Treating Diabetes To Lower Cardiovascular Disease Risk

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1 Treating Diabetes To Lower Cardiovascular Disease Risk Anne Peters, MD Profess, USC Keck School of Medicine Direct, USC Clinical Diabetes Programs

2 Disclosure of Financial Relationships 2015 Consultantship Abbott Diabetes Care Amgen BD, Biodel Janssen, Lexicon, Lilly Medscape, Merck NovoNdisk Sanofi, Takeda FDA Speakers Bureau Janssen Research Funding Janssen Medtronic Foundation

NEJM http://www.nejm.g/doi/full/10.1056/nejmoa1310799?viewt... ORIGINAL ARTICLE Changes in Diabetes-Related Complications in the United States, 1990 2010 Edward W. Gregg, Ph.D., Yanfeng Li, M.D., Jing Wang, M.

3 NEJM ORIGINAL ARTICLE Changes in Diabetes-Related Complications in the United States, Edward W. Gregg, Ph.D., Yanfeng Li, M.D., Jing Wang, M.D., Nilka Rios Burrows, M.P.H., Mohammed K. Ali, M.B., Ch.B., Debah Rolka, M.S., Desmond E. Williams, M.D., Ph.D., and Linda Geiss, M.A. N Engl J Med 2014; 370: April 17, 2014 DOI: /NEJMoa Abstract Gregg EW et al. N Engl J Med 2014;370: cases per 10,000 persons; 95% CI, 76.6 to 114.6), and the smallest absolute decline was in the number of deaths from hyperglycemic crisis ( 2.7; 95% CI, 2.4 to 3.0). Rate reductions were larger among

4 Clinical Event Rate LDL Cholesterol Targets in Diabetes CARDS PROVE IT HPS Post CABG ASCOT CARE LIPID Risk Attributable to LDL-C 4S Residual Risk of CVD? Role of other lipid and non-lipid facts LDL Cholesterol (mg/dl)

5 UKPDS: Legacy Effect of Insulin/Sulfonylurea Therapy Aggregate Endpoint Any diabetes related endpoint RRR: 12% 9% P: Microvascular disease RRR: 25% 24% P: Myocardial infarction RRR: 16% 15% P: All-cause mtality RRR: 6% 13% P: After median 8.8 years post-trial folup RRR = Relative Risk Reduction P = Log Rank Holman RR, et al. New England Journal of Medicine 2008; 359:

6 UKPDS: Legacy Effect of Insulin/Sulfonylurea vs Metfmin Therapy Holman RR, et al. New England Journal of Medicine 2008; 359:

7 Meta-Analysis of Glycemic Control Trials and Conary Heart Disease Ray KK, et al. Lancet. 2009;373:

8 Why haven t trials shown CHD risk reduction? Possible reasons that individual trials failed to show a beneficial effect on CHD Event rates were er than expected Differences in glycemic control were not large enough The intervention observation period was too sht Need to start intervention earlier in natural histy of the disease Mazzone T. Lancet ;373:

9 Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach Update to a Position Statement of the American Diabetes Association (ADA) and the European Association f the Study of Diabetes (EASD) Diabetes Care 2015;38: Diabetologia 2015; /s

The ADA/EASD Position Statement on Management of Hyperglycemia in Type 2 Diabetes ADA Richard M. Bergenstal MD Int l Diabetes Center, Minneapolis, MN John B.

10 The ADA/EASD Position Statement on Management of Hyperglycemia in Type 2 Diabetes ADA Richard M. Bergenstal MD Int l Diabetes Center, Minneapolis, MN John B. Buse MD, PhD University of Nth Carolina, Chapel Hill, NC Anne L. Peters MD Univ. of Southern Califnia, Los Angeles, CA Richard Wender MD Thomas Jefferson University, Philadelphia, PA Silvio E. Inzucchi MD (co-chair) Yale University, New Haven, CT EASD Michaela Diamant MD, PhD VU University, Amsterdam, The Netherlands Ele Ferrannini MD University of Pisa, Pisa, Italy Michael Nauck MD Diabeteszentrum, Bad Lauterberg, Germany Apostolos Tsapas MD, PhD Aristotle University, Thessaloniki, Greece David R. Matthews MD, Dphil Oxfd University, Oxfd, UK

