Cardiovascular Safety of Incretin Based Therapy

Transcription

1 Cardiovascular Safety of Incretin Based Therapy John B. Buse, MD, PhD Verne S. Caviness Distinguished Professor Chief, Division of Endocrinology Executive Associate Dean, Clinical Research University of North Carolina School of Medicine Chapel Hill, NC Disclosures I have been an investigator and/or consultant without any direct financial benefit under contracts between his employer (the University of North Carolina) and the following companies: Amylin Pharmaceuticals, Inc., Andromeda, AstraZeneca, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Dance Biopharm, Elcelyx Therapeutics Inc., Eli Lilly and Company, GI Dynamics, GlaxoSmithKline, Halozyme Therapeutics, F. Hoffmann- La Roche Ltd., Intarcia Therapeutics, Johnson & Johnson, Lexicon, LipoScience, Medtronic, Merck, Metavention, Novo Nordisk, Orexigen Therapeutics Inc., Osiris Therapeutics Inc., Pfizer Inc., PhaseBio Pharmaceuticals Inc, Quest Diagnostics, Sanofi, Santarus, Scion NeuroStim, Takeda, ToleRx and TransTech Pharma. I am a consultant to PhaseBio Pharmaceuticals, Inc. and have received payments, reimbursement for travel and stock options for that effort.

2 Nathanson MH. Am J Med (183) year History of Anti-hyperglycemic Therapeutics Number of classes of antihyperglycemic agents Phenformin Sulphonylurea Intermediate-acting insulin SGLT-2 inhibitor Bromocriptine-QR Bile acid sequestrant DPP-4 inhibitor GLP-1 receptor agonist Amylinomimetic Basal insulin analogue Glinide Thiazolidinedione Human insulin Alpha-glucosidase inhibitor Rapid-acting insulin analogue Metformin 2 Phenformin withdrawn 0 Soluble insulin Year UGDP, DCCT and UKPDS studies. Buse, JB

3 Targeting the Incretin System Incretin secretion and/or action is arguably impaired in type 2 diabetes Endogenous incretins have very short half-life due to inactivation by DPP-4 : DPP-4 inhibitors (incretin enhancers, oral) Block DPP-4, the enzyme that inactivates endogenous incretin (GLP-1 and GIP) GLP-1 receptor agonists (incretin mimetics, injectable) DPP-4 resistant GLP-1 mimetics, analogs or fusion peptides with longer half-life Drucker DJ, Nauck MA. Lancet. 2006; 368: DPP-4 Inhibitor in vitro Selectivity (Fold Selectivity for DPP-4 vs Other Enzymes) Selectivity QPP/DPP II PEP FAPα DPP-8 DPP-9 Sitagliptin High >5 550 >5 550 >5 550 >2 660 >5 550 Vildagliptin Moderate > Saxagliptin Moderate >50 000? > Alogliptin High > > > > > Linagliptin Moderate > > > Deacon; Diabetes Obes Metab 2011 Adapted from CF Deacon; IDF, Dubai 2011

4 The GLP-1 RA Class: Pharmacokinetic Properties GLP-1 RA Short-acting (<24 hours) Long-acting ( 24 hours) Exenatide BID Lixisenatide* OD * investigational Liraglutide OD Dulaglutide OW Albiglutide OW Exenatide OW GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; BID, twice daily; OD, once daily; OW, once weekly Individual package inserts. GLP-1 Enzymatic Cleavage, GLP-1 Metabolites, and GLP-1 Receptor Agonists. Ussher JR and Drucker DJ. Circulation Research. 2014; 114: GLP-1RA = GLP-1 receptor agonists

5 Actions of GLP-1 and GLP-1RA on the Atria and Vasculature Ussher JR and Drucker DJ. Circulation Research. 2014; 114: GLP-1RA = GLP-1 receptor agonists Potential Indirect Cardiovascular Effects of GLP-1RA Ussher JR and Drucker DJ. Circulation Research. 2014; 114: GLP-1RA = GLP-1 receptor agonists

6 A Cardioactive DPP-4 Substrates SDF-1α (1-68) GLP-1 (7-36) BNP (1-32) SP(1-11) NPY (1-36) PYY (1-36) GLP-2 (1-33) GIP (1-42) Progenitor Cell B Blood Vessel BNP (3-32) Kidney GLP-1 (9-36) Heart NPY (3-36) PYY (3-36) Brain DPP-4 Adipose Tissue Ussher, J.R., and Drucker, D. J., Endocrine Reviews Fig DPP4 Inhibitor Mechanisms of Action: Cardiovascular implications Pancreatic Islets Enhance β cell function (GLP-1/GIP) Decrease glucagon (GLP-1) Intestine Decrease lipoprotein production (GLP-1) Cardioprotection? GLP-1 SDF-1 Immune Cells Increase chemotaxis Mulvihill, E., & Drucker D. J., Endo Rev 2014 DPP4 inhibitors Progenitor Cells Increase egress and homing (SDF-1)

