Evidence-Based Glucose Management in Type 2 Diabetes

Evidence-Based Glucose Management in Type 2 Diabetes James R. Gavin III, MD, PhD CEO and Chief Medical Officer Healing Our Village, Inc. Clinical Professor of Medicine Emory University School of Medicine Atlanta, Georgia

MANDATE FOR EVIDENCE-BASED APPROACH TO MANAGEMENT OF TYPE 2 DIABETES Focus on earlier diagnosis (A1C helpful?) Focus on earlier, more intensive interventions, including multiple drugs Focus on treat-to-goal, not treat-to-failure Focus on save the beta, lose the belly Focus on agents that avoid hypos & wt. gain Focus on greater individualization of therapy

International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes Advantages of A1c in diagnosis Better standardized than glucose Better index of glycemic exposure Less biologic variability Less pre-analytic instability No need for fasting Less affected by stress or illness Currently used to guide tx THE INTERNATIONAL EXPERT COMMITTEE. Diabetes Care 2009;32:1327

International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes 6.5 THE INTERNATIONAL EXPERT COMMITTEE. Diabetes Care 2009;32:1327

Greater cost of individual test Limited availability of A1C testing in certain regions of the developing world Variable correlation between A1C and average glucose, especially in certain minority groups Incomplete overlap with FPG and 2 hour PCG Inaccurate in patients with anemia and hemoglobinopathies. Tan"

If we accomplish earlier diagnosis, is there some advantage to the achievement of early, intensive glucose control? Does the legacy effect exist in diabetes?

EDIC Results: In Diabetes Treatment, Start with Glucose Rx (Nephropathy A1c Levels) HbA1c (%) N=1349. Writing Team for the DCCT/ EDIC Research Group. JAMA. 2003;290:2159-2167.

DCCT EDIC: Early Intensive Therapy Reduced Risk of CVD Events in Type 1 Diabetes Cumulative Incidence Any Predefined CVD Outcome 42% Risk Reduction (95% CI, 9%-63%; P = 0.02) Conventional Treatment Intensive Treatment 57% Risk Reduction (95% CI, 12%-79%; P = 0.02) Nonfatal MI, Stroke, or Death From CVD 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years Since Entry Years Since Entry Predefined CVD outcome = nonfatal MI or stroke; death judged to be due to CVD; subclinical MI; angina, confirmed by ischemic changes on exercise tolerance testing or by clinically significant obstruction on coronary angiography; or the need for revascularization with angioplasty or coronary artery bypass. Nathan DM et al for the DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-2653. 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Legacy Effect of Earlier Glucose Control After Median 8.5 Years Post-trial Follow-up in UKPDS Aggregate Endpoint 1997 2007 Any diabetes-related endpoint RRR: 12% 9% P: 0.029 0.040 Microvascular disease RRR: 25% 24% P: 0.0099 0.001 Myocardial infarction RRR: 16% 15% P: 0.052 0.014 All-cause mortality RRR: 6% 13% P: 0.44 0.007 RRR = Relative Risk Reduction, P = Log Rank Holman RR et al. N Engl J Med. 2008;359:1577-1589.

The Importance of Getting to Goal: Reduction in Long-term Diabetes Complications Correlation between a 1% A1C decrease and reduced risk of complications 43% 37% 19% 16% 14% 12% Heart failure Cataract extraction Myocardial infarction Stroke Microvascular disease Cardiovascular complications Lower extremity amputation or fatal peripheral vascular disease Data from United Kingdom Prospective Diabetes Study (UKPDS). Stratton IM et al. BMJ. 2000;321:405-412.

Earlier Use of Combination Therapy May Improve Treating to Target Compared With Conventional Therapy Diet and exercise Traditional stepwise approach--- Early combination approach--- OAD monotherapy OAD uptitration OAD combination OAD + basal insulin OAD + multiple daily insulin injections A1C (%) Mean A1C of patients 10 9 8 7 6 Time Duration of diabetes Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345-1355 and Campbell IW. Br J Cardiol. 2000;7:625-631.

Mean Change from Baseline FPG (mg/dl) *P=0.001 N=632 Weeks DeFronzo RA et al. N Engl J Med. 1995;333:541-549.

β-cell Function Declines as DM Progresses: Can Treatment Fix This Problem? 100 β-cell function declines over time β-cell function (%) 75 50 25 0 IGT Postprandial hyperglycemia Diagnosis Type 2 Phase 1 Years from diagnosis β-cell decline exceeds 50% by time of diagnosis Type 2 Phase 2 Insulin initiation Type 2 Phase 3 12 8 4 0 4 8 12 Lebovitz HE. Diabetes Rev. 1999;7:139-153.

