Hyperglycemia in Type 2 Diabetes Results From Three Major Metabolic Defects
Relationship Between Obesity and Insulin Resistance and Dyslipidemia
Insulin Resistance: Associated Conditions
New Cases of ESRD in the United States
New Cases of ESRD in the United States by Cause and Ethnicity, 1998
Cardiovascular Disease and Diabetes
Probability of Death From CHD in Patients With Type 2 Diabetes With or Without Previous MI
The Metabolic Syndrome Insulin Resistance Hypertension Type 2 Diabetes Disordered Fibrinolysis Complex Dyslipidemia TG, LDL HDL Endothelial Dysfunction Systemic Inflammation Athero- sclerosis Visceral Obesity Adapted from the ADA. Diabetes Care. 1998;21:310-314; Pradhan AD et al. JAMA. 2001;286:327-334.
Revised ATP III Metabolic Syndrome Oct 2005 *Diagnosis is established when 3 of these risk factors are present. † Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. ‡ Some men develop metabolic risk factors when circumference is only marginally increased. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486-2497; Updated AHA/NHLBI Statement Oct 18, 2005: Grundy et al. Circulation 2005; 112 (epub). <40 mg/dL <50 mg/dL or Rx for ↓ HDL Men Women > 102 cm (>40 in) > 88 cm (>35 in) Men Women 100 mg/dL or Rx for ↑ glucose Fasting glucose 130/ 85 mm Hg or on HTN Rx Blood pressure HDL-C 150 mg/dL or Rx for ↑ TG TG Abdominal obesity † (Waist circumference ‡ ) Defining Level Risk Factor
International Diabetes Federation Definition: Abdominal obesity plus two other components: elevated BP, low HDL, elevated TG, or impaired fasting glucose
Prevalence of the Metabolic Syndrome Among US Adults NHANES 1988-1994 Age (years) Ford E et al. JAMA . 2002(287):356. 1999-2002 Prevalence by IDF vs. NCEP Definitions (Ford ES, Diabetes Care 2005; 28: 2745-9) (unadjusted, age 20+) NCEP : 33.7% in men and 35.4% in women IDF: 39.9% in men and 38.1% in women Prevalence (%) 0 5 10 15 20 25 30 35 40 45 20-29 30-39 40-49 50-59 60-69 > 70 Men Women
Prevalence of the NCEP Metabolic Syndrome: NHANES III by Sex and Race/Ethnicity Prevalence, % Men Ford ES et al. JAMA 2002;287:356-359. Women 25% 16% 28% 21% 23% 26% 36% 20% White African American Mexican American Other
Cardiovascular Disease (CVD) and Total Mortality: US Men and Women Ages 30-74 (age, gender, and risk-factor adjusted Cox regression) NHANES II Follow-Up (n=6255)(Malik and Wong, et al., Circulation 2004; 110: 1245-1250 ) * p<.05, ** p<.01, **** p<.0001 compared to none * *** *** *** ** *** *** *** *** *** ***
Metabolic Syndrome, CVD Events, and Mortality
European cohort studies (6156 men and 5356 women): Modified WHO definition of MetS associated with all-cause mortality (RR=1.44 [1.17-1.84] in men and 1.38 [1.02-1.87] in women) and CVD mortality (RR=2.26 [1.61-3.17] in men and 2.78 [1.57-4.94 in women) (Hu et al. Arch Intern Med 2004; 164: 1066-76)
Atherosclerosis Risk in Communities (ARIC) study (12,089 men and women): 11 year follow-up, ATP III MetS associated with 1.5-2-fold greater likelihood of developing CHD and stroke, but MetS did not improve prediction over FRS (McNeill et al. Diab Care 2005; 28: 385-90)
Cardiovascular Health Study (CHS) (2,175 elderly subjects): ATP III definition associated with 38% increased risk (p<0.01) of coronary/cerebrovascular events (Scuteri et al., Diab Care 2005; 28: 882-7)
Evidence Supporting Aggressive Glycemic Control
Treatment of Type 2 Diabetes
Sites of Action of Therapeutic Options for Type 2 Diabetes
DCCT: Effects of Intensive vs Conventional Glycemic Control
UKPDS: Effects of Intensive (Sulfonylurea/Insulin) Treatment
UKPDS: Effects of Intensive (Metformin) Treatment*
UKPDS: Effects of Glycemia Exposure Over Time
UKPDS: Risk Reduction in Diabetes- Related Complications (A 1c )
D iabetes P revention P rogram: Protocol Design
D iabetes P revention P rogram: Reduction in Diabetes Incidence
Thiazolidinediones: Rationale for Type 2 Diabetes Therapy
Change in Lipid Profile at Endpoint: ACTOS 26-Week Monotherapy
DREAM Study for Prevention of Diabetes
5,269 persons with pre-diabetes randomized to rosiglitazone (8 mg daily) vs. placebo and ramipril vs. placebo for median of 3 years
10.6% of those on rosiglitazone progressed to type 2 diabetes vs. 25% on placebo, a 62% risk reduction (p<0.0001).