11 ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, Patient-Centered Approach...providing care that is respectful of and responsive to individual patient preferences, needs, and values - ensuring that patient values guide all clinical decisions. Gauge patient s preferred level of involvement. Exple, where possible, therapeutic choices. Consider using decision aids. Shared Decision Making a collabative process between patient and clinician, using best available evidence and taking into account the patient s preferences and values Final decisions regarding lifestyle choices ultimately lie with the patient. Diabetes Care 2012;35: ; Diabetologia 2012;55:

12 Impact of Intensive Therapy f Diabetes: Summary of Maj Clinical Trials Study Microvasc CVD Mtality UKPDS DCCT / EDIC* ACCORD ADVANCE VADT Kendall DM, Bergenstal RM. International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckwth W et al. N Engl J Med 2009;360:129. (erratum: Mitz T. N Engl J Med 2009;361:1024) Initial Trial Long Term Fol-up * in T1DM

year) 3.1% 1.1% 0.7% 0.4% 12.0% 4.0% Annual mtality 5.0% 4.0% 3.0% 2.0% 2.8% 4.

13 Lessons from Accd Severe Hypoglycemia and Mtality Risk ACCORD ADVANCE VADT Severe Hypo Intensive Standard Intensive Standard Intensive Standard (%/ year) 3.1% 1.1% 0.7% 0.4% 12.0% 4.0% Annual mtality 5.0% 4.0% 3.0% 2.0% 2.8% 4.9% 1.0% 0.0% 1.3% Intensive 1.0% Standard Bonds et al. BMJ 2010;340:b4909

14 Severe Hypoglycemia in ACCORD Patients with type 2 diabetes who experience symptomatic, severe hypoglycaemia are at increased risk of death, regardless of the intensity of glucose control. The increased risk of death seen in the ACCORD trial among participants in the intensive glycaemia control arm cannot be attributed to the increased rate of severe hypoglycaemia in intensive arm participants. Bonds et al. BMJ 2010;340:b4909

15 ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, ANTI-HYPERGLYCEMIC THERAPY Glycemic targets - HbA1c < 7.0% (mean PG mg/dl [ mmol/l]) - Pre-prandial PG <130 mg/dl (7.2 mmol/l) - Post-prandial PG <180 mg/dl (10.0 mmol/l) - Individualization is key: Tighter targets ( %) - younger, healthier Looser targets ( % ) - older, combidities, hypoglycemia prone, etc. - Avoidance of hypoglycemia PG = plasma glucose Diabetes Care 2012;35: ; Diabetologia 2012;55:

16 Figure 1. Modulation of the intensiveness of glucose ering therapy in T2DM PATIENT / DISEASE FEATURES Risks potentially associated with hypoglycemia and other drug adverse effects me stringent Approach to the management of hyperglycemia HbA1c 7% less stringent Disease duration newly diagnosed long-standing Life expectancy long sht Usually not modifiable Imptant combidities absent few / mild severe Established vascular complications absent few / mild severe Patient attitude and expected treatment effts ly motivated, adherent, excellent self-care capacities less motivated, non-adherent, po self-care capacities Potentially modifiable Resources and suppt system Readily available limited Diabetes Care 2015;38: ; Diabetologia 2015; /s

17 Multiple, Complex Pathophysiological Abnmalities in T2DM incretin effect gut carbohydrate delivery & absption _ pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA _? hepatic glucose production renal glucose excretion peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

18 Multiple, Complex Pathophysiological Abnmalities in T2DM GLP-1R agonists incretin effect DPP-4 inhibits A G I s gut carbohydrate delivery & absption Metfmin hepatic glucose production _ pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA Bile acid sequestrants Insulin Glinides S U s Amylin mimetics renal glucose excretion _ DA agonists T Z D s? peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

