adjusted log(Hazard Ratio) by Treatment StrategyRelative to Standard at A1c of 6%
Standard strategy
6 8 97
Steady increase of risk from 6 to 9% A1c with intensive strategy
Excess risk with intensive strategy vs standard occurred above A1c 7%
Intensive strategy
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Rates of Death During 3.4 Years of Treatmentover a Range of 1-year Change of A1c
A1c decline from baseline over 12 months (%)0.0 0.5 1.0 1.5 2.0
Intensive strategy
Standard strategy
Dea
th r
ates
per
yea
r
Excess risk with intensive strategy vs standard occurredwhen intensive participants failed to reduce A1c in year 1
Adjusted Mortality Rates by Treatment Strategy
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The Algorithm
Screen, Diagnose, Treat
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Screening Triggers for Prediabetes and Type 2 Diabetes
Preferred screening test is a venous FPG Screen all individuals aged ≥ 45 years; if normal, repeat at 3-year intervals Consider earlier and more frequent screening in individuals who are
overweight (BMI ≥ 25 kg/m2) with additional risk factors:– Habitual physical inactivity
– First-degree relative with diabetes
– Members of a high-risk ethnic population (eg, African American, Latino, Native American, Asian American, Pacific Islander)
– History of delivering a baby weighing > 9 lbs and/or GDM
– Hypertension (≥ 140/90 mm Hg)
– HDL-C < 35 mg/dL and/or triglyceride level > 250 mg/dL
– Polycystic ovarian syndrome
– History of IGT or IFG
– Other conditions associated with insulin resistance (eg, acanthosis nigricans)
– History of vascular disease
American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12-S54.
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ADA and WHO Glucose Tolerance Categories
Fasting PlasmaGlucose
Normal
2-hr Plasma Glucose on OGTT
Diabetes Mellitus
* Diagnosis of DM can also be made based on unequivocal symptoms and a random glucose >200 mg/dL. Any abnormality should be repeated and confirmed on a separate day.
“Pre-Diabetes”100
mg/dL
Impaired Fasting
Glucose (IFG)
Normal
Diabetes Mellitus
Impaired Glucose
Tolerance (IGT)
126 mg/dL
200 mg/dL
140 mg/dL
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Glucose is NOT a Standardized Analyte CAP survey for glucose “120-170 mg/dL”, mean 144 mg/dl*
– In order for an institution to be considered “proficient”, results should deviate by no more than 12 mg/dL or 20% from the peer group
– Inter-laboratory CV is 15.1%- Variability in part due to differences between instruments- CVs for individual instruments range from 3.9-10.9%
– Bottom line, depending on the type of device used, the mean glucose measurement for a particular sample reported by CAP certifiable institutions varies across an approximately 30% range
– In comparison, this is ~5% for many other analytes
*Dungan K, et al. Diabetes Care 30: 403-409, 2007.
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NGSP Standardizationof the HbA1c Assay
7.0
8.0
9.0
10.0
11.0
12.0
13.0
14.0
15.0
16.0
17.0
18.0
19.0
20.0
21.0
%G
HB
1993 2007
Total GHB
HbA1
HbA1c
CAP Survey: Mean +/- 2sd
DCCTTarget
20011999
NGSPCertified
Not Certified
NGSP Certified
Not Certified
NGSP Certified Not Certified
©2007 David M. Nathan
CAP = College of American Pathologists
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HbA1c assay to be standardized worldwide using the new IFCC standard and expressed as:
Consensus StatementIFCC, EASD, IDF, ADA
All clinical guidelines should be expressed in these units
• % as currently used (DCCT values)
• IFCC units in mmol/mol
• eAG (estimated average glucose) in mg/dL
Diabetes Care 30:2399-2400, 2007
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ADA Expert Committee, 1997
ADA Expert Committee on Diagnosis, 1997Relation of FPG, 2hPG, HbA1c to Retinopathy: Egypt
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The HbA1c assay is standardized and aligned to DCCT/UKPDS
Better index of overall glycemic exposure
Equivalent in predicting risk for long-term complications
Predicts CVD
Substantially less laboratory variability
Substantially less pre-analytic instability
No need for fasting or timed samples
Unaffected by acute (e.g. stress or illness-related) perturbations in glucose levels
Used to guide management and adjust therapy
HbA1c Advantages Compared with FPG, OGTT
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Laboratory
► Expense
► Not universally available
Patient-related: determinants in addition to glycemia
► Hemoglobinopathies
► Variation in red cell lifespan (hemolysis, blood loss, etc.)