ADOPT: rosiglitazone reduces the rate of loss of β-cell function 0 Glibenclamide Metformin Rosiglitazone 2 Annual rate of β-cell function loss (%, HOMA analysis) 4 6 3.1 2.0 8 6.1 * 10 Error bars = 95% CI *P < 0.001 vs rosiglitazone P = 0.02 vs rosiglitazone Rate of decline from 6 months to 5 years Adapted from Kahn SE, et al. N Engl J Med 2006; 355:2427 2443.

Early initiation of insulin therapy restored beta-cell function Beta-cell function 1,400 1,200 1,000 800 600 400 200 Insulin in continuous subcutaneous infusion (CSII) Insulin in multi-injections (MDI) p < 0.0001 OAD p = 0.006 0-200 Before therapy After therapy At 1 year Newly-diagnosed (382) T2DM patients treated until Euglycaemia was achieved, then followed on diet and exercise Beta-cell function assessed by acute insulin response (first-phase β-cell insulin secretion) Weng et al. Lancet. 2008;371:1753-1760.

GLP-1 Receptor Agonists Exhibit Early Favorable Effects on β-cell Function 3-year treatment with EXN BID vs. insulin glargine with a 4-week w/o period EXN, n = 16; IG, n = 20 A1C Reduction 1 st Phase Insulin Secretion a Insulin Sensitivity a EXN BID IG P -0.7% -0.5% =.186 +1.43-0.99 =.028 +39% - EXN =. 006 IG =.647 a Measured as C-peptide secretion with euglycemic/ hyperinsulinemic and arginine-stimulated hyperglycemia clamp and calculated disposition index (DI). b P<.0001; c P<.0001 vs. LIRA 1.2 mg; d once daily. Meta-analysis of 6 LIRA trials 26-week treatment LIRA 1.8, n = 1363; LIRA 1.2, n = 896; RSG, n = 231; GLIM, n = 490; PBO, n = 524; EXN, n = 231 LIRA 1.2 mg d LIRA 1.8 mg d Δ HOMA-B (%) ΔP/IR 35.1-0.08 31.7-0.08 EXN BID 5.7 b -0.10 PBO 7.4 b,c 0.03 b,c Bunck M, et al. Diabetes. 2010; 59(suppl1): 728-P; Matthews D, et al. Diabetes. 2010; 59(suppl1): 1513-P.

NEW DIRECTIONS IN APPROACH TO MANAGEMENT OF TYPE 2 DIABETES Focus on earlier diagnosis (A1C helpful?) Focus on earlier, more intensive interventions, including multiple drugs Focus on treat-to-goal, not treat-to-failure Shift to save the beta, lose the belly Focus on agents that avoid hypos & wt. gain Focus on greater individualization of therapy

WE NEED HELP WITH THE OBESITY EPIDEMIC! Diabetes Obesity Hypertension Dyslipidemia 10/16/10 SYDNEY Study Group NeuroDiab 2001, Aberdeen 18

Exenatide Twice Daily: Weight Control in Individuals Without Diabetes Obese individuals without diabetes: Placebo/exenatide + lifestyle regimen N = 152 intent-totreat population Average BMI at baseline = 39.6 kg/m 2 77% of exenatide vs 56% of placebo patients with IGT or IFG normalized during the study P <.001 Rosenstock J, et al. Diabetes Care. 2010 Mar 23. [Epub ahead of print].

Liraglutide Reduces Weight and Reverses Prediabetes a in Nondiabetic Adults c b Liraglutide 1.8 mg Liraglutide 1.2 mg Orlistat PBO Median Change in β-cell Function in 20 Weeks PBO -21% Orlistat -17% Liraglutide 1.2 mg +21.4% Liraglutide 1.8 mg +27.5% a Prediabetes = impaired glucose tolerance and impaired fasting glucose, measured by OGTT at randomization and week 20; n = 98 PBO; n = 95 LIRA 1.2; n = 90 LIRA 1.8; b P <.0001 vs PBO or Orlistat; n = 95 Orlistat c P =.008 vs Orlistat. Astrup A, et al. Lancet. 2009;374:1606-1618.

Improvement in CV Risk Factors With Exenatide Treatment (3.5 yr f/u) CV Risk Factor 3.5-Year Completer Population (N = 151) Baseline (mean ± SEM) TG (mg/dl) 225.1 ± 11.6 Change From Baseline (mean ± SEM) -44.4 ± 12.1-12 Mean % Change 95% CI P value -68.3, -20.5 0.0003 TC (mg/dl) 184.4 ± 3.0-10.8 ± 3.1-5 -17.0, -4.6 0.0007 HDL-C (mg/dl) 38.6 ± 0.8 8.5 ± 0.6 +24 7.2, 9.7 <0.0001 LDL-C (mg/dl) 113.7 ± 2.7-11.8 ± 2.9-6 -17.5, -6.1 <0.0001 Systolic BP (mmhg) 129.3 ± 1.0-3.5 ± 1.2-2 -5.9, -1.0 0.0063 Diastolic BP (mmhg) 79.2 ± 0.6-3.3 ± 0.8-4 -4.9, -1.7 <0.0001 21 Klonoff DC, et al. Curr Med Res Opin. 2008;24:275 286.

