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New Diabetes Drugs and Heart Failure: What Have We Learnt?

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New Diabetes Drugs and Heart Failure: What Have We Learnt? Satellite symposium on: Heart failure, diabetes and renal dysfunction HFA Congress, Paris, 1 May 2017 New diabetes drugs and heart failure: What have we learnt? John McMurray BHF Cardiovascular Research Centre, University of Glasgow & Queen Elizabeth University Hospital, Glasgow. Why are we talking about heart failure in diabetes? • HF is one of the most common cardiovascular complications of type 2 diabetes • HF is the most disabling and deadly complication of diabetes • Most patients with HF have either diabetes or pre-diabetic dysglycaemia • Diabetes is one of the most disabling and comorbidities complicating HF So how should we treat diabetes in patients with HF? • What do we know about treatments for diabetes and reducing the risk of developing HF (incident HF)? • What do we know about treatments for diabetes in patients with established HF (prevalent HF)? Outcome trials in T2DM: A timeline ACCORD UGDP UKPDS ADVANCE PROactive VADT 1970 1998 2002 2005 2008 Major CV outcome trials in type 2 diabetes SAVOR- Omarigliptin¶ : DPP4i TIMI 53 CAROLINA (n = 4000) (n = 16,492) N = 6041 Q42017 : SGLT2i 1222 MACE3 MACE4 ? MACE4 : GLP1 EXAMINE CARMELINA TECOS (n = 5380) N = 8300 (n = 14,723) 621 MACE3 MACE4 1300 MACE4 2012 2013 2014 2015 2016 2017 2018 2019 Ertugliflozin REWIND# ELIXA* CVOT LEADER† EXSCEL§ (n = 9622) (n = 6000) (n = 3900) (n = 9341) (n = 14000) FREEDOM§ MACE3 *lixisenatide (Sanofi, post-ACS). 844 MACE4 611 MACE3 MACE3 (n = 4000) MACE3 †liraglutide (Novo Nordisk). ? MACE4 ‡semaglutide (Novo Nordisk). CREDENCE DECLARE- §exenatide (Amylin). (n = 3627) TIMI 58 §§albiglutide (GSK) CANVAS-R Cardiorenal SUSTAIN-6‡ (n = 5700) (n = 27,000) ¶once-weekly DPP4i (Merck). EMPA-REG (n = 3260) Alb.uria MACE3 #dulaglutide (Eli Lilly). OUTCOME MACE3 N = 7034 CANVAS HARMONY §§ MACE3 (n = 4339) (n = 9400) MACE3 MACE3 ACS, acute coronary syndrome; CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP1, glucagon-like peptide 1; HR, hazard ratio; SGLT2i, sodium glucose cotransporter 2 inhibitor; UL, upper limit. Outcome trials in T2DM: A timeline ACCORD UGDP UKPDS ADVANCE PROactive VADT 1970 1998 2002 2005 2008 FDA guidance Rosiglitazone increases risk of myocardial infarction? United States FDA guidance FDA guidance Unacceptable harm must be excluded FDA guidance – what endpoints? The events should include cardiovascular mortality, myocardial infarction and stroke …and can include hospitalization for acute coronary syndrome, urgent revascularization procedures ….and possibly other endpoints FDA guidance – what endpoints? The events should include cardiovascular mortality, myocardial infarction and stroke …and can include hospitalization for acute coronary syndrome, urgent revascularization procedures ….and possibly other endpoints “Fluid retention” or heart failure? HF in diabetes trials is real and deadly RECORD: Design Patients on monotherapy Randomized to dual therapy add Rosiglitazone Metformin or Sulfonylurea add Sulfonylurea or Metformin Mean follow-up: 5.5 years Rescue therapy: Rosiglitazone group i) intensify to triple oral therapy ii) stop rosiglitazone and start insulin Metformin/SU group i) start insulin RECORD: HF with rosiglitazone Congestive Heart Failure (Adjudicated) What happened to patients who developed HF in RECORD? Any heart failure (fatal or non-fatal): 29 