MANAGING THE HYPERGLYCEMIA OF DIABETES: SHOULD CVOTs IMPACT MEDICATIONS?

Transcription

1 MANAGING THE HYPERGLYCEMIA OF DIABETES: SHOULD CVOTs IMPACT MEDICATIONS? Ralph A. DeFronzo, M.D. Professor of Medicine Chief, Diabetes Division University of Texas Health Science Center San Antonio, Texas

2 HYPERGLYCEMIA AND MICROVASCULAR COMPLICATIONS Retinopathy Nephropathy Neuropathy

3 1 UKPDS: EPIDEMIOLOGIC ANALYSIS MICROVASCULAR ENDPOINTS Stratton et al, BMJ 321:45412, 2 37% decrease per 1% reduction in HbA 1C Hazard Ratio 5 1 P<.1 adjusted for age, sex, smoking, albuminuria, BP, LDL, HDL, TG HbA 1C (%)

4 MACROVASCULAR DISEASE* Heart attack Stroke PVD (Amputation) *accounts for ~8% of all mortality in T2DM NDDG; Diabetes in America, 1995

5 WHAT ROLE DOES HYPERGLYCEMIA PLAY IN THE PATHOGENESIS OF ATHEROSCLEROSIS IN T2DM?

6 UKPDS: EPIDEMIOLOGIC ANALYSIS CARDIOVASCULAR ENDPOINTS Stratton et al, BMJ 321:45412, 2 Hazard Ratio 1 1 MYOCARDIAL INFARCTION 14% decrease per 1% reduction in HbA 1C STROKE 12% decrease per 1% reduction in HbA 1C P<.1 P< HbA 1C (%)

7 UKPDS: RISK REDUCTION IN DIABETES RELATED COMPLICATIONS FOR 1% DECLINE IN HbA 1C Risk Reduction (%) UKPDS, Lancet 352:837853, %** Microvascular 14% 12% MI P=NS STROKE

8 If hyperglycemia does not play a major role in the development of ASCVD in T2DM, what factors are responsible for the accelerated atherogenesis?

9 INSULIN RESISTANCE SYNDROME Obesity (visceral) Diabetes/IGT Hypertension Dyslipidemia Increased PAI1 Endothelial Dysfunction Lipotoxicity NAFLD/NASH Inflammation ASCVD Hyperinsulinemia INSULIN RESISTANCE

10 INSULIN SENSITIVITY IN THE IRS Glucose Uptake (mg/m 2 min) Bressler & DeFronzo, Diabetologia 39:13455, 1996 CON Lean T2DM * p <.1 vs CON ** p <.1 vs CON ** * * * * Obese NGT HTN Hyper Trigly CAD *

11 PREDICTIVE (%) VALUE OF FRAMINGHAM CARDIOVASCULAR RISK ENGINE IN MEN D Agostino RB et al, JAMA 286:1887, 21 1 PERCENT (%) White (M) White UNEXPLAINED RISK=31% Black White (F) Japanese Amer Hispanic Native Amer White 69% FHS ARIC ARIC FHS HHP PR SHS CHS MEAN

12 ALL CAUSE MORTALITY AND CARDIOVASCULAR DEATH IN T2DM (N=2,287,362) AND MATCHED CONTROLS (N=457,473) IN SWEDISH NATIONAL DIABETES REGISTRY Rawshani et al, NEJM 376:14718, 217 Death from any Cause Death from Cardiovascular Disease 4 25 Incidence Rate (per 1, personyr) Controls T2DM Incidence Rate (per 1, personyr) Controls T2DM

13 ANTIDIABETIC MEDICATIONS WITH DOCUMENTED CARDIOVASCULAR BENEFIT Pioglitazone GLP1 RAs SGLT2 INHIBITORS

14 mg/kg FFM min EFFECT OF THIAZOLIDINEDIONES ON INSULINMEDIATED GLUCOSE DISPOSAL Miyazaki & DeFronzo, Diabetologia 44: 221, 21 Diabetes Care 24: 71, 21 * * Before PIO ROSI GLY SYNTH GOX

15 EFFECT OF TZD AND PLACEBO TREATMENT ON ISR IN RELATIONSHIP TO INSULIN RESISTANCE 1 IR x 25 2 Before Rx After Rx * * ISR (AUC) Glucose (AUC) * Gastaldelli, DeFronzo et al, AJP 292:E87183, 27

16 PROACTIVE In high risk type 2 diabetics: To examine whether pioglitazone reduces total mortality and macrovascular morbidity 19 European Countries 5238 Type 2 Diabetics

17 PIOGLITAZONE REDUCES CARDIOVASCULAR EVENTS KaplanMeier Event Rate PROACTIVE (n=5238): TIME TO DEATH, MI, OR STROKE Plc PIO # Events LANCET 366:127989,25 3 Year Estimate 14.4% 12.3% Placebo P=.27 HR =.84 Pioglitazone TIME (months) CARDIOVASCULAR OUTCOMES FROM PIOGLITAZONE METAANALYSIS OF CLINICAL TRIALS (n = 5,23) FDA and Center for Drug Evaluation & Research; July 3,27 Comparator Pioglitazone (n = 5,944) TIME (weeks) HR=.75 CI =.551.2

