Diabetes Guidelines in View of Recent Clinical Trials Are They Still Applicable?

Diabetes Guidelines in View of Recent Clinical Trials Are They Still Applicable? Jay S. Skyler, MD, MACP Division of Endocrinology, Diabetes, and Metabolism and Diabetes Research Institute University of Miami Miller School of Medicine

Diabetes Treatment Components Aspirin/Anti-Platelet Therapy Blood Pressure Control Cholesterol Control Statin Therapy Diet Exercise Fat Decrease Body Weight Glucose Control

Recommendations for BP and Lipids BP measurement BP targets Lipid measurements LDL target Triglyceride target HDL target ADA At every visit IDF Annually (at every visit if above target) ESC/EASD <130/80 mmhg <130/80 mmhg <130/80 mmhg Annually 100 mg/dl (2.6 mmol/l) 150 mg/dl (1.7 mmol/l) male >40 mg/dl (>1.0 mmol/l) female >50 mg/dl (>1.3 mmol/l) Annually - <95 mg/dl (2.5 mmol/l) <200 mg/dl (<2.3 mmol/l) >39 mg/dl (>1.0 mmol/l) - <70 mg/dl (1.8 mmol/l) <150 mg/dl (<1.7 mmol/l) male >40 mg/dl (>1.0 mmol/l) female >46 mg/dl (>1.2 mmol/l) IDF Clinical Guidelines Task Force. Brussels, 2005. ADA. Diabetes Care 2009; 31(Suppl. 1):S13 61. Ryden L, et al. Eur Heart J 2007; 28:88 136.

A1c Targets in Current Guidelines ADA/EASD <7 IDF 6.5 NICE <6.5 ACE/AACE 6.5 France <6.5* Canada Australia A1c target (%) 7 7 Latin America <6.5 * If on single or double therapy; if on triple therapy or insulin, n, then A1c <7%

American Diabetes Association. Diabetes Care 2009; 32 (suppl 1):S13 :S13-S61S61

2009 ADA Treatment Goals in Diabetes A1c <7.0%* Blood pressure LDL-cholesterol <130/80 mmhg <100 mg/dl (2.6 mmol/l) or <70 mg/dl (1.8 mmol/l) (or ~30-40% reduction from baseline) Serum triglycerides <150 mg/dl (1.7 mmol/l) HDL cholesterol Smoking cessation Aspirin therapy Men: >40 mg/dl Women: >50 mg/dl mg/dl (1.04 mmol/l) mg/dl (1.3 mmol/l) Yes If history (or increased risk) of cardiovascular disease American Diabetes Association. Diabetes Care. 2009; 32 (suppl 1):S13 :S13-S61S61

2009; Issue 3

Cochrane Review Treating patients to lower than standard BP targets, 140-160/90 160/90-100100 mmhg, does not reduce mortality or morbidity. Because guidelines are recommending even lower targets for diabetes mellitus and chronic renal disease, we are currently conducting systematic reviews in those groups of patients. 2009; Issue 3

Relative risk of CHD in BP trials according to pretreatment DBP and SBP Law, M R et al. BMJ 2009;338:b1665

Relative risk of stroke in BP trials according to pretreatment DBP and SBP Law, M R et al. BMJ 2009;338:b1665

Reduction in incidence of CHD & stroke in relation to reduction in DBP and age Law, M R et al. BMJ 2009;338:b1665

Reduction in incidence of CHD & stroke in relation to reduction in SBP and age Law, M R et al. BMJ 2009;338:b1665

Blood Pressure Should the target BP be 110/70? Should all persons be treated with anti-hypertensive agents regardless of BP? Law, M R et al. BMJ 2009;338:b1665

Effect of ACE or ARB Rx on Diabetic Retinopathy Effects of Enalapril and Losartan on Retinopathy, as Measured by the Odds Ratio of Progression, during the Five-Year Follow-up Period Mauer M et al. N Engl J Med 2009;361:40-51

2009 ADA Treatment Goals in Diabetes A1c <7.0%* Blood pressure LDL-cholesterol <130/80 mmhg <100 mg/dl (2.6 mmol/l) or <70 mg/dl (1.8 mmol/l) (or ~30-40% reduction from baseline) Serum triglycerides <150 mg/dl (1.7 mmol/l) HDL cholesterol Smoking cessation Aspirin therapy Men: >40 mg/dl Women: >50 mg/dl mg/dl (1.04 mmol/l) mg/dl (1.3 mmol/l) Yes If history (or increased risk) of cardiovascular disease American Diabetes Association. Diabetes Care. 2009; 32 (suppl 1):S13 :S13-S61S61

