Update on Oral Agents for T2DM and Obesity

Transcription

1 Update on Oral Agents for T2DM and Obesity This presentation will: Outline the clinical considerations in the selection of pharmacotherapy for type 2 diabetes, including degree of A1C lowering achieved, patient-specific concerns, adverse drug reactions, and contraindications Discuss the role and timing of combination therapy in achieving A1C goals Explain the implications of recent, large randomized clinical trials on clinical decision-making

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3 Prediabetes Treatment Algorithm T2DM = type 2 diabetes mellitus BP = blood pressure CVD = cardiovascular disease TZD = thiazolidinedione GLP-1 RA= glucagon-like peptide-1 receptor agonist Weight-loss agents orlistat, lorcaserin, and phentermine/topiramate can prevent progression to T2DM Improve BP, triglycerides, and insulin sensitivity Metformin and acarbose can reduce progression to T2DM by 25% - 30% Use for prediabetes is off-label Both are safe, confer CVD risk benefit; metformin is well tolerated TZDs prevented progression to T2DM in 60% - 75% of patients in clinical trials Associated with adverse outcomes GLP-1 receptor agonists may be as effective as TZDs Promote weight loss, but inadequate safety data TZDs and GLP-1 RAs reserved for patients not responding to conventional therapies or at highest risk for T2DM AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3):

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5 AACE Diabetes Algorithm Guide therapy based on A1C level Focus on lifestyle intensification at all levels Important tenets: Target A1C is <6.5% Based on associated lower risk of micro- and macrovascular complications Recommend monitoring A1C quarterly, along with fasting and postprandial blood glucose, with intensification of therapy until goal A1C is achieved Individualize A1C target based on comorbidities Patient should monitor fasting and postprandial blood glucose levels Use agents with maximal efficacy, associated with lowest risk of hypoglycemia Sulfonylureas are therefore much lower in algorithm Earlier use of incretin mimetics and DPP-4 inhibitors to stimulate insulin secretion without hypoglycemia A1C = glycated hemoglobin; DPP-4 = dipeptidyl-peptidase 4 AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3):

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7 Algorithm To Achieve Glycemic Goals Baseline A1C 6.5% - 7.5% Monotherapy may be effective in this range Metformin first choice for monotherapy if no contraindications Consider DPP-4 if PP and FPG, GLP-1 if PP, TZD if metabolic syndrome or NAFLD, AGI if PP Do not recommend secretagogue (SU or glinide) in this range due to risk of hypoglycemia; short-lived effect If monotherapy is unsuccessful, move on to dual oral rx; often need to augment reduction in PP BG to get to goal in this A1C range DPP-4=dipeptidyl peptidase-4; PP=post-prandial; FPG=fasting plasma glucose; GLP-1 = glucagon-like peptide-1; TZD=thiazolidinedione; NAFLD=non-alcoholic fatty liver disease; AGI=alpha-glucosidase inhibitor; SU=sulfonylurea; A1C=glycated hemoglobin; SGLT-2=sodium glucose transport-2 AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3):

8 Algorithm to Achieve Glycemic Goals Baseline A1C 7.6%-9.0% Dual therapy with metformin provides superior glycemic control over metformin alone. If dual oral rx is unsuccessful, consider triple therapy If triple oral rx fails to achieve A1C goal, initiate insulin GLP-1 RA = glucagon-like peptide-1 receptor agonist DPP4-i=dipeptidyl peptidase 4 inhibitor TZD=thiazolidinedione SGLT-2=sodium glucose cotransporter 2 inhibitor QR=quick-release AG-i=alpha-glucosidase inhibitor SU=sulfonylurea GLN=glinide AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3):

9 Algorithm to Achieve Glycemic Goals Baseline A1C > 9.0% If patient is asymptomatic with recent onset of disease and drug naïve, may consider starting with dual or triple oral regimens If symptomatic, start insulin Once A1C has improved to <7.5%, consider initiation of dual oral therapy with tapering and possible discontinuation of insulin rx AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3):