19 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin neutral/loss GI / lactic acidosis If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea moderate risk hypoglycemia Metfmin Sulfonylurea Metfmin edema, HF, fxs Metfmin Thiazolidinedione Thiazolidinedione Metfmin DPP-4 inhibit intermediate neutral rare Metfmin Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) est risk hypoglycemia variable Metfmin Insulin (basal) Combination injectable therapy Figure 2. Anti-hyperglycemic therapy in T2DM: General recommendations If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add mealtime insulin. In refracty patients consider adding : Metfmin Basal Insulin Mealtime Insulin Diabetes Care 2015;38: ; Diabetologia 2015; /s

Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity &

preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea moderate risk hypoglycemia Metfmin Sulfonylurea Metfmin edema, HF, fxs Metfmin Thiazolidinedione

20 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin neutral/loss GI / lactic acidosis If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea moderate risk hypoglycemia Metfmin Sulfonylurea Metfmin edema, HF, fxs Metfmin Thiazolidinedione Thiazolidinedione Metfmin DPP-4 inhibit intermediate neutral rare Metfmin Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) est risk hypoglycemia variable Metfmin Insulin (basal) Combination injectable therapy Figure 2. Anti-hyperglycemic therapy in T2DM: General recommendations If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add mealtime insulin. In refracty patients consider adding : Metfmin Basal Insulin Mealtime Insulin Diabetes Care 2015;38: ; Diabetologia 2015; /s

21 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin neutral/loss GI / lactic acidosis If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea moderate risk hypoglycemia Metfmin Sulfonylurea Metfmin edema, HF, fxs Metfmin Thiazolidinedione Thiazolidinedione Metfmin DPP-4 inhibit intermediate neutral rare Metfmin Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) est risk hypoglycemia variable Metfmin Insulin (basal) Combination injectable therapy Figure 2. Anti-hyperglycemic therapy in T2DM: General recommendations If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add mealtime insulin. In refracty patients consider adding : Metfmin Basal Insulin Mealtime Insulin Diabetes Care 2015;38: ; Diabetologia 2015; /s

22 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin neutral/loss GI / lactic acidosis If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea moderate risk hypoglycemia Metfmin Sulfonylurea Metfmin edema, HF, fxs Metfmin Thiazolidinedione Thiazolidinedione Metfmin DPP-4 inhibit intermediate neutral rare Metfmin Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) est risk hypoglycemia variable Metfmin Insulin (basal) Combination injectable therapy If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add mealtime insulin. In refracty patients consider adding : Metfmin Basal Insulin Mealtime Insulin Diabetes Care 2015;38: ; Diabetologia 2015; /s

23 Monotherapy Efficacy * Hypo risk Weight Side effects Metfmin Costs intolerance contraindication HbA1c 9% Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin neutral/loss GI / lactic acidosis If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea moderate risk hypoglycemia Metfmin Sulfonylurea Metfmin edema, HF, fxs Metfmin Thiazolidinedione Thiazolidinedione Metfmin DPP-4 inhibit intermediate neutral rare Metfmin Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) est risk hypoglycemia variable Metfmin Insulin (basal) Uncontrolled hyperglycemia (catabolic features, BG mg/dl, HbA1c 10-12%) Combination injectable therapy Basal Insulin If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add mealtime insulin. In refracty patients consider adding : Metfmin Mealtime Insulin Diabetes Care 2015;38: ; Diabetologia 2015; /s

24 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin neutral/loss GI / lactic acidosis If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea moderate risk hypoglycemia Metfmin Sulfonylurea Metfmin edema, HF, fxs Metfmin Thiazolidinedione Thiazolidinedione Metfmin DPP-4 inhibit intermediate neutral rare Metfmin Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) est risk hypoglycemia variable Metfmin Insulin (basal) Figure 2B. Anti-hyperglycemic Combination therapy injectable in T2DM: Avoidance therapy of hypoglycemia If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add mealtime insulin. In refracty patients consider adding : Metfmin Basal Insulin Mealtime Insulin Diabetes Care 2015;38: ; Diabetologia 2015; /s