Lipids If drug-treated patients do not reach targets on maximal tolerated statin therapy, a reduction in LDL cholesterol of 30 40% from baseline is an alternative therapeutic goal American Diabetes Association. Diabetes Care. 2009; 32 (suppl 1):S13 :S13-S61S61

Lipids Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients: with overt CVD (A) without CVD who are over the age of 40 and have one or more other CVD risk factors. (A) American Diabetes Association. Diabetes Care. 2009; 32 (suppl 1):S13 :S13-S61S61

Statins for Primary Prevention Brugts, J J et al. BMJ 2009;338:b2376

Statins for Primary Prevention Brugts, J J et al. BMJ 2009;338:b2376

2009 ADA Treatment Goals in Diabetes A1c <7.0%* Blood pressure LDL-cholesterol <130/80 mmhg <100 mg/dl (2.6 mmol/l) or <70 mg/dl (1.8 mmol/l) (or ~30-40% reduction from baseline) Serum triglycerides <150 mg/dl (1.7 mmol/l) HDL cholesterol Smoking cessation Aspirin therapy Men: >40 mg/dl Women: >50 mg/dl mg/dl (1.04 mmol/l) mg/dl (1.3 mmol/l) Yes If history (or increased risk) of cardiovascular disease American Diabetes Association. Diabetes Care. 2009; 32 (suppl 1):S13 :S13-S61S61

Anti-Platelet Therapy Revision Use aspirin therapy (75-162 mg/day) as a primary prevention strategy in those with T1D or T2D at increased CVD risk, including those >40 years old or with additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria) For patients with CVD and aspirin allergy, clopidogrel (75 mg/day) should be used Combination therapy with aspirin (75 162 mg/day) and clopidogrel (75 mg/day) is reasonable for up to 1 year after an acute coronary episode American Diabetes Association. Diabetes Care. 2009; 32 (suppl 1):S13 :S13-S61S61

Aspirin for Primary Prevention serious vascular events dropped from 0 57% to 0 51% 0 per year by the use of aspirin risk of major bleeds increased from 0 07% 0 07% to 0 10% 0 per year by the use of aspirin. Antithrombotic Trialists (ATT) Collaboration; Lancet 2009; 373: 1849 1860 1860

Serious Vascular Events Antithrombotic Trialists (ATT) Collaboration; Lancet 2009; 373: 1849 1860 1860

2009 ADA Treatment Goals in Diabetes A1c <7.0%* Blood pressure LDL-cholesterol <130/80 mmhg <100 mg/dl (2.6 mmol/l) or <70 mg/dl (1.8 mmol/l) (or ~30-40% reduction from baseline) Serum triglycerides <150 mg/dl (1.7 mmol/l) HDL cholesterol Smoking cessation Aspirin therapy Men: >40 mg/dl Women: >50 mg/dl mg/dl (1.04 mmol/l) mg/dl (1.3 mmol/l) Yes If history (or increased risk) of cardiovascular disease American Diabetes Association. Diabetes Care. 2009; 32 (suppl 1):S13 :S13-S61S61

Targets for Glycemic Control* ADA Target (for patients in general) A1C < 7.0% Normal A1C < 6.0% ADA 2006: The A1C goal for the individual patient is an A1C as close to normal (<6%) as possible without significant hypoglycemia Realistic target: lowest A1C level possible without unacceptable adverse effects *DCCT referenced assays: normal range 4% 6%. American Diabetes Association. Diabetes Care. 2008; 31 (suppl 1):S13 :S13-S54. S54.