Primary endpoint of development of diabetes or death from any cause reduced by 60%
51% of those on rosiglitazone vs. 30% on placebo returned to normal blood sugar
No significant difference in future cardiovascular events, but higher rate of new heart failure in those on rosiglitazone (0.5%) vs. placebo (0.1%). Body weight increased 2.2kg more in the rosiglitazone vs. placebo group.
The DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-105.
PROACTIVE Study: Secondary Prevention of Macrovascular Events in Persons with Diabetes from Pioglitazone
5238 patients with type 2 diabetes who had evidence of macrovascular disease assigned to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), taken w/existing drugs.
Primary endpoint: combined all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle.
Over an average of 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group achieved the primary endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095).
Lancet 2005; 366: 1279-89
Collaborative Atorvastatin Diabetes Study (CARDS)
2838 patients aged 40-75 with type 2 diabetes, no prior CVD, but at least 1 of the following: retinopathy, albuminuria, smoking, or hypertension
Randomization to 10 mg atorvastatin or placebo
Mean follow-up 3.9 years
Reduction in all CVD events of 37% (p=0.001), all cause mortality 27% (p=0.059). CHD events reduced 36% and stroke 48%.
Colhoun HM et al., The Lancet 2004; 364: 685-696
Relative Risk of Events in 4S Study Adapted from Haffner et al. Arch Intern Med . 1999;159:2661. NFG IFG DM NFG IFG DM NFG IFG DM Patients (%) CAD Events Revascularization Total Mortality 16.6 16.7 0 5 10 15 20 25 Patients (%) 26.2 0 10 20 30 40 Patients (%) Placebo Simvastatin n = 1631/1606 P <0.001 95% CI = 0.59-0.79 RR = 0.68 n = 335/343 P <0.003 95% CI = 0.46-0.85 RR = 0.62 n = 232/251 P <0.001 95% CI = 0.41-0.80 RR = 0.58 n = 1631/1606 P <0.001 95% CI = 0.55-0.80 RR = 0.67 n = 335/343 P <0.01 95% CI = 0.37-.87 RR = .57 n = 232/251 P <0.005 95% CI = 0.32-0.82 RR = 0.52 n = 1631/1606 P <0.005 0.57-0.90 95% CI = RR = 0.72 n = 335/343 P <0.02 0.35-0.93 95% CI = RR = 0.57 n = 232/251 P <0.34 95% CI = 0.49-1.27 RR = 0.79 21.1 11.5 10.2 11.6 30.4 37.5 18.6 19.5 23.5
Reduction in CHD Event Rates With Statin Treatment (WOSCOPS) Sattar N, et al. Circulation . 2003;108:414-419 10.4 6.2 7.7 4.4 0 2 4 6 8 10 12 CHD event rate (%) Patients With Metabolic Syndrome Patients Without Metabolic Syndrome Placebo Pravastatin
Are LDL and HDL Effects Additive? R2 = 0.8512 0 20 40 60 80 100 0 10 20 30 40 50 60 70 80 % Absolute Change in LDL+HDL % CV Event RRR 4S VA HIT DAIS BIP AFCAPS/ TexCAPS WOSCOPS LIPID CARE, HPS HHS CDP ASCOT ALLHAT PROSPER 2 nd Order Relationship HATS FATS FATS F/U
UKPDS: Effects of Tight vs Less-Tight Blood Pressure Control
Metabolic Syndrome: Lifestyle Management
Obesity / weight management: low fat – high fiber diet resulting in 500-1000 calorie reduction per day to provide a 7-10% reduction on body weight over 6-12 mos, ideal goal BMI <25
Physical activity: at least 30, pref. 60 min moderate intensity on most or all days of the week as appropriate to individual
Nutritional recommendations per ATP III guidelines: low intake of saturated fats, trans fats, and cholesterol, reduced consumption of simple sugars, and increased intakes of fruits, vegetables, and whole grains are reasonable
Grundy SM, Hansen B, Smith SC, et al. Clinical management of metabolic syndrome. Report of the American Heart Association / National Heart, Lung, and Blood Institute / American Diabetes Association Conference on Scientific Issues Related to Management. Circulation 2004; 109: 551-556
Therapeutic Lifestyle Changes Nutrient Composition of TLC Diet
Nutrient Recommended Intake
Saturated fat Less than 7% of total calories
Polyunsaturated fat Up to 10% of total calories
Monounsaturated fat Up to 20% of total calories
Total fat 25–35% of total calories
Carbohydrate 50–60% of total calories
Fiber 20–30 grams per day
Protein Approximately 15% of total calories
Cholesterol Less than 200 mg/day
Total calories (energy) Balance energy intake and expenditure to maintain desirable body weight/ prevent weight gain
Effect of Mediterranean-style diet in the metabolic syndrome
180 pts with metabolic syndrome randomized to Mediterranean-style vs. prudent diet for 2 years
Those in intervention group lost more weight (-4kg) than those in the control group (+0.6kg) (p<0.01), and significant reductions in CRP and Il-6.