► Unexplained racial differences
Not useful as acute measure
Selecting a diagnostic cut point
► On what basis?
► Will not always agree with diagnoses by FPG or OGTT
► Break with the past
HbA1c: Limitations
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2-hr PG (n=237)10%
HbA1c (n=182)7%
FPG (n=165)7%
73
221
1837
17
125
None = 2142Any = 293 (12%)Total = 2435
Numbers of people with HbA1c ≥ 6.5%, FPG ≥ 126 mg/dl, or 2hPG ≥ 200 mg/dl.
2435 adult Pima Indians without previous dx.
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Study Subjects InterventionRelative Risk
Reduction
DaQingFinnish DPSUS DPP
IGTIGT
IGT + “IFG”
Diet or Exercise or BothLifestyleLifestyle
64%/53%/61%IGTIGT
US DPPSTOP-NIDDMEDITTRIPODXENDOSDREAMACT-NOWORIGINNAVIGATOR
IGT + “IFG”IGTIFG
Prior GDMIGTIGTIGT
IFG or IGTIGT+IFG
MetforminAcarbose
Metformin or Acarbose or BothTroglitazone
OrlistatRosiglitazone or Ramipril or Both
PioglitazoneGlargine or Fish oil or Both
Nateglinide or Valsartan or Both
31%25%NS
35%45%
61%/NS81%
~2010 ~2009
Prevention of Type 2 DiabetesB
ehav
ior
Med
icat
ion
Li et al., Lancet 2008;371:1783-1789. ADA Position Statement on the Prevention or Delay of Type 2 Diabetes. Diabetes Care. 2002;25:742-749. Torgerson JS, et al. Diabetes Care. 2004;27:155-161. DREAM Trial Investigators. Lancet. 2006;368:1096-1105. DREAM Trial Investigators. N Engl J Med. 2006;355:1551-1562. DeFronzo RA, et al. ADA 68th Scientific Sessions 2008. Origin Trial Investigators. Am Heart J 2008;155:26-32.
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Lifestyle therapy can be very effective in preventing or delaying diabetes
The lifestyle therapy that works involves three core features– Balanced low-calorie nutrition:
- low fat, high in fiber (vegetables, fruits, whole grains)– Regular physical activity:
- aerobic and resistance, 30+ minutes most days of the week– Frequent intervention with dietitians and lifestyle coaches:
- ~weekly for first month- ~monthly for the first three months- ~every three months for life
Prevention Of Type 2 Diabetes: Completed Lifestyle Trials In IGT
Key Points
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Study Subjects InterventionRelative Risk
Reduction
DaQingFinnish DPSUS DPP
IGTIGT
IGT + “IFG”
Diet or Exercise or BothLifestyleLifestyle
64%/53%/61%IGTIGT
US DPPSTOP-NIDDMEDITTRIPODXENDOSDREAMACT-NOWORIGINNAVIGATOR
IGT + “IFG”IGTIFG
Prior GDMIGTIGTIGT
IFG or IGTIGT+IFG
MetforminAcarbose
Metformin or Acarbose or BothTroglitazone
OrlistatRosiglitazone or Ramipril or Both
PioglitazoneGlargine or Fish oil or Both
Nateglinide or Valsartan or Both
31%25%NS
35%45%
61%/NS81%
~2010 ~2009
Prevention of Type 2 DiabetesB
ehav
ior
Med
icat
ion
Li et al., Lancet 2008;371:1783-1789. ADA Position Statement on the Prevention or Delay of Type 2 Diabetes. Diabetes Care. 2002;25:742-749. Torgerson JS, et al. Diabetes Care. 2004;27:155-161. DREAM Trial Investigators. Lancet. 2006;368:1096-1105. DREAM Trial Investigators. N Engl J Med. 2006;355:1551-1562. DeFronzo RA, et al. ADA 68th Scientific Sessions 2008. Origin Trial Investigators. Am Heart J 2008;155:26-32.