American Diabetes Association. Diabetes Care 2009; 32 (suppl 1):S13 :S13-S61S61

Impact of Intensive Therapy in Diabetes Summary of Major Clinical Trials Study Microvascular CVD Mortality DCCT/EDIC UKPDS ACCORD? ADVANCE VADT UKPDS / UKPDS fu UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. Holman RR. N Engl J Med. 2008 Oct 9;359(15):1577-89 DCCT / EDIC DCCT Research Group. N Engl J Med 329;977-986, 1993 Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. ACCORD Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559. ADVANCE Patel A, et al. N Engl J Med. 2008;358:2560-2572. VADT Duckworth W et al. N Engl J Med 2009;360 Initial Trial Long Term Follow-up

Effect of more vs less intensive control of glucose on Non-Fatal Myocardial Infarction Study Odds Ratio (95% CI) Weight (%) UKPDS PROactive ADVANCE VADT ACCORD Overall 0.78 (0.62, 0.98) 0.83 (0.64, 1.06) 0.98 (0.78, 1.23) 0.81 (0.58, 1.15) 0.78 (0.64, 0.95) 0.83 (0.75, 0.93) 21.81 18.03 21.86 9.44 28.86 100.00 I-squared = 0% (95% CI 0% to 69.3%), p = 0.61.4.6.8 1 1.2 1.4 1.6 1.8 2 Odds Ratio Intensive therapy better Standard therapy better Ray KK et al; Lancet 2009; 373: 1765 1772 1772

Effect of more vs less intensive control of glucose on Coronary Heart Disease Study Odds Ratio (95% CI) Weight (%) UKPDS PROactive* ADVANCE VADT ACCORD Overall 0.75 (0.54, 1.04) 0.81 (0.65, 1.00) 0.92 (0.78, 1.07) 0.85 (0.62, 1.17) 0.82 (0.68, 0.99) 0.85 (0.77, 0.93) 8.59 20.22 36.48 9.03 25.68 100.00 I-squared = 0% (95% CI 0% to 53%), p = 0.78.4.6.8 1 1.2 1.4 1.6 1.8 2 Intensive therapy better Odds Ratio Standard therapy better Ray KK et al; Lancet 2009; 373: 1765 1772 1772

Effect of more vs less intensive control of glucose on Stroke Study Odds Ratio (95% CI) Weight (%) UKPDS PROactive* ADVANCE VADT* ACCORD Overall I-squared = 0% (95% CI 0% to 62%), p = 0.70 0.91 (0.51, 1.61) 0.81 (0.60, 1.08) 0.97 (0.81, 1.16) 0.78 (0.47, 1.28) 1.05 (0.76, 1.46) 0.93 (0.81, 1.06) 5.18 20.47 51.38 6.76 16.21 100.00.4.6.8 1 1.2 1.4 1.6 1.8 2 Odds Ratio Intensive therapy better Standard therapy better Ray KK et al; Lancet 2009; 373: 1765 1772 1772

Effect of more vs less intensive control of glucose on Death Study Odds Ratio (95% CI) Weight (%) UKPDS PROactive ADVANCE VADT ACCORD Overall I-squared = 58% (95% CI 0% to 84%), p = 0.049 0.79 (0.53, 1.20) 0.96 (0.77, 1.19) 0.93 (0.82, 1.05) 1.09 (0.81, 1.47) 1.28 (1.06, 1.54) 1.02 (0.87, 1.19) 10.05 21.47 29.38 15.46 23.64 100.00.4.6.8 1 1.2 1.4 1.6 1.8 2 Intensive therapy better Odds Ratio Standard therapy better Ray KK et al; Lancet 2009; 373: 1765 1772 1772

Intensive Glycemic Control in Diabetes: Implications of ACCORD, ADVANCE and VADT A1C targets for diabetes Lowering A1C to < 7% has been shown to significantly reduce the risk of microvascular complications in both type 1 and type 2 diabetes Controlled trials of more intensive glycemic control have not shown a decrease in CVD risk Long-term follow-up suggests that A1C < 7% in the years following diagnosis is associated with a reduction in CVD risk Until more evidence becomes available, the general A1C target of < 7% appears reasonable For some patients, individualized glycemic targets may be appropriate riate For CVD risk reduction in patients with diabetes: Continue to follow evidence-based recommendations for BP, lipids, aspirin, tobacco A position statement of the ADA and a scientific statement of the e ACC and the AHA. Diabetes Care 32; 2009; 187-192 192

Conclusions & Implications Comprehensive care involves treatment of all modifiable CVD risk factors DCCT and UKPDS follow-up studies demonstrate intensive glycemic control reduces micro- and macrovascular disease Glycemic control seems to provide CVD benefit if initiated early in the disease course Intensive treatment of BP and lipids reduces the impact of glycemic control on micro- and macrovascular complications