After 2 years, 40 pts in intervention group still had features of metabolic syndrome compared to 78 pts in the control group
Esposito K et al. JAMA 2004; 292(12): 1440-6.
Therapeutic Goals and Recommendations for Clinical Management of Metabolic Syndrome (Grundy et al. Circulation 2005; 112 (epub) Oct 18) Dyslipidemia LDL-C, HDL-C, TG, non-HDL-C Elevated Blood Pressure Elevated Glucose Prothrombotic and Proinflammatory States
ABC’s of Metabolic Syndrome Management Aim for BP <130/85 mm Hg, or <130/80 mm Hg for type 2 diabetes . Consider ACE-I or ARBs and low dose diuretics in combination rx. BP Control B Treat all high-risk patients with low-dose aspirin (or clopidogrel in those with CVD if aspirin is contraindicated) and consider low-dose aspirin in moderately high-risk patients. Antiplatelet agent A Goals / Treatment Intervention
ABC’s of Metabolic Syndrome Management Long term smoking cessation Cigarette Smoking
LDL-C targets, ATP III guidelines
– High Risk : CHD, CHD risk equivalents (incl. >20% 10-year risk): <100 mg/dL (option <70 mg/dl if CVD present)
– Moderately High Risk (10-20% risk or subclinical disease) 2 RF: <130 mg/dL, option <100 mg/dL
– Moderate Risk (2+ RF, <10%) <130 mg/dL
-- Low Risk : 0-1 RF: <160 mg/dL
Non-HDL-C targets 30 mg/dL higher
HDL-C: >40 mg/dL (men)
>50 mg/dL (women)
TG: <150 mg/dL
Cholesterol Management C Goals Intervention
Goals for Elevated Glucose
For IFG delay progression to type 2 diabetes; for diabetes, HgbA1c <7.0%
For IFG encourage weight reduction and increased physical activity
For type 2 diabetes, lifestyle therapy and if necessary, pharmacologic therapy to achieve near normal HgbA1c <7%; modify other risk factors and behaviors.
Limited clinical trial data on treatment to reduce CVD events; neither metformin or thiazolidinediones recommended just for prevention of diabetes because cost-effectiveness and long-term safety not yet documented.
Grundy et al. AHA/NHLBI scientific statement on diagnosis and management of metabolic syndrome. Circulation Oct 18, 2005; 112 (e pub)
ADA 2007 Algorithm for Glycemic Management of Type 2 DM (Diabetes Care, 2007)
Rationale for the ADA Goal of HbA1c <7%: DCCT and UKPDS Results
On the basis of the DCCT and UKPDS, the ADA recommended the HbA1c goal to be <7% for most adults with diabetes
DCCT involving Type 1 diabetes patients showed an approximately 60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy between intensively treated pts (goal A1c<6%, mean achieved 7%) and standard group (A1c=9%) over 6.5 Years (NEJM 1993; 329: 977-986). A 9-year follow-up of this cohort has now shown a 42% reduction (p=0.02) in CVD outcomes and a 57% reduction (p=0.02) in risk of nonfatal MI, stroke, or CVD death compared to those in the standard arm (NEJM 2005; 353: 2643-2653).
Rationale for HbA1c<7% goal and Trials to Examine Effect of Intensive Glycemic Control
The UKPDS involving newly diagnosed patients with Type 2 diabetes followed for 10 years showed microvascular complications to be reduced by 25% in the intensive control (mean A1c=7%) vs. conventional arm (mean A1c=7.9%). There was a nonsignificant (p=0.052) reduction in cardiovascular complications (Lancet 1998; 352: 854-65).
Epidemiologic analysis of the UKPDS cohort showed, however, that for every percentage point reduction in A1c level, there was a statistically significant 18% reduction in CVD events with no glycemic threshold.
Several large-scale clinical trials have since been launched to better address the question of intensive glycemic control on CVD outcomes.
ACCORD: Is too aggressive lowering of HbA1c harmful?
NHLBI-sponsored ACCORD study randomized 10,251 participants with T2DM with hx of CVD, significant CVD risk or 2+ risk factors and tested control of HbA1c to <6% vs. standard strategy for HbA1c 7-7.9%.