25 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin neutral/loss GI / lactic acidosis If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea moderate risk hypoglycemia Metfmin Sulfonylurea Metfmin edema, HF, fxs Metfmin Thiazolidinedione Thiazolidinedione Metfmin DPP-4 inhibit intermediate neutral rare Metfmin Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) est risk hypoglycemia variable Metfmin Insulin (basal) Figure 2B. Anti-hyperglycemic Combination therapy injectable in T2DM: Avoidance therapy of weight If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add mealtime insulin. In refracty patients consider adding : Metfmin Basal Insulin Mealtime Insulin Diabetes Care 2015;38: ; Diabetologia 2015; /s

26 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin neutral/loss GI / lactic acidosis If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea moderate risk hypoglycemia Metfmin Sulfonylurea Metfmin edema, HF, fxs Metfmin Thiazolidinedione Thiazolidinedione Metfmin DPP-4 inhibit intermediate neutral rare Metfmin Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) est risk hypoglycemia variable Metfmin Insulin (basal) Figure 2C. Anti-hyperglycemic Combination therapy injectable in T2DM: Minimization therapy of costs If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add mealtime insulin. In refracty patients consider adding : Metfmin Basal Insulin Mealtime Insulin Diabetes Care 2015;38: ; Diabetologia 2015; /s

27 LookAHEAD Study Objective To determine the long-term effects (up to 13.5 years) of an intensive lifestyle intervention program designed to produce weight loss and increase physical activity on cardiovascular mbidity and mtality in overweight obese persons with type 2 diabetes. The Look AHEAD Research Group. N Engl J Med 2013;369:

28 16 Clinical Sites Seattle Denver Minneapolis Pittsburgh Boston Providence New Yk Philadelphia Baltime Los Angeles Phoenix Shiprock Memphis Winston-Salem San Antonio Houston Birmingham Baton Rouge Clinical Site Codinating Center

29 Results: Weight Loss Mean F/U 9.6 years 1-yr wt loss: 8.6% ILI 0.7% control group Study end: 6.0% ILI 3.5% control group The Look AHEAD Research Group. N Engl J Med, June 24, 2013

30 Results: Primary Outcome Events/100 person-yrs: 1.83 ILI 1.92 Control Hazard ratio 0.95 (95% CI , P=0.51) The Look AHEAD Research Group. N Engl J Med, June 24, 2013

31 Percentage Weight Loss 4-Yr Wt Loss Trajecties of 887 ILI Participants Who Lost 10% Initial Weight at Yr 1 (~35%) 4 N= Gained (9.9%) % 5-6.9% N=174 (19.6%) N=99 (11.2%) % N=152 (17.1%) 12 10% N=374 (42.2%) Years

32 Meal Replacements Kcal/wk of Activity Mean Annual Number of Meal Replacements Used in Years 2-4 Mean Weekly Kcal Expenditure at Year 4 (as Determined by Paffenbarger) p <.02 p < p < f all comparisons with > 10% group > 10% 5-9.9% 0-4.9% Gained > 10% 5-9.9% 0-4.9% Gained Weight Change- Year 4 Weight Change- Year 4

33 Metfmin: The Only Choice in Type 2 DM? Most commonly used therapy f T2 DM (2/3rds of patients) Clinical effects Lowers A1C 1-2% (especially at baseline A1C), no weight Maximal clinical effect at mg/day Possible side effects and precautions GI side effects common less well tolerated by up to 10% Not advised if significant renal liver disease, heart failure (~20%) Other features Lower CV risk in obese patients (UKPDS) Extensive clinical experience and er cost? Favable impact on cancer risk and mtality

34 Sulfonylureas and the Secretagogues How Do We Use Them Now? Most common (traditional) 2nd agent in T2 DM Stimulate insulin release during hyperglycemia and post-meal Clinical Use Inexpensive and commonly used, rapid glucose ering Limited dose effect and limited durability of effect Side effects Associated with weight and risk of hypoglycemia Precautions and contraindications Associated with risk of severe hypoglycemia (elderly, renal disease) Highest risk of hypoglycemia with GLYBURIDE May not be good f those at CVD risk (longstanding discussion)