Conclusions & Implications Glycemic goals for most patients should remain unchanged, i.e. targeting A1C <7% Higher A1C targets are acceptable for patients with hypoglycemia unawareness and/or a known history of severe hypoglycemia, established CVD, and in older frail patients Lower A1C targets are appropriate in patients with shorter duration of diabetes and those without established CVD

Benefit of different interventions per 200 diabetic pts treated for 5 years 5 0 Per 4mmHg lower SBP Per 1mmol/L lower LDL-C (38.7 mg/dl) Per 0.9% lower A1c CV events 5 10 8.2 2.9 15 12.5 20 Ray KK et al; Lancet 2009; 373: 1765 1772 1772

2009 ADA Treatment Goals in Diabetes A1c <7.0%* Blood pressure LDL-cholesterol <130/80 mmhg <100 mg/dl (2.6 mmol/l) or <70 mg/dl (1.8 mmol/l) (or ~30-40% reduction from baseline) Serum triglycerides <150 mg/dl (1.7 mmol/l) HDL cholesterol Smoking cessation Aspirin therapy Men: >40 mg/dl Women: >50 mg/dl mg/dl (1.04 mmol/l) mg/dl (1.3 mmol/l) Yes If history (or increased risk) of cardiovascular disease American Diabetes Association. Diabetes Care. 2009; 32 (suppl 1):S13 :S13-S61S61

A1c Not the Whole Story

A1C and estimated Average Glucose - eag Formula: 28.7 X A1C 46.7 = eag (mg/dl) Nathan et al. Diabetes Care 31:1473-1478, 1478, 2008

A1C and eag not tell whole story 300 Blood Glucose Control mg/dl 200 100 6 AM 10 AM 2 PM 6 PM 10 PM Time of Day 2 AM High postprandial glucoses and glucose variability correlate with poor outcomes but there is not proof that treating to reduce PPG or variability improves outcome

Glycemia Treatment Algorithms

IDF Type 2 DM Treatment Algorithm Lifestyle Intervention A1c >6.5% Monotherapy If Renal Impairment or Heart Failure Sulfonylurea If A1c >6.5% If Intolerance Dual Therapy + SU or MET or TZD If A1c >6.5% Triple Therapy SU+MET or MET+TZD + TZD or SU If A1c >7.5% Insulin Therapy SU + MET + Once Daily Basal Insulin IDF. Global Guideline for Type 2 Diabetes. Available from: www.idf.org

Previous ADA/EASD Treatment Algorithm Lifestyle intervention + metformin If A1c 7% Add basal insulin (most effective) Add sulfonylurea (least expensive) Add glitazone (no hypoglycemia) If A1c 7% If A1c 7% If A1c 7% Intensify insulin Add glitazone Add basal insulin Add sulfonylurea If A1c 7% If A1c 7% Add basal or intensify insulin Intensive insulin + metformin +/- glitazone Nathan DM, et al. Diabetes Care 2008; 31:173 5.

Diabetes Care. 2009; 32: 193 203.

2009 ADA/EASD Consensus Algorithm Revised Treatment Algorithm STEP 1 At diagnosis: Lifestyle + Metformin STEP 2 1 st Add Basal insulin st Tier* Add Sulfonylurea HbA1C >7.0% 2 nd nd Tier Add GLP 1 1 agonist Add Pioglitazone STEP 3 Intensive insulin *1 st Tier: Well validated core therapies. 2 nd Tier: Less well validated therapies. Nathan DM et al. Diabetes Care. 2009; 32: 193 203.

Pathophysiologic-Based Algorithm Lifestyle + Triple Combination: TZD + Metformin + Exenatide A1c < 6.0% Ralph DeFronzo, Banting Lecture, ADA Annual Meeting 2008.

Comparison of Treatment Algorithms Durability β Cell Preservation Hypoglycemia Weight Gain ADA No No Yes Yes Pathophysiologic- Based Yes Yes No No Ralph DeFronzo, Banting Lecture, ADA Annual Meeting 2008.