7 GLP-1 Receptors Fairly Ubiquitously Expressed Cardiac Myocytes α and β cells CNS, PNS Heart Kidney Lung GI tract Vascular endothelial cells Medial SMCs Vascular endothelium Smooth muscle cells Endocardium Ban et al. Circulation 2008;117: Clinical Cardiovascular Effects of Incretin Based Therapies Hypertension Weight Loss Lipids Heart Rate Cardiovascular Outcomes Ischemia reperfusion injury in AMI Meta-analysis of MACE Cardiovascular Outcome Clinical Trials 14

8 Clinical Cardiovascular Effects of Incretin Based Therapies Hypertension Weight Loss Lipids Heart Rate Cardiovascular Outcomes Ischemia reperfusion injury in AMI Meta-analysis of MACE Cardiovascular Outcome Clinical Trials 15 Liraglutide vs Exenatide: HTN & Lipids Liraglutide Exenatide Estimated Treatment Difference P-value Blood Pressure Systolic BP (mmhg) Diastolic BP (mmhg) Lipid profiles Total cholesterol (mmol/l) LDL cholesterol (mmol/l) VLDL cholesterol (mmol/l) HDL cholesterol (mmol/l) Triglycerides (mmol/l) Free fatty acids (mmol/l) Apolipoprotein B (g/l) Buse et al. Lancet 2009;374:

9 Weight Changes Drucker D. Lancet 2006; 368: Heart Rate and GLP-1 Receptor Agonists Astrup et al. Int J Obesity 2011; doi: /ijo

10 Clinical Cardiovascular Effects of Incretin Based Therapies Hypertension Weight Loss Lipids Heart Rate Cardiovascular Outcomes Ischemia reperfusion injury in AMI Meta-analysis of MACE Cardiovascular Outcome Clinical Trials 19 Native GLP-1

11 Native GLP-1: Endothelial Function in Type 2 Diabetes with Stable CAD 7 GLP-1 effect on endothelialdependent vasodilation Change in FMD (%) from baseline * p<0.05 compared with saline (onset and clamp) and with GLP-1 (onset) 0 Control (saline) GLP-1 Data are mean ± SEM. FMD = Flow-Mediated Dilation (endothelial-dependent vasodilation) of brachial artery. Nystrom T et al, Am J Phsiol Endocrinol Metab 2004; 287:E Native GLP-1 limits infarct size in an ischemic rat model of MI Infarct size (%) N=116 *p<0.001 vs. saline and VP Saline DPP-4 inhibitor Native GLP-1 + DPP-4 * Rat model of ischemia In vivo protection against MI Protection abolished by GLP-1 receptor antagonist Native GLP-1 protection mediated by the induction of multiple pro-survival kinases data are mean + SE Bose et al. Diabetes 2005;54:

12 Native GLP-1 improves left ventricular function in high-risk cardiac patients LVEF (%) Baseline p<0.01 Control Post IV GLP-1 Native GLP-1 Regional wall motion score* Baseline p<0.01 Post IV GLP-1 Effect of GLP-1 infusion, in patients with acute MI and high risk of post-mi heart failure, after successful reperfusion (independent of DM status and MI location) Data are mean ± SE; post i.v. GLP-1, post 72-h intravenous GLP-1 infusion; *measures regional systolic function. A decrease in regional wall motion score is beneficial. Nikolaidis et al. Circulation 2004;109:962 5; Moller et al. Am Heart J 2006;151: Summary Pre-CVOT Ussher JR and Drucker DJ. Circulation Research. 2014; 114:

13 DPP-4 Inhibitors DPP-4 Inhibitor Cardiovascular Outcome Trials * Drug Trial Name Identifier Sitagliptin TECOS NCT Alogliptin EXAMINE NCT Saxagliptin SAVOR-TIMI 53 NCT * Accessed April 30, 2013; CV death, nonfatal MI, and nonfatal stroke; Based on renal function; CV death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization; **CVD or specified diabetes end-organ damage or age 70 years or 2 CRFs ACS=acute coronary syndromes; CRF=cardiovascular risk factors; CVD=cardiovascular disease; CKD, chronic kidney disease; CHF= chronic heart failure; MACE=major adverse cardiovascular events

