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
Framingham Heart Study 30-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-64) 10 9 20 11 9 6 38 19 3* 30 0 2 4 6 8 10 Age-adjusted annual rate/1,000 Men Women Total CVD CHD Cardiac failure Intermittent claudication Stroke Risk ratio P <0.001 for all values except * P <0.05. Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N et al, eds. Oxford; 1992.
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
Intra-abdominal (Visceral) Fat The dangerous inner fat! Back Visceral AT Subcutaneous AT Front
Relationship Between Visceral Adipose Tissue and Insulin Action Banerji M, et al. Am J Physiol. 1997;273(2 pt 1):E425-E432. 18 16 14 12 10 8 6 4 2 0 1,000 2,000 3,000 4,000 5,000 Visceral adipose tissue volume per unit surface area (mL/m 2 ) Glucose disposal (mg/kg LBM/min) Women Men
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
Structures of Thiazolidinediones
Thiazolidinediones: Mechanism of Insulin Sensitization
PPAR α vs. gamma
PPAR α (fibrates) work mostly in the liver and lower VLDL triglycerides and increase HDL-C but do not affect FFA, glucose, or insulin sensitivity
PPAR gammas (TZDs such as rosiglitazone or pioglitazone) promote new fat cells in subcutaneous tissue and decrease intramuscular and visceral fat.
Thiazolidinediones: Rationale for Type 2 Diabetes Therapy
ACTOS, an Insulin Sensitizer
Reduced Insulin Resistance Suggested by HOMA Analysis of Pioglitazone Therapy
Improved β-Cell Response Suggested by HOMA Analysis of Pioglitazone Therapy
Changes in A 1c From Baseline in All Treated Patients
Endpoint Changes in Patients With Lower Baseline A 1c (Mean 9.0%)*
Change in FPG From Baseline in All Treated Patients
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.
PERISCOPE: Comparison of Pioglitazone vs. Glimepiride on Progression of Coronary Atherosclerosis in Patients with Type 2 Diabetes Steve E. Nissen, MD Cleveland Clinic Foundation Cleveland, Ohio ACC Scientific Sessions, Late Breaker Monday March 31, 2008 Chicago, Illinois
Cardiovascular disease is the leading cause of death in patients with diabetes
Few studies have compared outcomes for diabetes medications beyond their glucose lowering efficacy
Sought to compare coronary disease progression measured by intravascular ultrasound for two alternative treatment strategies:
Glimepiride (an insulin secretagogue)
Pioglitazone (an insulin sensitizer)
To directly compare the effectiveness of these 2 alternative approaches, an insulin-providing vs an insulin-sensitizing strategy, in reducing progression of atherosclerosis in patients with type 2 diabetes and coexisting coronary artery disease
Nissen S. JAMA .2008;299(13):1561-1573
543 patients with type 2 diabetes undergoing angiography for clinical indications Glimepiride 1-4mg (titrated to maximally tolerated dose) Repeat Intravascular Ultrasonography Examination at 16 weeks Primary Outcome Measure: Change in percent atheroma volume (PAV) from baseline to study completion Pioglitazone 15-45mg ( titrated to maximally tolerated dose ) PERISCOPE Study Design Nissen S. JAMA .2008;299(13):1561-1573
Pioglitazone PERISCOPE Primary Efficacy Parameter Change in Percent Atheroma Volume (%) P<0.001 P=0.44 Change in PAV(%) 0.73 -0.16 Difference between groups P=0.002 Nissen S. JAMA .2008;299(13):1561-1573
PERISCOPE Other Adverse Events Nissen S. JAMA .2008;299(13):1561-1573 <0.001 +3.6kg +1.6kg Change in Body Weight 0.004 3.0% 0% Bone Fractures 0.07 4.8% 8.8% Hypertension 0.69 1.1% 0.7% Creatinine > 2.0 mg/dL 0.01 10.7% 4.8% BUN >30 mg/dL 0.05 7.0% 12.1% Angina 0.02 17.8% 11.0% Edema <0.001 15.2% 37.0% Hypoglycemia P Value Pioglitazone (n=270) Glimepiride (n=273)
UKPDS: Effects of Tight vs Less-Tight Blood Pressure Control
ACCORD: Is too aggressive lowering of HbA1c harmful?
NHLBI-sponsored ACCORD study of approx. 10,000 T2DM pts with CHD or 2+ risk factors tested control of HbA1c to <6% vs. standard strategy for HbA1c 7-7.9%.
Median HbA1c achieved 6.4% vs. 7.5%
The trial was stopped early (Feb 6, 2008) due to more deaths in intensive arm (257, or 14/1000 person years) vs. standard arm (203, or 11/1000 person years).
There were, however, 10% fewer MIs in intensive arm and no link to any particular medication causing increases in deaths was noted.
No change in general recommendation by ADA to achieve for HbA1c <7% in most diabetics; in older diabetics with prior CHD or other risk factors like in ACCORD population, less stringent goals of around 7% might be appropriate.
ADVANCE and VADT
In light of ACCORD, a larger study, ADVANCE, in progress of 11,140 pts with T2DM also did an interim analysis reported February 14 but did not find any evidence of increased risks.
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 shorter (8 vs. 10 years) and somewhat lower HbA1c at baseline.
It is possible that it is the intensity of treatment or rather than the HbA1c achieved which is the problem but that will need to be examined further.
The U.S. VA Diabetes Trial, also examining the relation of intensive glycemic control to cardiovascular outcomes will report its results soon.
The ADA plans to evaluate the results from all these studies before making further recommendations.
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
Hypertension Optimal Treatment (HOT): Outcomes in Patients With Diabetes
Most CHD Events May be Preventable by Control of Blood Pressure, HDL-C, LDL-C to “Optimal” Levels in Persons with the Metabolic Syndrome (Wong et al., Am J Cardiol 2003; 91: 1421-26) ** * * p<0.05, ** p<0.01 compared to men
The endocannabinoid system
An endogenous signaling system which contributes to physiologic regulation of energy balance, food intake, and lipid and glucose metabolism through both central and peripheral effects
Effects of cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors over 1 year: RIO Europe Study
1,507 pts with BMI >=30 or >27 with dyslipidemia and/or hypertension randomized to placebo, 5mg or 20 mg rimonabant, w/hypocaloric diet
Weight loss at 1 year: -3.4 kg w/5mg, -6.6 kg w/10 mg rimonabant vs. placebo (-1.8 kg)
Rimonabant 20 mg produced greater improvements in waist circumference, HDL-C, triglycerides, LDL-C, insulin, and prevalence of metabolic syndrome (reduced by 34% w/placebo vs. 64.8% with rimonabant)
Van Gaal LF, et al. Lancet 2005; 365: 1389-97
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)