NO
T F
DA
AP
PR
OV
ED
FO
R P
RE
VE
NT
ION
NO
T F
DA
AP
PR
OV
ED
FO
R P
RE
VE
NT
ION
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Screening and Diagnosis: Intervention and Follow-Up
Screen for Diabetes:FPGor
2-hour, 75-g OGTT
American Diabetes Association. Diabetes Care. 2009;32(suppl 1):S13-S61.
Normal
Re-evaluate in ≤3 years if risk factors remain
Diabetes
Lifestyle intervention plus metformin; follow-up† @ 3 mo.
• Diabetes: fasting ≥126 mg/dl or 2-hour ≥200 mg/dl; should be confirmed on a separate day unless unequivocally elevated and/or symptomatic
IFG and IGT + Other Features*
Lifestyle intervention and/or metformin; follow-up† @ 6 mo.
* “Other features”: < 60 years of age and BMI ≥ 30 kg/m2 and either A1C > 6.0%, hypertension, low HDL, high triglycerides or family history of diabetes in first-degree relative
• IFG: fasting (8 hours) plasma glucose 100-125 mg/dL• IGT: 2-hour value in 75-g OGTT 140-199 mg/dL
Lifestyle intervention;follow-up† @ 1 year
IFG or IGT
† Follow-up here refers to formal reassesment of glycemic status. Follow-up should be individualized with respect to venue, frequency and goals.
METFORMIN IS NOT FDA APPROVED FOR PREVENTION
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Updated ADA/EASD Consensus Algorithm
Nathan DM, et al., Diabetes Care 2008;31:1-11.
At Diagnosis:Lifestyle
+Metformin Lifestyle + Metformin
+Sulfonylureaa
Lifestyle + Metformin+
Basal Insulin
Lifestyle + Metformin+
Intensive Insulin
Lifestyle + Metformin+
Pioglitazone
Lifestyle + Metformin+
GLP-1 agonistb
Lifestyle + Metformin+
Basal Insulin
Lifestyle + Metformin+
Pioglitazone+
Sulfonylureaa
STEP 1 STEP 2 STEP 3
Tier 2: Less well-validated therapies
Tier 1: Well-validated therapies
Reinforce lifestyle interventions at every visit and check A1C every three months until A1C < 7.0 %, then at least every 6 months thereafter. Change interventions whenever A1C ≥ 7.0 %. aSulfonylureas other than glybenclamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety.
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0.75 1.25 1.5 1.751.0
1.4 FDA: all ischemic events, no CI given
Hazard Ratio
1.43 Nissen meta-analysis: MI
1.64Nissen meta-analysis: CV death
1.31 GSK analysis:CV death, MI, stroke
1.16RECORD: MI
Psaty/Furberg (RECORD, ADOPT, DREAM, all small trials): MI 1.33
FDA: CV death, MI, stroke1.2
FDA-PIO meta-analysis0.75
PROactive 2°0.84
0.83
FDA-PIO meta-analysis + PROactive
Adapted from: Lincoff AM, et al. JAMA. 2007;298:1180-1188; Singh S, et al. JAMA. 2007;298:1189-1195.
PROactive 1° 0.90
Hazard Ratio for Cardiovascular Events Rosiglitazone vs Pioglitazone
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Kahn SE, et al. Diabetes Care. 2008;31:845-851.