14 Study Design SAVOR EXAMINE Primary end-point Design Treatment composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke Multicenter, double blind and randomized Saxagliptin vs placebo in addition to existing antihyperglycemic therapy Alogliptin vs placebo in addition to existing antihyperglycemic therapy Patients Follow-up 2.1 years 18 months Scirica BM, et al. N Engl J Med. 2013; 369: and Circulation. 2014; 130: ; Scirica BM, et al. N Engl J Med. 2013; 369: and Circulation. 2014; 130: ;

15 CV death, MI or ischemic CVA (%) Primary End Point HR 1.00 [ ] P<0.001 (non inferiority) 2y KM Saxagliptin 7.3% Placebo 7.2% Placebo 8212 Saxagliptin Months Scirica BM, et al. N Engl J Med. 2013; 369: and Circulation. 2014; 130: ; Individual End Points 2-year KM rate (%) Placebo (N=8 212) Saxagliptin (N=8 280) HR P-value for superiority CV death ( ) 0.72 MI ( ) 0.52 Ischemic stroke ( ) 0.38 Hosp for cor. revasc ( ) 0.18 Hosp for UA ( ) 0.24 Hosp for heart failure ( ) All-cause mortality ( ) 0.15 Scirica BM, et al. N Engl J Med. 2013; 369: and Circulation. 2014; 130: ;

16 SAVOR-TIMI 53 - Risk of Hospitalization for Heart Failure over Time 4% Saxagliptin Placebo n= HR 1.27 ( ) P=0.007 Hospitalization for Heart Failure 3% 2% 1% HR 1.80 ( ) P= % HR 1.46 ( ) P= % 1.3% 3.5% 2.8% 0.6% Days from Randomization Scirica BM, et al. N Engl J Med. 2013; 369: and Circulation. 2014; 130: ; Study Design White WB, et al. N Engl J Med. 2013; 369:

17 Primary End Point White WB, et al. N Engl J Med. 2013; 369: EXAMINE: Primary Endpoint by Components Primary endpoint: CV death, nonfatal MI, or nonfatal stroke, No. (%) Alogliptin n=2701 Placebo n= (11.3) 316 (11.8) Hazard Ratio for Alogliptin Group (95% CI) 0.96 ( 1.16)* CV death 89 (3.3) 111 (4.1) Nonfatal MI 187 (6.9) 173 (6.5) Nonfatal stroke 29 (1.1) 32 (1.2) 0.79 (0.60, 1.04) 1.08 (0.88, 1.33) 0.91 (0.55, 1.50) *99% one-sided confidence interval, P<.001 for non-inferiority; P=.32 for superiority White W, et al. N Engl J Med. 2013;369:

18 EXAMINE: Post-hoc Composite Endpoint Inclusive of Hospitalized Heart Failure Composite endpoint inclusive of hospitalized heart failure, No. (%) CV mortality, No. (%) Hospitalization for heart failure, No. (%) Alogliptin n=2701 Placebo n=2679 HR for Alogliptin (95% CI) P-Value 201 (7.4) 207 (7.5) 0.89 (0.82, 1.21) (3.5) 112 (4.2) 0.84 (0.64, 1.10) (3.9) 89(3.3) 1.19 (0.90, 1.58).22 White W on behalf of EXAMINE Investigators at EASD Do Dipeptidyl Peptidase IV (DPP-IV) Inhibitors Cause Heart Failure? More HF w Placebo More HF w DPP 4i Forest plot separated by cohort and randomized, controlled trial (RCT) based studies. EXAMINE = Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care; SAVOR-TIMI 53 = Saxagliptin Assessment of Vascular Outcomes Recorded in... Cliftin P. Clinical Therapeutics, Volume 36, Issue 12, 2014,

19 TECOS: Summary of Study Design 1,2 Patients with T2DM aged 50 years with pre-existing CVD and HbA1c 6.5% 8.0% (48 64 mmol/mol) and dose-stable for 3 months on Metformin, pioglitazone, or sulfonylurea as monotherapy or any dual combination therapy OR Insulin alone or in combination with metformin R Sitagliptin 100 mg once daily a Placebo Additional oral AHA agents or insulin added as part of usual care to target HbA1c goals according to current guidelines V1 Randomization (day 1) V2 M4 V3 M8 AV M12 T M15 Brief visit M18 T M21 AV M24 T M27 Brief visit M30 T M33 AV M36 T M39 Brief visit M42 T M45 AV M48 End of study visit b T2DM = type 2 diabetes mellitus; CVD = cardiovascular disease; HbA 1c = hemoglobin A 1c ; R = randomization; AHA = antihyperglycemic agent; V = visit; M = month; AV = annual visit; T = telephone contact (study participants will also see their usual care physician regularly). a Patients with moderate renal impairment 50 mg once daily (dose dependant on renal function). b Physician visits and telephone contact until completion of the trial 1. Trial Evaluating Cardiovascular Outcomes with Sitagliptin. University of Oxford Web site. Accessed June 17, Sitagliptin cardiovascular outcome study ( AM1) (TECOS). Accessed June 17, Merck Announces the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) Met Primary Endpoint Kenilworth, N.J., April 27, 2015 Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) of Merck s DPP-4 inhibitor, sitagliptin, achieved its primary endpoint of non-inferiority for the composite cardiovascular (CV) endpoint. Among secondary endpoints, there was no increase in hospitalization for heart failure in the sitagliptin group versus placebo ,724 participants from 38 countries.... ~3 year follow-up.