10 Risk of Hypoglycemia Plays a significant role in choice of agents in AACE algorithm For patients at highest risk of hypoglycemia, may consider close evaluation of agents chosen as well as therapeutic goal Patients with type 2 diabetes at highest risk of low blood glucose include those with: Diabetes duration >15 years Advanced macrovascular disease Hypoglycemia unawareness Limited life expectancy Severe comorbidities AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3): ; AACE Algorithm for Glycemic Control, Endocr Pract. 2009;15(6):

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12 AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3): Sitagliptin [package insert]. Whitehouse Station, NJ; Merck Co. Inc.; Saxagliptin [package insert]. Princeton, NJ; Bristol Meyers Squibb; 2009; Linagliptin [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Clinical Considerations Combining therapeutic agents with different modes of action may be advantageous Use insulin sensitizers such as metformin and/or TZDs as part of the therapeutic regimen in most patients (unless contraindicated or intolerance to these agents has been demonstrated) Insulin and secretagogues are the only medications that cause significant hypoglycemia Therefore, dosage of secretagogues or insulin should be adjusted as blood glucose levels decline, when used in combination with metformin, TZD, DPP-4 inhibitors, and/or incretin mimetics (GLP-1 agonists) TZD = thiazolidinediones; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1

13 Clinical Considerations The weight gain associated with thiazolidinediones in some patients may be partly offset by combination therapy with metformin If A1C is elevated and preprandial blood glucose measurements are at target levels, carefully assess postprandial glucose levels Individualize treatment regimens! AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3): ;

14 Effect of Glucose-lowering Drugs on Patient Weight Therapeutic Options Weight Sulfonylurea 1,2 TZD 3,4 Insulin 5,6 Metformin 7 DPP-4 inhibitor 8 GLP-1 receptor agonist 9 SGLT-2 Inhibitors 10 A1C = glycated hemoglobin; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; SGLT-2 = sodium glucose co-transporter-2; TZD = thiazolidinedione 1. Malone M. Ann Pharmacother. 2005;39: Glipizide [package insert]. New York, NY; Pfizer; Pioglitazone [package insert]. Deerfield, IL: Takeda Pharmaceuticals America; Rosiglitazone [package insert]. Research Triangle Park, NC; GlaxoSmithKline; Nathan DM, et al. Diabetes Care. 2008;31(1): Holman RR. NEJM. 2007;357(17): Metformin[package insert]. Princeton NJ; Bristol Meyers Squibb; Sitagliptin [package insert].

15 Biguanides Metformin Mechanism Insulin sensitivity Hepatic glucose production FPG more than PPG Efficacy A1C 1%-2% Advantages Disadvantages Contraindications No weight gain or hypoglycemia, potential weight loss GI side effects Lactic acidosis (rare) Renal disease; CHF Combinations available with SU, TZD, repaglinide, and DPP-4 inhibitors A1C = glycated hemoglobin; CHF = congestive heart failure; DPP-4 = dipeptidyl peptidase-4; FPG = fasting plasma glucose; GI = gastrointestinal; PPG = post-prandial glucose; SU = sulfonylurea; TZD = thiazolidinedione Metformin [package insert]. Princeton NJ; Bristol Myers Squibb; 2009.

16 Mechanism Sulfonylureas and Glinides Glipizide, Glimepiride, Glyburide Repaglinide, Nateglinide Insulin secretion FPG PPG Efficacy Advantages Moderate Strong short term efficacy Disadvantages Contraindications Combinations available with metformin, TZD FPG = fasting plasma glucose; PPG = post-prandial glucose; TZD = thiazolidinedione Weight gain, hypoglycemia, tend to lose efficacy after several years Avoid in severe hepatic and renal impairment Glyburide [package insert]. New York, NY; Pfizer; Glipizide [package insert]. New York, NY; Pfizer; Glimepiride [package insert]. Scoppito, Italy; Aventis Pharma S.p.A; Kahn SE, et al. NEJM. 2006;355:23.