18 EFFECT OF PIOGLITAZONE VERSUS PLACEBO ON RECURRENT STROKE / MI IN IRIS STUDY 1 Kernan et al, NEJM, February 17, 216 Cumulative Probability of Eventsfree Survival HR =.76 95% CI = P =.7 N = 3,876 Pioglitazone Placebo Number at risk Pioglitazone Placebo Years since Randomization

19 ANTIDIABETIC MEDICATIONS WITH DOCUMENTED CARDIOVASCULAR BENEFIT Pioglitazone GLP1 RAs SGLT2 INHIBITORS

20 INCRETINS In response to equivalent hyperglycemic stimuli, ORAL glucose elicits a greater insulin response than IV glucose Glucagonlike Peptide 1 (GLP1) and GlucoseDependent Insulinotrophic Polypeptide (GIP) account for ~9% of the incretin effect and 67% of insulin secreted during a meal

21 GLP1 ANALOGUES Exenatide BID Liraglutide Exenatide QW Albiglutide QW Dulaglutide QW Lixisenatide Semaglutide QW Intarcia 65 Semaglutide oral

22 GLP1 RECEPTOR AGONISTS Effectively reduce HbA 1c Preserve beta cell function Promote weight loss Correct known pathophysiologic defects in T2DM Do not cause hypoglycemia Have an excellent safety profile Reduce cardiovascular events Rad 3/2/ Triplitt & DeFronzo, Expert Rev Endo Metab 1:32941, 26

23 TIME COURSE OF EFFECT OF EXENATIDE ON HbA 1c HbA 1c (%).5 1. Time (weeks) Placebo Exenatide 1 g bid Baseline HbA 1C =8.3% DeFronzo et al, Diabetes Care 28:19211, 25 Klonoff et al, Curr Med Res Opin 24:275285, Exenatide 1 g bid PlaceboControlled Trials OpenLabel Extension

24 MOLECULAR ACTIONS OF GLP1 ON BETA CELL INSULIN SECRETION Glucose Dependent camp PKA Epac2 IC Ca ++ PI3K Insulin Secretion INSULIN GENE TRANSCRIPTION Pdx1 replenishes beta cell insulin stores prevents beta cell exhaustion BETA CELL GLUCOSE SENSITIVITY increased GLUT2 and Glucokinase restores glucose responsitivity to resistant beta cells BETA CELL APOPTOSIS PI3K/Akt inhibition of caspase activation

25 DEFN7 53/9 ETI OLO GYO FT2 DM Imp aired Insul in Inc rease dlip olysis Secre tion Increa HG sed P Hype rglyc emia Decrea U sedg ptake lucose GLP1 Decreased Insulin Secretion OMINOUS OCTET Decreased Incretin Effect GLP1 Increased Lipolysis Islet cell Increased Glucagon Secretion GLP1 Increased HGP GLP1 HYPERGLYCEMIA Neurotransmitter Dysfunction GLP1 Increased Glucose Reabsorption Decreased Glucose Uptake GLP1 Diabetes 58:773795, 29

26 EFFECT OF LIRAGLUTIDE ON MACE IN LEADER EFFECT OF SEMAGLUTIDE ON MACE IN SUSTAIN6 EFFECT OF ONCE WEEKLY EXENATIDE ON MACE IN EXSCEL Patients with Events (%) N = 9,34 HR =.87 95% Cl, P=.1 Placebo Liraglutide N = 3297 HR =.74 95% Cl, P =.2 Placebo Semaglutide N = 14,752 HR =.91 95% CI =.831. P=.6 Placebo Exenatide Years Weeks Years Marso et al, NEJM June 13, 216 Marso et al, NEJM, Sept 16, 216 Holman et al, NEJM, Sept 13, 217

27 DPP4 INHIBITORS

28 EFFECT OF SAXAGLIPTIN ON HbA 1c : CHANGE FROM PLACEBO (BASELINE HbA 1c 8.%) Int J Clin Prac 63:1395, 29; Diab Ob Metab 1:376, 28 Diab Care 32:1649, 29; JCEM 94:481, 29 HbA 1c (%) DRUG NAIVE GLYBURIDE METFORMIN PIO/ROSI ADDITION OF SAXAGLIPTIN TO:

29 KAPLANMEIER PLOT TO TIME OF OCCURRENCE OF PRIMARY (MACE) ENDPOINT WITH SAXAGLIPTIN (N=16,492) Scirica et al, NEJM 369:131726, 213 Patients with End Point (%) HR = 1. (95% CI, ) P<.1 for noninferiority P=.99 for superiority 2 yr KaplanMeier rate: Saxagliptin, 7.3% Placebo, 7.2% Days Saxagliptin Placebo SAXA increased risk of hospitalization for heart failure and hypoglycemia 72 9