20 GLP-1 Receptor Agonists Liraglutide in Mice: Survival and Infarct Size after AMI Liraglutide-200 Liraglutide-75 Placebo Sham operation 100 Overall Survival Survival (%) Days n=60 per group AMI: acute myocardial infarction Noyan-Ashraf, Drucker et al. Diabetes 2009;58: Infarct size 28 days post MI (%) *

21 Exenatide Infusion as an Adjunct to 1º Angioplasty in ST-segment Elevation MI Occluded Coronary Artery Reperfusion Conventional PPCI Reperfusion injury PPCI + iv exenatide 15 min 6 hrs Reperfusion injury Drug Lønborg et al. European Heart Journal 2011; /eurheartj/ehr309 Method- Salvage Index MR: acute phase MR: 3 mdr. post-stemi Salvage Index: Area at Risk - Infarct Area at Risk X 100% Lønborg et al. European Heart Journal 2011; /eurheartj/ehr309

22 Outcomes MRI Infarct size/area at risk 50 Exenatide Placebo Percentage P= P= P= All infarctions Anterior location Non-anterior location Lønborg et al. European Heart Journal 2011; /eurheartj/ehr309 Outcomes MRI Salvage index 15% 19% Exenatide Placebo Percentage P=0.003 P=0.023 P= All infarctions Anterior location Non-anterior location Lønborg et al. European Heart Journal 2011; /eurheartj/ehr309

23 Risk of Primary MACE and Secondary CV Endpoints with Exenatide BID Relative to Pooled Comparators Ratner R et al. Cardiovascular Diabetology 2011; 10:22 45 Integrated Meta-Analysis of Liraglutide for Adjudicated MACE Marso et al. Diabetes Vasc Dis Res 2011;8:

24 GLP-1 Receptor Agonist: Cardiovascular Outcome Trial * Drug Study Name Study Population Primary Outcome Dose n Duration (y) End Date Identifier Lixisenatide ELIXA T2D and ACS (within >180 days) MACE 20 mg qd ~ NCT * Accessed April 30, 2013; CV death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization ACS=acute coronary syndromes; MACE=major adverse cardiovascular events 47 Sanofi Announces Top-Line Results for CV Outcome Study of Lixisenatide PARIS, March 19, 2015 /PRNewswire/ -- Sanofi announced today top-line results of the Phase IIIb ELIXA cardiovascular outcomes study, which compared lixisenatide to placebo in a high-risk population* of adults with type 2 diabetes evaluating cardiovascular safety. The study showed that lixisenatide was non-inferior, although not superior, to placebo for cardiovascular safety. ELIXA full results will be presented Monday, June 8, 2015, at the American Diabetes Association 75th Scientific Sessions in Boston by the ELIXA steering committee, chaired by Dr. Marc Pfeffer.... Lixisenatide is not approved in the United States. * ~6000 participants, eligible within 180 days post-acs, ~4 years follow-up html. And Both accessed April 12, 2015

25 CVOT in Type 2 Diabetes Katz P, et al. Diabetes and Vascular Disease Research 2014; 11: Summary GLP-1 effects in preclinical and clinical settings suggest intermediate term cardiovascular (CV) benefits. DPP-4 inhibitors have broad potential to affect CV mechanisms and events. CV outcomes trials suggest CV safety in high risk patients Congestive heart failure (CHF) hospitalizations increased with saxagliptin, trends with alogliptin. Preliminary results from a sitagliptin trial suggests no increased risk. GLP-1 receptor agonists in preclinical and clinical setting suggests intermediate term CV benefits. Preliminary results with lixisenatide (not FDA approved) suggest neither harms nor benefits Many more studies will be reported over the next few years. Studies targeting lower risk patients may have greater potential to demonstrate benefits.