17 Sulfonylurea Driven Insulin Secretion is Not Glucose Sensitive SU Ca ++ ATP-sensitive K + channel SUR Depolarization Voltage-dependent Ca ++ channel K + h ATP mitochondrion Pyruvate Glucose-6-Phosphate Glucokinase Nucleus (islet transcription factors) Secretory granules GLUT 2 Glucose Insulin and amylin

18 Thiazolidinediones Pioglitazone, Rosiglitazone A1C = glycated hemoglobin; ALT = alanine aminotransferase; CHF = congestive heart failure; FPG = fasting plasma glucose; PPG = post-prandial glucose Pioglitazone [package insert]. Deerfield, IL: Takeda Pharmaceuticals America. 2011; Rosiglitazone Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline Mechanism Insulin sensitivity, especially at muscle, lowers both FPG and PPG, but effect may be delayed Efficacy Moderate ( A1C 1.0%-1.5%) Advantages No hypoglycemia, no reliance on renal excretion Disadvantages Contraindications Fluid retention, edema, heart failure, weight gain, slow onset of action, bone fractures, macular edema, osteoporosis, anemia, and bladder cancer Class III or IV CHF or hepatic impairment w/alt >2.5 times upper normal limits Combinations available with metformin and sulfonylurea

19 TZD MECHANISM OF ACTION Effect of Meds on Fat Topography IR, TG, FFA Insulin, BP, Inflam. En Dys. Intra-muscular fat TZD Subcutaneous fat IR, TG, FFA Insulin, BP Inflam. En Dys. Intra-abdominal fat Intra-hepatic fat Direct PPAR effect on vascular cells to decrease endothelial dysfunction and inflammation

20 Alpha-Glucosidase Inhibitors Acarbose, Miglitol Mechanism Efficacy Advantages Disadvantages Contraindications Rate of gut polysaccharide breakdown, thereby slowing absorption Modest ( A1C 0.5%-1.0%), PPG lowering Weight-neutral, non-systemic drug, targets postprandial glucose Bloating, flatulence, diarrhea w/slow titration, frequent dosing Severe renal impairment, diabetic ketoacidosis, malabsorption, obstruction, inflammatory bowel, or conditions aggravated by gas production Combinations available with sulfonylureas A1C = glycated hemoglobin; PPG = post-prandial glucose Acarbose [package insert]. Wayne, NJ; Bayer HealthCare Pharmaceuticals Inc.; Miglitol [package insert]. Wayne, NJ; Bayer HealthCare Pharmaceuticals Inc.; 2010.

21 Mechanism Dopamine Receptor Agonist Bromocriptine Exact mechanism of action unclear, believed to reduce sympathetic tone, inflammation, and insulin resistance Efficacy Modest ( A1C 0.5%) Advantages Disadvantages Contraindications May decrease cardiovascular risk Hypotension, Syncope, Hypoglycemia, Nausea History of psychosis or during breastfeeding. Use caution with renal or hepatic impairment. Cincotta et al. Taylor and Francis, Eds Hansen, B Shafrir, E London, Defronzo RA et al. Diabetes Care Apr;34(4):

22 Fast-Acting Bromocriptine Safety Trial Cumulative Percent Composite CVD Endpoint HR 0.58; 95% CI, RRR=42% Bromocriptine *MI, Stroke, hospitalization unstable angina, hospitalization CHF, or coronary revasc. KM Curve: the separation in favor of Bromocriptine begins 3 months and persists through the end of the study CHF = congestive heart failure; CVD = cardiovascular disease; MI = myocardial infarction Gaziano M. Diabetes Care, 2010 Jul;33(7):

23 Glycemic Benefit of Ranolazine: Proportional to Baseline HgA1c

24 Bile Acid Sequestrants Colesevelam Mechanism Raises cholecystokinin which slows gastric emptying and post prandial glucose Efficacy Modest ( A1C 0.5%) Advantages Disadvantages LDL-C, weight neutral, no hypoglycemia, can complement statin treatment in lowering LDL and cardiac event risk Constipation, nausea, dyspepsia, myalgia, pharyngitis, triglycerides, drug interactions Contraindications A1C = glycated hemoglobin; LDL-C = low-density lipoprotein cholesterol; TG = triglyceride History of bowel obstruction, TGs > 500 mg/dl; history of hypertriglyceridemia-induced pancreatitis Bays HE, et al. Arch Intern Med. 2008;168: Fonseca VA, et al. Diabetes Care. 2008; 31: Goldberg RB, et al. Arch Intern Med. 2008;168: ; Colesevelam [package insert]. Parsippany, NJ; Daiichi Sankyo, 2011.