GIVEN THE BENEFITS OF INCRETIN ACTIONS IN T2DM---IS IT TIME TO RETIRE THE MORE TRADITIONAL SECRETAGOGUES, OR AT LEAST CONSIDER IT? The secretagogues (i.e. SFUs) have poor durability of effectiveness in glucose-lowering in T2DM The secretagogues show no ability to preserve beta cell function or promote neogenesis The secretagogues do not predictably behave in a glucose-dependent fashion, promoting hypoglycemia Secretagogues have been associated with toxic effects on ischemic myocardium (there may in fact be other risks!) There are no documented beneficial effects of secretagogues on cardiovascular risk factors

Mean HbA1C (%) Over Time --- a further indictment of sulfonylureas? Background Metformin Background Sulfonylurea HbA1C (%) HbA1C (%) 8.0 8.0 Sulfonylurea: n=1084 Metformin: n=1096 7.6 P<0.0001 7.6 P<0.0001 7.2 Rosiglitazone: n=1106 7.2 Rosiglitazone: n=1083 6.8 0 1 2 3 4 5 Time (years) Model-adjusted mean (%, SE) N=5000 6.8 0 1 2 3 4 5 Time (years) Home PD, Pocock SJ, Beck- Nielsen H, et al; RECORD Study Team. Lancet. 2009;373(9681):2125-2135.

Incretin-Based Therapies as the New Secretagogues: Effects on β-cell Function Sulfonylureas (SU) do not have pleiotropic effects on β cells and may actually worsen β- cell function Preclinical animal studies of GLP-1 agonists and DPP-4 inhibitors have demonstrated β-cell proliferation and preservation Clinical studies of GLP-1 agonists and DPP-4 inhibitors have demonstrated improved indices of β-cell function Actual preservation of such function in humans over time remains to be established DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1. Drab SR. Pharmacotherapy. 2009;29(12 Pt 2):43S-54S; Kim W, Egan JM. Pharmacol Rev. 2008;60:470-512; Riche DM et al. Am J Med Sci. 2009;337:321-328.

Once DM is Treated---How Tight Should Glucose Control Be? Epidemiologic studies have shown a relationship between A1C levels and CV events in patients with type 2 diabetes Lessons learned from three randomized controlled trials ACCORD (average age 62.2 years, 27% Hispanic or African-American) ADVANCE (average age 66 years, 37% Asian) VADT (average age 60.5 years, 38% Hispanic, African- American or Native American) Average age in the UKPDS was 53 years

HOW TIGHT SHOULD GLUCOSE CONTROL BE TO REDUCE CVD? Outcome ACCORD ADVANCE VADT HbA 1c (%) (Intensive vs. Standard) Nonfatal MI (%) (Intensive vs. Standard) CV Death (%) (Intensive vs. Standard) 6.4 vs.7.5 6.4 vs. 7.0 6.9 vs. 8.4 3.6 vs. 4.6% 2.7 vs.2.8 6.3 vs. 6.1 2.6 vs. 1.8 4.5 vs. 5.2 2.1 vs.1.7 indicates statistical significance Lesson: Goal of HbA1c <7.0% may be appropriate for those with advanced age, if it can be done safely; use individualized, patient-centered approach Loosen targets for those with advanced cardiovascular disease

ADA/ACC/AHA Recommended A1C Goals: Putting CV Trials in Perspective Target Pa)ent Characteris)cs <7% General diabeic populaion Lower than <7% Less stringent than <7% Short duraion of diabetes Long life expectancy No significant CVD No significant hypoglycemia or other adverse effects of treatment History of severe hypoglycemia Limited life expectancy Advanced microvascular or macrovascular complicaions Extensive comorbid condiions Longstanding diabetes in which the general goal has been difficult to a[ain despite DSME, appropriate glucose monitoring, and effecive doses of muliple glucose- lowering agents including insulin Skyler JS, et al. Diabetes Care. 2009;32(1):187-192.

Major Conclusions Concerning Use of Algorithms and Guidelines for Control Multidisciplinary care should be initiated at diagnosis and throughout care Metformin is cornerstone of therapy Match drug the needs of the individual patient Frequent medication adjustments required---no inertia! Use all of the available treatments when required to achieve goals, including insulin, achieving synergy

Informed, Empowered Patient: An Essential Element of Good Chronic Illness Care Informed, empowered patients What characterizes an informed, empowered patient?