30 ANTIDIABETIC MEDICATIONS WITH DOCUMENTED CARDIOVASCULAR BENEFIT Pioglitazone GLP1 RAs SGLT2 INHIBITORS

31 SGLT2 INHIBITION: A NOVEL TREATMENT STRATEGY FOR TYPE 2 DIABETES MELLITUS Dapagliflozin Canagliflozin Empagliflozin

32 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

33 EFFECT OF Empagliflozin ON MACE IN EMPAREG EFFECT OF EMPAGLIFLOZIN ON CV DEATH IN EMPAREG EFFECT OF EMPAGLIFLOZIN ON HOSPITALIZATION FOR HEART FAILURE Patients with Events (%) Hazard ratio=.86 (95% CI,.74.99) p=.4 N = 7,2 Placebo Empagliflozin Months Hazard ratio =.62 (95% Cl,.49.77) P<.l Placebo Empagliflozin Months 7 Hazard ratio =.65 6 (95% Cl,.5.85) P= Placebo Empagliflozin Months Zinman et al, NEJM, Sept 2, 215 Zinman et al, NEJM, Sept 2, 215

34 KEY OUTCOMES IN CANVAS AND EMPA REG OUTCOME CV death, nonfatai MI, nonfatal stroke CV death Hazard ratio (95% CI) CANVAS Program EMPAREG OUTCOME Nonfatal myocardial infarction Nonfatal stroke Hospitalization for heart failure CV death or hospitalization for heart failure Allcause mortality Progression to macroalbuminuria* Renal composite *CANVAS Program endpoints comparable with EMPAREG OUTCOME. Zinman B et al. N Engl J Med. 215; 373: Wanner K et al. N Engl J Med. 216; 375: Favors SGLT2i Favors placebo

35 CONTRIBUTION OF SGLT2 INHIBITORS TO ALLCAUSE DEATH AND HHF IN CVDREAL (N=39,46) Kosiborad et al, Circulation 136:249259, 217 Proportion of Exposure Time (%) EMPA 6.7% EMPA 5.3% EMPA 8.3% DAPA 19.3% DAPA 51.% CANA 42.3% All countries combined CANA 75.4% US only DAPA 9.1% European countries combined CANA 1.5

36 ALLCAUSE DEATH IN CVDREAL Number # of Events HR US 143, Norway 25, Denmark 18, Sweden 18, UK 1, Total 215, (P<.1) Favor SGLT2i Hazard Ratio: Favor OGLD

37 HOSPITALIZATION FOR HEART FAILURE IN CVD REAL Number # of Events HR US 233, Norway 25, Denmark 18, Sweden 18, UK 1, Germany Total 39, (P<.1) Favor SGLT2i Hazard Ratio: Favor OGLD

38 KAPLAN MEIER CURVES FOR MACE AND HHF IN CVREAL NORDIC Persson F et al, Diab Ob Metab, 217 Cum Incidence (%) 4 2 HR=.79 P=.6 DPP4i (n=3,681).5 MACE Dapagliflozin (n=1,227) Years HEART FAILURE HOSPITALIZATION Cum Incidence (%) 4 2 HR=.62 P<.1.5 DPP4i 1. Years Dapagliflozin

39 DECLARETIMI58 TRIAL: CURRENTLY THE LARGEST OUTCOME TRIAL ONGOING INVOLVING SGLT2 INHIBITORS Study is well powered to answer the question as to whether DAPAGLIFLOZIN COULD OFFER CV BENEFITS, as well as addressing other safety related questions. 1 Plans to include 17,15 individuals with T2DM and has indicated a target of 139 3point MACE Primary Outcome Measures: [ Time Frame: up to 6 years ]. Time to first event included in the composite endpoint of CV death, MI or ischemic stroke THE MUCH LARGER DECLARE TIMI58: EXPECTED TO REPORT IN 218. Secondary Outcome Measures: [ Time Frame: up to 6 years ]. Time to first event of Hospitalization for Congestive Heart Failure Time to first event included in the composite endpoint of CV death, MI, ischemic stroke, hospitalization for heart failure, hospitalization for unstable angina pectoris, or hospitalization for any revascularization Time to All cause mortality Body weight change from baseline

40 SGLT2 Inhibitors and Potential CV Impact Insulin Resistance Blood pressure & Heart rate Plasma Volume Glucose Arterial stiffness Weight loss and reduced visceral fat SNS activity Uric acid Inflammation & Oxidative stress Ketones Na + H + Ang 17 AT 2 receptor

41 COMBINATION THERAPY WITH SGLT2 INHIBITOR AND GLP1 RECEPTOR AGONIST DeFronzo RA, Diab Obes Metab 19: , 217 GLP1 RAs SGLT2i GLP1 RA/SGLT2i MACE Atherogenesis Hemodynamic benefit Glycemic control (A1c) Insulin sensitivity Beta cell function Weight

42 CARDIOVASCULAR INTERVENTION TRIALS GLP1 Receptor Agonists LEADER, SUSTAIN6 EXSCEL (P=.6) Pioglitazone PROactive, IRIS, FDA Periscope, Chicago SGLT2 Inhibitor EMPAREG OUTCOME CANVAS CV REAL Metformin UKPDS (n=342)

43 THE FAB FOUR SGLT2i PIOGLITAZONE GLP1 RAs METFORMIN