25 Strategies for Enhancing GLP-1 Action GLP-1 receptor agonists (injectable therapies) Exenatide Liraglutide DPP-4 inhibitors (oral therapies) Inhibit actions of DPP-4 Sitagliptin, Saxagliptin, Linagliptin, Alogliptin

26 Drucker D. J. Cell Metabolism 2006 Summary of Incretin Actions on Different Target Tissues Neuroprotection Appetite Brain Stomach Heart Gastric emptying Liver Cardioprotection Cardiac output Glucose production Insulin sensitivity Muscle GLP-1 GI tract Insulin secretion Glucagon secretion Insulin biosynthesis b cell proliferation b cell apoptosis

27 Characteristics of DPP-4 Inhibitors Alogliptin, Linagliptin, Saxagliptin, Sitagliptin Mechanism Inhibit enzymatic degradation of GLP-1 and GIP; glucose-dependent Efficacy Decrease A1C levels 0.6% 0.9% Dosing Side effects Main risk Once daily Headaches, nasopharyngitis Viral infection; long-term safety unknown A1C = glycated hemoglobin; GIP = gastric inhibitory polypeptide; GLP-1 = glucagon-like peptide-1 Rosenstock J, et al. Curr Opin Endocrinol Diabetes Obes. 2007;14: Nathan DM, et al. Diabetes Care. 2008;31:

28 A1C (%) Glucose Control With Sitagliptin: Selected Mono and Combination Therapy Studies Monotherapy vs Glipizide 52 Weeks 1 Initial Combo w/ Metformin 24 Weeks 2 Add-on to Metformin 24 Weeks 3 Add-on to Insulin 24 Weeks 4 Add-on to Pioglitazone vs Met + Pio 12 Months 5 Add-on to Rosiglitazone + Metformin 54 Weeks 6 N Treatment Sit Glip Sit Met Sit+ Met Met Sit+ Met Ins Sit+ Ins Met + Pio Sit + Pio Rosi + Met Sit + Rosi + Met Baseline A1C (%) * * *P<0.001 vs active comparator monotherapy. P<0.001 vs active comparator dual therapy. 1. Nauck MA, et al. Diabetes Obes Metab. 2007;9: Goldstein BJ, et al. Diabetes Care. 2007;30: Charbonnel B, et al. Diabetes Care. 2006;29: Vilsbøll T, et al. Diabetes Obes Metab. 2010;12: Derosa G, et al. Metab Clin Exp. 2010;59: Dobs AS, et al. J Diabetes. 2013;5: *

29 Weight (kg) Weight Changes With Saxagliptin: Mono and Combination Therapy Monotherapy 24 Weeks 1 Initial Combo w/ Metformin 24 Weeks 2 Add-on to Metformin 24 Weeks 3 Add-on to Metformin 18 Weeks 4 Add-on to Glyburide vs Uptitration 24 Weeks 5 Add-on to TZD 24 Weeks 6 N Treatment PBO Sax Met Sax + Met Met Sax + Met Sit + Met Sax + Met Gly Sax + Gly TZD Sax + TZD * *P=0.01 vs glyburide uptitration.. 1. Rosenstock J, et al. Curr Med Res Opin. 2009;25: Jadzinsky M, et al. Diabetes Obes Metab. 2009;11: DeFronzo RA, et al. Diabetes Care. 2009;32: Scheen AJ, et al. Diabetes Metab Res Rev. 2010;26: Chacra AR, et al. Int J Clin Pract. 2009;63: Hollander P, et al. J Clin Endocrinol Metab. 2009;94:

