Evidence Supporting Aggressive Glycemic Control

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Evidence Supporting Aggressive Glycemic Control
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Treatment of Type 2 Diabetes
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Sites of Action of Therapeutic Options for Type
2 Diabetes
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DCCT Effects of Intensive vs Conventional
Glycemic Control
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UKPDS Design
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UKPDS Effects of Intensive (Sulfonylurea/Insulin
) Treatment
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UKPDS Effects of Intensive (Metformin)
Treatment
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UKPDS Effects of Glycemia Exposure Over Time
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UKPDS Risk Reduction in Diabetes-Related
Complications (A1c)
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Diabetes Prevention Program Protocol Design
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Diabetes Prevention Program Reduction in
Diabetes Incidence
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Structures of Thiazolidinediones
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Thiazolidinediones Mechanism of Insulin
Sensitization
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PPAR a vs. gamma

• PPAR a (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.

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ThiazolidinedionesRationale for Type 2 Diabetes
Therapy
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ACTOS, an Insulin Sensitizer
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Reduced Insulin Resistance Suggested by HOMA
Analysis of Pioglitazone Therapy
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Improved ß-Cell Response Suggested by HOMA
Analysis of Pioglitazone Therapy
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Changes in A1c From Baseline in All Treated
Patients
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Endpoint Changes in Patients With Lower Baseline
A1c (Mean 9.0)
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Change in FPG From Baseline in All Treated
Patients
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Change in Lipid Profile at Endpoint ACTOS
26-Week Monotherapy
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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 (plt0.0001).
• 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.

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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
  (n2605) or matching placebo (n2633), 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, p0.095).

Lancet 2005 366 1279-89
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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
  reductionapprox 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 (RR1.00).
• 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

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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 (p0.001), all
  cause mortality 27 (p0.059). CHD events
  reduced 36 and stroke 48.

Colhoun HM et al., The Lancet 2004 364 685-696
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Relative Risk of Events in 4S Study
Placebo
Simvastatin
40
CAD Events
26.2

30
20
Patients ()
10
0
NFG
IFG
DM
Revascularization
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16.6
16.7
20
15
Patients ()
10
5
0
NFG
IFG
DM
Total Mortality
Patients ()
NFG
IFG
DM
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Reduction in CHD Event Rates With Statin
Treatment (WOSCOPS)
Sattar N, et al. Circulation. 2003108414-419
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Are LDL and HDL Effects Additive?
2nd Order Relationship
Absolute Change in LDLHDL
0
10
20
30
40
50
60
70
80
0
ALLHAT
BIP
CDP
PROSPER
20
CARE, HPS
LIPID
VA HIT
DAIS
4S
HHS
40
CV Event RRR
WOSCOPS
AFCAPS/ TexCAPS
60
ASCOT
80
R2 0.8512
100
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Hypertension Optimal Treatment (HOT) Outcomes in
Patients With Diabetes
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UKPDS Effects of Tight vs Less-Tight Blood
Pressure Control
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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)


plt0.05, plt0.01 compared to men
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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

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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 gt30 or gt27 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
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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 lt25
• 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
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Therapeutic Lifestyle ChangesNutrient
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 2535 of total calories
• Carbohydrate 5060 of total calories
• Fiber 2030 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

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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)
  (plt0.01), 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.
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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
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ABCs of Metabolic Syndrome Management
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ABCs of Metabolic Syndrome Management
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Goals for Elevated Glucose

• For IFG delay progression to type 2 diabetes for
  diabetes, HgbA1c lt7.0
• 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 lt7 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)