35 Thiazolidinediones (s) Do We Target Insulin Resistance? Clinical application Targeted patients with clinical markers of insulin resistance Dyslipidemia, HTN, established CVD, central obesity May limit CVD risk and alter progression of diabetes Adverse effects and considerations Significant weight and increase risk of edema and HF Increased risk of long-bone fractures Macular edema Patient selection Higher CVD risk particularly with dyslipidemia, est. CVD Those at er risk f fracture and with central obesity, NASH Grey A et al. J Clin Endocrinol Metab. 2007;92:

36 Summary Of Pioglitazone Clinical Trials Center f Drug Evaluation & Research, July 30, 2007 PIO Meta-analysis - without PROactive PROactive 0.75 PIO Meta-Analysis plus PROactive #CV Events # of Subjects PIO COMP Hazard Ratio

37 DPP-4 Inhibits: Sitagliptin (Januvia), Saxagliptin (Onglyza), Linagliptin (Tradjenta) and Alopglitin (Nesina) Clinical Use Moderate effectiveness (A1C reduction ~ %) Use in both combo and mono therapy Unique Features Limited side effect profile, very well tolerated, pancreatitis? Weight neutral, no significant weight loss, no hypoglycemia Variable clinical response (A1C reduction %) Reduced dosing in chronic kidney disease (except f linagliptin) Saxagliptin increased risk of CHF in risk population

38 GLP-1 RA s: Exenatide (Byetta, Bydureon), liraglutide (Victoza), albiglutide (Tanzuem), dulaglutide (Trulicity) Clinical Use Lowers A1C 1 1.5% Often associated with weight loss Side Effects/Features Injected once twice daily once weekly GI side effects common; rare hypoglycemia Warnings: pancreatitis; MCT Drug-specific features Potential CVD benefits

39 Potential Cardiovascular Effects of GLP-1- Based Therapies Improved weight, SBP, lipids Improved endothelial function Increased vaselaxation Increased peripheral and conary f Increased ventricular function Decreased microvascular permeability Reduced inflammation Okerson T, Chilton R. Cardiovasc Ther 30:e146-55, 2012

40 Incretin Cardiovascular Outcome Trials Risk Facts Stable CAD-CVD-PAD ACS patients SAVOR-TIMI 53 - Saxagliptin n=16,500 TECOS - Sitagliptin n=14,000 CARMELINA (vs pbo) - Linagliptin n=8,300 CAROLINA (vs ) - Linagliptin n=6,000 LEADER - Liraglutide n=9,340 EXAMINE - Alogliptin n=5,400 ELIXA - Lixisenatide n=6,000 September 2013 September 2013 December 2014 January 2018 September 2018 January 2015 October 2015 STAIN 6 - Semaglutide n=3,297 January 2016 EXSCEL - Exenatide LAR n=14,000 REWIND - Dulaglutide n=9,622 April 2018 April 2019

41 SGLT-2 Inhibits Canagliflozin, Dapagliflozin, Empagliflozin Clinical Effects Novel mechanism of action/al agent Most will respond action independent of beta-cell function A1C reduction ~1% with 2-3 kg weight loss Possible Side Effects and Precautions Mycotic genital infections Findings due to volume depletion Don t use if egfr <45% Other Features Lowers BP slightly Raises LDL cholesterol Jacobsen LV, et al. Br J Clin Pharmacol. 2009;68: Linnebjerg H, et al. Br J Clin Pharmacol. 2007;64:

42 Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study Screening T2DM on metfmin alone HbA1c >6.8% at screening < 10 years duration at randomization Metfmin run-in Titrate metfmin to 1000 (min) 2000 (goal) mg/day HbA1c % at final run-in visit Randomization n=5000 eligible subjects Sulfonylurea (glimepiride) n=1250 DPP-IV inhibit (sitagliptin) n=1250 GLP-1 analog (liraglutide) n=1250 Insulin (glargine) n=1250

43 Reducing CVD Risk Treating T2DM o o o o Use statins, control BP, give aspirin Use diabetes drugs that don t cause hypoglycemia minimize hypos in drugs that do Improve control early and maintain it Never fget imptance of lifestyle RxList, 2014.

44 Thank You RxList, 2014.

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach Update to a Position Statement of the American Diabetes Association (ADA) and the European Association f the Study of Diabetes