30 Patients Reporting Hypoglycemia (%) Hypoglycemia With Linagliptin: Mono and Combination Therapy Monotherapy Initial Combo w/ 24 Weeks 1 Metformin 24 Weeks 2 Initial Combo w/ Pioglitazone 24 Weeks 3 Add-on to Metformin 24 Weeks 4 Add-on to Metformin 2 Years 5 Add-on to Metformin + SU 24 Weeks 6 N Treatment PBO Lin Lin Met HD Lin + Met LD Lin + Met HD Pio Lin + Pio Met Lin + Met Glim + Met Lin + Met Met + SU Lin + Met + SU HD, high-dose metformin (1000 mg twice daily); LD, low-dose metformin (500 mg twice daily). 1. Del Prato S, et al. Diabetes Obes Metab. 2011;13: Haak T, et al. Diabetes Obes Metab. 2012;14: Gomis R, et al. Diabetes Obes Metab. 2011;13: Taskinen MR, et al. Diabetes Obes Metab. 2011;13: Gallwitz B, et al. Lancet. 2012;380: Owens DR, et al. Diabet Med. 2011;28:

31 A1C (%) Glucose Control With Alogliptin: Mono and Combination Therapy Monotherapy Initial Combo w/ 26 Weeks 1 Pioglitazone 26 Weeks 2 Add-on to Metformin 26 Weeks 3 Add-on to Glyburide 26 Weeks 4 Add-on to Met + Pio 52 Weeks 5 Add-on to Insulin +/- Met 26 Weeks 6 N Treatment PBO Alo Pio Alo Alo + Pio Baseline A1C (%) Met Alo + Met Gly Alo + Gly Met + Pio Alo + Met + Pio Ins +/- Met Alo + Ins +/- Met * * * * * P< vs comparator. * 1. DeFronzo RA, et al. Diabetes Care. 2008;31: Rosenstock J, et al. Diabetes Care. 2010;33: Nauck MA, et al. Int J Clin Pract. 2009;63: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Bosi E, et al. Diabetes Obes Metab. 2011;13: Rosenstock J, et al. Diabetes Obes Metab. 2009;11:

32 Renal Glucose Transport in Type 2 DM With increasing plasma glucose, filtered glucose increases in linear relationship When transport system becomes saturated, excess glucose is excreted in urine Renal threshold for glucose is 200 mg/dl in normal glucose tolerant individuals In patients with type 2 DM, transport maximum for glucose increases, and glucosuria occurs at more elevated glucose levels Glucose reabsorption enhanced, worsening hyperglycemia Bays, H. Diabetes Therapy, 2013

33 Bays, H. Diabetes Therapy, 2013 Chao EC, et al. Nat Rev Drug Discovery. 2010;9: Sodium Glucose Co-Transporter 2 Reabsorption of glucose is mediated by SGLTs in proximal convoluted tubule Independent of insulin SGLT2 and SGLT1 located on luminal surface of epithelial cells lining proximal convoluted tubule SGLTs in other organs 2: liver 1: small intestine S1 segment of proximal tubule: SGLT2 S3 segment of proximal tubule: SGLT1 90% reabsorption 10% reabsorption 90% glucose is reabsorbed in S1 by SGLT2 Low affinity, high capacity transporter 10% reabsorbed in S3 by SGLT1 High affinity, low capacity transporter

34 Mechanism of action: SGLT2 Inhibitors Decrease reabsorption of glucose in the proximal convoluted tubule Decrease renal threshold so urinary glucose excretion occurs at lower plasma glucose concentration FDA approved Canagliflozin Dapagliflozin Empagliflozin Bays, H. Diabetes Therapy, 2013

35 SGLT 2 INHIBITION: MEETING UNMET NEEDS IN DIABETES CARE Corrects a Novel Pathophysiologic Defect Reduces HbA 1c Promotes Weight Loss Improves Glycemic Control and CVRFs Complements Action of Other Antidiabetic Agents Reduces Blood Pressure No Hypoglycemia Reversal of Glucotoxicity