Fractures in Women Treated With Glitazones
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ClassA1C
ReductionFastingvs PPG
Hypo-glycemia
WeightChange
Dosing(times/day)
OutcomeStudies
Metformin 1.5 Fasting No Neutral 2 UKPDS
Insulin, long acting 1.5 - 2.5 Fasting Yes Gain 1, Injected DIGAMI, UKPDS, (DCCT)
Insulin, rapid acting 1.5 - 2.5 PPG Yes Gain 1-4, Injected DIGAMI, UKPDS, (DCCT)
Sulfonylureas 1.5 Fasting Yes Gain 1 UKPDS
Thiazolidinediones 0.5 - 1.4 Fasting No Gain 1 PROactive, RECORD
GLP-1 agonists 0.5 - 1.0 PPG No Loss 2, Injected None
Repaglinide 1 - 1.5 Both Yes Gain 3 None
Nateglinide 0.5 - 0.8 PPG Rare Gain 3 NAVIGATOR Pending
α-Glucosidase inhibitor 0.5 - 0.8 PPG No Neutral 3 ACE pending
Amylin mimetics 0.5 - 1.0 PPG No Loss 3, Injected None
DPP-4 inhibitors 0.6 - 0.8 Both No Neutral 1 TECOS pending
Bile acid sequestrant 0.5 Fasting No Neutral 1-2 None
Bromocriptine 0.7 PPG No Neutral 1 None
Adapted from: Nathan DM, et al. Diabetes Care. 2007;30:753-759. Nathan DM, et al. Diabetes Care. 2006;29:1963-1972. Nathan DM, et al. Diabetes Care. 2009;32:193-203. ADA. Diabetes Care. 2008;31:S12-S54. WelChol PI. 1/2008. Cycloset PI. 5/2009.
13 Classes of Antihyperglycemic Agents Available for Treatment of Type 2 Diabetes
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Suggested Treatment Goals in Patients with CMR and Lipoprotein Abnormalities
Goals
LDL cholesterol
Non-HDL cholesterol ApoB
(mg/dl)
Highest-risk patients, including those with 1) known CVD or 2) diabetes plus one or more additional major CVD risk factor
<70 <100 <80
High-risk patients, including those with 1) no diabetes or known clinical CVD but two or more additional major CVD risk factors or 2) diabetes but no other major CVD risk factors
<100 <130 <90
Other major risk factors (beyond dyslipoproteinemia) include smoking, hypertension, and family history of premature CAD.
Brunzell JD, et al. Diabetes Care 31:811-822, 2008
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Effectiveness of Aspirin in Diabetes
PatientsExperiencing
CardiovascularEvents
(%)
* * Physician’s Health Study, NEJM 1989† Antiplatelet Trialists’ Collaboration, BMJ 1994‡ Early Treatment Diabetes Retinopathy Study, JAMA 1992
25
20
15
10
5
0
10%
Placebo ASA
4%
22%
Placebo ASA
18%
Placebo
12%
ASA
9%
US MDs* APT† ETDRS‡
RR .39p = ns
RR .81p < 0.002
RR .83p = 0.004
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Improvement In Key Clinical Measures
% of Adult Patients with% of Adult Patients with
26.7
51.6
56.4
33.8
15.8
44.1
10.9
55.1
7.5
45.3
74.1
64.1
61.2
83.8
75.4
0 20 40 60 80 100
LDL Control (<100 mg dl)
LDL Control (<130 mg dl)
BP Control (< 140/90 mm Hg)
Good A1C Control (<7.0%)
Poor A1C Control* (>9.0%)
1999 2002 2005
``
* Lower is better for this measure.* Lower is better for this measure.
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Gaede P. Gaede P. N Engl J MedN Engl J Med 2008; 2008; 358: 580-591
STENO -2 Multi-Risk Factor Intervention in Type 2 DM
STENO -2 Multi-Risk Factor Intervention in Type 2 DM
Intensive group end results: A1C 7.7%, BP 140/74, LDL 71 mg/dL, HDL 51 mg/dl, TG 99 mg/dL, aspirin 85%
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Room for Improvement in Therapy Implementation and Change
A1C (%) BP (mm Hg) LDL (mg/dL)
>8 >9 >130 >160>140/90 >150/100
<50% of Patients With A1C Above Goal had Their Medication Changed
Even Lower Percentage of Patients Whose CV Goals Were not Met had Medication Started
% of Patients
N=1765 Patients With Diabetes
*P<.05 for A1C and LDL (P values are derived from Mantel-Haenszel test for trend).Grant RW, et al. Diabetes Care. 2005;28:337-442.
Rates of Medical Regimen Change in 30 US Academic Medical Centers
>7 >1000
10
20
30
40
50
60
70
80
90
100
>130/80