Median HbA1c achieved 6.4% vs. 7.5%.
The primary outcome of MI, stroke, or CVD death was reduced in the intensive vs. control group due to fewer nonfatal MIs, but was not significant (HR=0.90, p=0.16)
But the trial was stopped early due to increased all-cause mortality (5.0% vs. 4.0%, HR=1.2, p<0.05) and death from CVD (2.6% vs. 1.8%) in the intensive arm, despite a reduction in non-fatal MI (3.6% vs. 4.6%). Major hypoglycemia requiring assistance was also significantly higher (3.1% vs. 1.0%).
But in those without a prior CVD event and who had a baseline HbA1c <8% had a significant reduction in the primary CVD outcome suggesting a possible benefit of intensive therapy this subgroup of T2DM pts.
In both arms of the study, those with vs. without severe hypoglycemia had a higher mortality.
NEJM 2008; 358: 2545-9
A larger study, ADVANCE, in 11,140 pts with T2DM done in Europe, Australia/NZ, Canada, and Asia did not find an increased risk (8.9% vs. 9.6% for total deaths, 4.5 vs. 5.2% for CVD death).
The primary intensive therapy was the sulfonylurea gliclizide with addl medications to achieve HbA1c < 6.5%
These pts achieved the same HbA1c of 6.4% as achieved in the ACCORD intensive therapy arm, but ADVANCE pts had less severe diabetes--duration 8 vs. 10 years and somewhat lower HbA1c at baseline.
A significant reduction in the primary endpoint of combined microvascular and macrosvascular events was achieved (HR=0.90, p=0.01) mainly due to reduction in microvascular outcomes (macrovascular endpoints not reduced, HR=0.94,p=0.32)
This study also showed those without prior macrovascular disease to show a benefit (14% risk reduction, p<0.05) from the intensive therapy. No benefit seen in those with prior disease.
NEJM 2008; 358: 2560-2572)
ACCORD vs. ADVANCE
One possible explanation of the difference in findings between the two studies was that the rate of HbA1c reduction was much greater in ACCORD (1.4% reduction within 4 months than in ADVANCE 0.5% at 6 months and 0.6% at 12 months).
Experts speculate that more aggressive treatment can more likely lead to hypoglycemia requiring attention, as was clearly the case in ACCORD.
VA Diabetes Trial (VADT)
1,791 veterans, 97% men, 62% white, mean age 60 years), 7.5 year intervention
Intensive HbA1c <7% vs. standard control.
Baseline glycemic control worst of the recent trials at 9.5%; 40% had prior CVD events, 80% had HTN, 50% had dyslpidemia, most were obese
N Engl J Med . 2009 Jan 8;360(2):129-39
No significant difference in primary outcome of CVD events: 263 in standard control and 231 in intensive control, HR=0.88, p=0.12.
More CVD deaths in the intensive arm compared to the standard arm (38 vs. 29, n.s.)
Most important finding was that severe hypoglycemia (impairment/loss of consciousness within prior 3 months) was a power predictor of CVD events (HR=2.1, p=0.02) and occurred in 21% of intensive control and 10% of standard control subjects.
An ancillary study showed that the primary CVD endpoint was significantly reduced in those with low, but not high baseline coronary calcium scores.
Why no benefit from these trials?
Other CVD risk factors were treated to a moderate or high degree, so had lower overall rates of CVD in the standard arm than originally predicted.
The additive benefits of intensive glycemic control may be smaller and more difficult to show in the background of aggressive treatment of other risk factors.
The three trials compared intensive vs. conventional treatment in the flatter part of the observational glycemic-CVD risk curve.
The trials were also conducted in persons with established diabetes in combination whether with CVD or multiple risk factors; subset analyses of the 3 trials suggested a significant benefit in those without known CVD, or with a shorter duration of diabetes or lower A1c upon entry.
Circulation 2009; 119: 351-357
ADA / AHA / ACC Statement Recommendations (Circulation 2009; 119: 351-357)
Findings from ACCORD, ADVANCE, and VADT do not suggest need for major changes in targets, but additionally clarification for individualizing therapy.
General goal of <7% HbA1c remains reasonable for non-complicated DM pts based on benefits seen from DCCT and UKPDS for microvascular disease (ACC/AHA Class Ia – Level of Evidence A) and based on follow-up of these trials, macrovascular disease (ADA B-Level, ACC/AHA Class IIb - A).
An additional benefit for microvascular disease may be obtained from even lower goals if they can be achieved without significant hypoglycemia (ADA B-Level, ACC/AHA, Class IIa – C).
Less stringent goals may be appropriate for those with a hx of severe hypoglycemia, difficult to control DM pts, and those with advanced micro or macrovascular complications or major comorbidities (ADA, C-level recommendation, ACC/AHA, Class IIa – C).