36 Renal Tubular Lumen SGLT2 Glucose Na+ Interstitium

37 Mechanism SGLT2 Inhibitors Canagliflozin, Dapagliflozin, Empagliflozin Inhibits sodium-glucose transport protein subtype 2 (SGLT2) which is responsible for at least 90% of glucose reabsorption in the kidney causing blood glucose is eliminated in the urine Efficacy Modest ( A1C %) Advantages Disadvantages Contraindications Insulin-independent glucose reduction, Low risk of hypoglycemia, Weight loss (to 4% BW), Blood pressure-lowering Osmotic diuresis causing Polyuria and lightheadedness, Bacterial urinary tract infections ( 5%), Fungal genital infections ( 10%), Increased LDL cholesterol, Hyperkalemia (canagliflozin), Bladder cancer concerns (dapagliflozin) History of genital fungal infections, caution in chronic kidney disease Invokana [Package Insert] Janssen Pharmaceuticals, Inc. Titusville, NJ.; Lavalle-gonzález FJ, Januszewicz A, Davidson J, et al. Diabetologia. 2013; Stenlöf K, Cefalu WT, Kim KA, et al. Diabetes Obes Metab. 2013;15(4):372-82; Burki TK. Lancet. 2012;379(9815):507.

38 Canagliflozin Effects on A1c A1c Change % 0.2 Monotherapy Add on to Metformin vs. Glimepiride + Metformin Comb with Met + SU Comb with Met + SU vs. sitagliptin Comb with Met and pio Add on to Insulin mg 300 mg placebo/comparator Invokana Package Insert, 2013

39 Dapagliflozin Effects on Weight Weight Change in kg 2 Initial comb with metformin Add on to metformin Add on to met vs. glipizide + met 1.4 Comb with glimepiride Comb with pio Comb with sitagliptin Comb with insulin mg 10 mg Placebo/comparator Farxiga Package Insert, 2014

40 Empa-Reg reduction in All-cause mortality HR 0.68 (95% CI 0.57, 0.82) p< Kaplan-Meier estimate. HR, hazard ratio 40

41 Inhalable Insulin In June 2014, the FDA approved the first rapid-active, insulin human inhalation powder for glycemic control in adults with diabetes 1 The inhalable insulin is rapid-acting and should be administered at the start of each meal 2 In patients with T1DM, inhalable insulin should be used in combination with long-acting insulin 2 A black box warning cautions against use in patients with chronic lung disease, such as asthma or COPD 2 Use of inhalable insulin can cause acute bronchospasm in these patients 1. U.S. Food and Drug Administraion. News Release Afrezza Prescribing Information. MannKind. 2014

42 Landmark Glycemia Trials Action to Control Cardiovascular Risk in Diabetes (ACCORD) Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation (ADVANCE) Veterans Affairs Diabetes Trial (VADT) All conducted in: Older patients ( 60 years of age) Patients with cardiovascular disease (CVD; 1/3 to 1/2 of cohorts) or 1 CVD risk factors Ray et al. Lancet. 2009;373:

43 A1C Targets in ADVANCE, VADT, and ACCORD ADVANCE ACCORD VADT A1C (%) A1C = glycated hemoglobin; ACCORD = The Action to Control Cardiovascular Risk in Diabetes study; ADVANCE = The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation trial; VADT = Veterans Affairs Diabetes Trial The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 2008;358: Abraira, C, et al. J Diab Comp, 2003; Patel, A. et al. N Engl J Med, 2008;358:

44 Severe Hypoglycemia In ACCORD, ADVANCE and VADT ACCORD ADVANCE VADT Intensive Standard Intensive Standard Intensive Standard (% / year) 3.1% 1.1% 0.7% 0.4% 12.0% 4.0% ACCORD = The Action to Control Cardiovascular Risk in Diabetes study; ADVANCE = The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation trial; VADT = Veterans Affairs Diabetes Trial The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008; 358: Abraira, C, et al. J Diab Comp, 2003; Patel, A. et al. N Engl J Med, 2008;358:

45 CVD Outcomes In ACCORD, ADVANCE, and VADT ACCORD ADVANCE VADT Intensive Standard Intensive Standard Intensive Standard Baseline 8.1% 8.1% 7.5% 7.5% 9.4% 9.4% Final 6.4% 7.5% 6.4% 7.0% 6.9% 8.4% CVD/year 2.1% 2.3% 2.0% 2.1% 3.8% 4.9% ACCORD = The Action to Control Cardiovascular Risk in Diabetes study; ADVANCE = The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation trial; CVD = cardiovascular disease; VADT = Veterans Affairs Diabetes Trial The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008; 358: Abraira, C, et al. J Diab Comp, 2003; Patel, A. et al. N Engl J Med, 2008;358:

