Supporting Evidence 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: Design
UKPDS: Effects of Intensive (Sulfonylurea/Insulin) Treatment
UKPDS: Effects of Intensive (Metformin) Treatment*
UKPDS: Effects of Glycemia Exposure Over Time
UKPDS: Risk Reduction in DiabetesRelated Complications (A1c)
Diabetes Prevention Program: Protocol Design
Diabetes Prevention Program: Reduction in Diabetes Incidence
Structures of Thiazolidinediones
Thiazolidinediones: Mechanism of Insulin Sensitization
PPAR vs. gamma
PPAR (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 -Cell Response Suggested by HOMA Analysis of Pioglitazone Therapy
Changes in A1c From Baseline in All Treated Patients
Endpoint Changes in Patients With Lower Baseline A1c (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.
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
PROACTIVE Study: Secondary Prevention of Macrovascular Events in Persons with Diabetes from Pioglitazone
Cholesterol Treatment Trialists' (CCT) Collaboration: Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis fo data from 90,056 participants in 14 randomized trials of statins (The Lancet 9/27/05) Over average 5 year treatment period (per mmol/L reduction--approx 40 mg/dl in LDL-C): 12% reduction in all-cause mortality 19% reduction in coronary mortality 23% reduction in MI or CHD death 17% reduction in stroke 21% reduction in major vascular events No difference in cancer incidence (RR=1.00). Statin therapy can safely reduce 5-year incidence of major coronary events, revascularization, and stroke by about 20% per mmol/L (about 38 mg/dl) reduction in LDL-C
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
Placebo Simvastatin 26.2 18.6 30.4 19.5
CAD Events 40 30 Patients (%) 20 10 0 Revascularization
25 20 Patients (%) 15 10 5 0
37.5 23.5
NFG 95% CI = 0.59RR = 0.68 0.79 P <0.001 n = 1631/1606 16.6 11.5
RR = 0.62 95% CI = 0.46-0.85RR = 0.58 95% CI = 0.41-0.80 P <0.001 n = 232/251 P <0.003 n = 335/343 21.1
16.7 10.2 11.6
IFG
DM
Total Mortality
25 20 15 Patients (%) 10 5 0
RR = 0.67 P <0.001
NFG IFG 95% CI = 0.55-0.80 RR = .57 95% CI = 0.37-.87 RR = 0.52 P <0.01 n = 335/343 n = 1631/1606 P <0.005
DM 95% CI = 0.32-0.82 n = 232/251
10.4
13.1 7.7 7.3
16.4
12.8
RR = 0.72 P <0.005
NFG IFG 95% CI = 0.57-0.90 RR = 0.57 95% CI = 0.35-0.93RR = 0.79 n = 1631/1606 P <0.02 n = 335/343 P <0.34
DM 95% CI = 0.49-1.27 n = 232/251
Reduction in CHD Event Rates With Statin Treatment (WOSCOPS)
12 CHD event rate (%) 10 8 6 4 2 0 Patients With Metabolic Syndrome Patients Without Metabolic Syndrome 7.7 6.2 4.4 Placebo Pravastatin 10.4
Sattar N, et al. Circulation. 2003;108:414-419
Are LDL and HDL Effects Additive?
2nd Order Relationship
% Absolute Change in LDL+HDL 0 0
BIP
10
20
30
40
ALLHAT
50
60
70
80
% CV Event RRR
20
VA HIT DAIS LIPID HHS
CDP
PROSPER HPS CARE, 4S AFCAPS/ TexCAPS
40 60 80 100
WOSCOPS ASCOT
FATS F/U
R2 = 0.8512
HATS
FATS
Hypertension Optimal Treatment (HOT): Outcomes in Patients With Diabetes
UKPDS: Effects of Tight vs Less-Tight Blood Pressure Control
Most CHD Events May be Preventable by Control of Blood Pressure, HDL-C, LDL-C to "Optimal" Levels in Persons with the Metabolic Syndrome
Proportion of CHD Events Prevented (PAR%)
90 80 70 60 50 40 30 20 10 0
28.2
(Wong et al., Am J Cardiol 2003; 91: 1421-26)
80.5 82.1
51.2 46.2
45.1
**
50.6 38.1
*
Men
BP only HDL-C only LDL-C only
Women
All 3 factors
* 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 Saturated fat Polyunsaturated fat Monounsaturated fat Total fat Carbohydrate Fiber Protein Cholesterol Total calories (energy) expenditure Recommended Intake Less than 7% of total calories Up to 10% of total calories Up to 20% of total calories 2535% of total calories 5060% of total calories 2030 grams per day Approximately 15% of total calories Less than 200 mg/day Balance energy intake and 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
Intervention Goals / Treatment
with low-dose aspirin (or clopidogrel in those with CVD if aspirin is contraindicated) and consider low-dose aspirin in moderately high-risk patients. 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.
A
Antiplatelet agent Treat all high-risk patients
B
BP Control
ABC's of Metabolic Syndrome Management
Interventio Goals n
C
Cholesterol Management
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 Long term smoking cessation
Cigarette
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)