2009 ADA/EASD Consensus Algorithm Revised Treatment Algorithm STEP 1 At diagnosis: Lifestyle + Metformin STEP 2 1 st Add Basal insulin st Tier* Add Sulfonylurea HbA1C >7.0% 2 nd nd Tier Add GLP 1 1 agonist Add Pioglitazone STEP 3 Intensive insulin *1 st Tier: Well validated core therapies. 2 nd Tier: Less well validated therapies. Nathan DM et al. Diabetes Care. 2009; 32: 193 203.

UKPDS - A1c 9 CONVENTIONAL GROUP A1c, % 8 7 INTENSIVE GROUP 6 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 YEARS ukpds Lancet 1998; 352: 837-853

UKPDS: Change in Body Weight CHANGE IN WEIGHT (kg) 7.5 5 2.5 0 Cross-Sectional, Mean Values INTENSIVE GROUP CONVENTIONAL GROUP 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 YEARS ukpds Lancet 1998; 352: 837-853

2009 ADA/EASD Consensus Algorithm Revised Treatment Algorithm STEP 1 At diagnosis: Lifestyle + Metformin STEP 2 1 st Add Basal insulin st Tier* Add Sulfonylurea HbA1C >7.0% 2 nd nd Tier Add GLP 1 1 agonist Add Pioglitazone STEP 3 Intensive insulin *1 st Tier: Well validated core therapies. 2 nd Tier: Less well validated therapies. Nathan DM et al. Diabetes Care. 2009; 32: 193 203.

ADOPT - A1c Over Time 8.0 7.5 Glyburide Metformin % 7.0 Rosiglitazone 6.5 6.0 0 0 1 2 3 4 5 Time (years) NEJM 2006; 355: 2427-2443 2443

DPP4 Inhibitors vs Sulfonylureas DPP4 Inhibitors Glucose dependent insulin secretion Modulation of glucagon secretion No weight gain No hypoglycemia??? Side effects $$$ Sulfonylureas Insulin secretion not glucose dependent No effect Weight gain Hypoglycemia Black box warning

2009 ADA/EASD Consensus Algorithm Revised Treatment Algorithm STEP 1 At diagnosis: Lifestyle + Metformin STEP 2 1 st Add Basal insulin st Tier* Add Sulfonylurea HbA1C >7.0% 2 nd nd Tier Add GLP 1 1 agonist Add Pioglitazone STEP 3 Intensive insulin *1 st Tier: Well validated core therapies. 2 nd Tier: Less well validated therapies. Nathan DM et al. Diabetes Care. 2009; 32: 193 203.

2009 ADA/EASD Consensus Algorithm Revised Treatment Algorithm STEP 1 At diagnosis: Lifestyle + Metformin Introduced in 1957 STEP 2 1 st Add Basal insulin st Tier* Add Sulfonylurea Introduced in 1950s HbA1C >7.0% 2 nd nd Tier Add GLP 1 1 agonist Add Pioglitazone STEP 3 Introduced in 1922 Intensive insulin *1 st Tier: Well validated core therapies. 2 nd Tier: Less well validated therapies. Nathan DM et al. Diabetes Care. 2009; 32: 193 203.

2009 ADA/EASD Consensus Algorithm Revised Treatment Algorithm STEP 1 At diagnosis: Lifestyle + Metformin STEP 2 1 st Add Basal insulin st Tier* Add Sulfonylurea Cause Weight HbA1C >7.0% Gain!! 2 nd nd Tier Add GLP 1 1 agonist Add Pioglitazone STEP 3 Intensive insulin *1 st Tier: Well validated core therapies. 2 nd Tier: Less well validated therapies. Nathan DM et al. Diabetes Care. 2009; 32: 193 203.

2009 ADA/EASD Consensus Algorithm Revised Treatment Algorithm STEP 1 At diagnosis: Lifestyle + Metformin STEP 2 1 st Add Basal insulin st Tier* Add Sulfonylurea HbA1C >7.0% 2 nd nd Tier Add GLP 1 1 agonist Add Pioglitazone STEP 3 Intensive insulin *1 st Tier: Well validated core therapies. 2 nd Tier: Less well validated therapies. Nathan DM et al. Diabetes Care. 2009; 32: 193 203.

Skyler Algorithm 2009 Lifestyle Metformin? + DPP4 Exenatide Basal insulin

Diabetes Treatment Components Aspirin/Anti-Platelet Therapy Blood Pressure Control Cholesterol Control Statin Therapy Diet Exercise Fat Decrease Body Weight Glucose Control