46 Probability of Non-fatal Myocardial Infarction Events with Intensive Glucose-lowering vs. Standard Treatment Non-fatal myocardial infarction Ray et al. Lancet. 2009;373:

47 Probability of All-cause Mortality with Intensive Glucose-lowering vs. Standard Treatment All-cause mortality Ray et al. Lancet. 2009;373:

48 Implications for Clinical Care The lack of significant reductions in CVD events should not lead clinicians to abandon the general target A1C of <7.0% or <6.5% There is still a proven reduction in microvascular complications! Patients with diabetes need comprehensive care involving lipids, BP, and glycemic control Severe and/or frequent hypoglycemia should be avoided Hypoglycemia is associated with sequelae that increase mortality, such as arrhythmia caused by lengthened QT interval A1C = glycated hemoglobin; BP = blood pressure; CVD = cardiovascular disease Skyler JS, et al. J Am Coll Cardiol 2009;53: ; Currie CJ et al Lancet, 2010;375(9713):481-9.

49 UKPDS: Benefits of Glycemic Control Every 1% decrease in A1C led to significant reductions in diabetes-related complications 14% 21% 37% 43% Risk of myocardial infarction Risk of diabetesrelated death Risk of microvascular complications Risk of amputation or PVD Death Decrease was statistically significant for all comparisons shown Stratton IM et al. BMJ. 2000;321:

50 UKPDS: United Kingdom Prospective Diabetes Study Follow-Up A1C Mean A1C levels for patients originally assigned to receive either sulfonylurea insulin or conventional therapy are shown Clinical data were not available in years 6 through 10 (when questionnaires were used) Holman R et al NEJM, 2008;359:

51 UKPDS: United Kingdom Prospective Diabetes Study Follow-Up Any diabetes-related endpoint Study follow-up revealed a sustained decrease in the number of diabetesrelated endpoint events for patients who received initial intensive treatment Holman R et al NEJM, 2008;359:

52 UKPDS: United Kingdom Prospective Diabetes Study Follow-Up All-cause mortality A similar long-term benefit in terms of reduced mortality risk was observed for patients who received initial intensive treatment Holman R et al NEJM, 2008;359:

53 Myocardial Infarction Hazard Ratio (fatal or non-fatal myocardial infarction or sudden death) Intensive (SU/Ins) vs. Conventional Glucose Control HR (95%CI) Conventional Intensive Δ Ins = insulin; HR = hazard ratio; SU = sulfonylurea Holman R et al NEJM, 2008;359:

54 Myocardial Infarction Hazard Ratio UKPDS 10-year follow-up (fatal or non-fatal myocardial infarction or sudden death) Intensive (metformin) vs. conventional glucose control Conventional Intensive Δ Holman R et al NEJM, 2008;359:

55 Glucose and Cardiovascular (CV) Risk In Advanced Type 2 Diabetes If other CV risk factor control is good, there is no additional CV benefit of lowering A1C from 8.4% to 6.9% in older people with advanced DM (VADT) If other CV risk factor control is good, there may be CV harm in lowering A1C from 7.5% to 6.4% in older people with advanced DM (ACCORD), perhaps due to hypoglycemia (VADT) Therefore, it is important to individualize A1C targets A1C = glycated hemoglobin; ACCORD = The Action to Control Cardiovascular Risk in Diabetes study; CV = cardiovascular; DM = diabetes mellitus; VADT = Veterans Affairs Diabetes Trial The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 2008; 358: Patel, A. et al. N Engl J Med, 2008;358:

56 Treatment of Type 2 Diabetes What Have We Learned? Outlined the clinical considerations in the selection of pharmacotherapy for type 2 diabetes Discussed the role of combination therapy and when it should be initiated based on A1C goals Discussed modes of action and clinical potential of recently introduced agents in the management of patients with type 2 diabetes Explained the implications of recent clinical trials and metaanalyses on clinical practice decisions