control patients vs. 61 rosiglitazone patients Survived first heart failure event: 29 control patients vs. 57 rosiglitazone patients Subsequent risk of death: 8 control patients (28%) vs. 17 rosiglitazone patients (30%) Major CV outcome trials in type 2 diabetes SAVOR- Omarigliptin¶ : DPP4i TIMI 53 CAROLINA (n = 4000) (n = 16,492) N = 6041 Q42017 : SGLT2i 1222 MACE3 MACE4 ? MACE4 : GLP1 EXAMINE CARMELINA TECOS (n = 5380) N = 8300 (n = 14,723) 621 MACE3 MACE4 1300 MACE4 2012 2013 2014 2015 2016 2017 2018 2019 Ertugliflozin REWIND# ELIXA* CVOT LEADER† EXSCEL§ (n = 9622) (n = 6000) (n = 3900) (n = 9341) (n = 14000) FREEDOM§ MACE3 *lixisenatide (Sanofi, post-ACS). 844 MACE4 611 MACE3 MACE3 (n = 4000) MACE3 †liraglutide (Novo Nordisk). ? MACE4 ‡semaglutide (Novo Nordisk). CREDENCE DECLARE- §exenatide (Amylin). (n = 3627) TIMI 58 §§albiglutide (GSK) CANVAS-R Cardiorenal SUSTAIN-6‡ (n = 5700) (n = 27,000) ¶once-weekly DPP4i (Merck). EMPA-REG (n = 3260) Alb.uria MACE3 #dulaglutide (Eli Lilly). OUTCOME MACE3 N = 7034 CANVAS HARMONY §§ MACE3 (n = 4339) (n = 9400) MACE3 MACE3 ACS, acute coronary syndrome; CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP1, glucagon-like peptide 1; HR, hazard ratio; SGLT2i, sodium glucose cotransporter 2 inhibitor; UL, upper limit. Glucagon-like peptide-1/ Incretin therapies New approaches to reducing blood glucose Inhibit gastro- GLP-1 agonists/analogues intestinal absorption e.g. exenatide (α-glucosidase inhib’s) Stimulate insulin Incretins release Reduce •(GIP) blood glucose •GLP-1 Inhibit glucagon DPP4 release Breakdown Inhibit renal products DPP4 inhibitors re-absorption (“gliptins”) (SGLT2 inhibitors) Major DPP-4 inhibitor CV outcome trials 1 2 3 4 5 DPP-4 inhibitor Saxagliptin Alogliptin Sitagliptin Linagliptin Linagliptin Comparator Placebo Placebo Placebo SU Placebo No. of patients 16,492 5,380 14,723 6,041 ~8,3000 Trial initiation/ May 2010 Sept. 2009 Nov. 2008 Oct. 2010 July 2013 completion May 2013 June 2013 June 2015 Sept. 2018 Jan. 2018 Excluded DPP-4i DPP-4i DPP-4i DPP-4i DPP-4i background GLP-1 RA GLP-1 RA GLP-1 RA GLP-1 RA GLP-1 RA therapy Rosiglitazone TZD SGLT-2i CVD/CV risk CVD/ subclinical CVD & Patients ACS CVD factors (RF) CVD/CVRF UACR/renal dysf. SAVOR-TIMI53 Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus SAVOR-TIMI53 Design: T2DM aged ≥40 yr. with established CV disease or aged ≥55 yr. (≥60 yr. women) with ≥1 risk factor for CV disease. HbA1c 6.5-12.0%. Superiority design. Patients enrolled: 16,492 patients. Mean age 65 yr. 33% female. 79% CV disease. Mean HbA1c 8.0%. BMI 31 kg/m2. Median duration of diabetes 10.0 yr. Insulin treated 41%. Placebo-corrected decrease in HbA1c: 0.3% at 2 yr (0.2% end-of-study). Primary outcome: CV death, MI or ischaemic stroke. Intervention: Randomized 1:1 to placebo or saxagliptin 5mg/d (2.5 mg if eGFR ≤50 ml/min/1.73m2). Follow-up: Median 2.1 years. NEJM 2013; 369:1317-1326 SAVOR-TIMI53: Primary outcome NEJM 2013; 369:1317-1326 SAVOR-TIMI53 % MI HF Stroke* CV death 4 3,5 3 2,5 2 1,5 1 0,5 0 n = 278 228 141 260 * Ischaemic stroke NEJM 2013; 369:1317-1326 SAVOR-TIMI53 % MI HF Stroke* CV death saxagliptin 4 p = 0.007 3,5 3 2,5 2 1,5 1 0,5 0 n = 278 265 228 289 141 157 260 269 * Ischaemic stroke NEJM 2013; 369:1317-1326 It was real heart failure! Subsequent risk in patients hospitalized with heart failure Placebo Saxagliptin HR Death 25.9% 26.3% 1.01 (0.72-1.43) Readmission for HF 25.0% 27.7% 1.06 (0.75-1.50) The DPP-4 inhibitor trials DPP-4 inhibitor trials First hospitalization for heart failure Cardiovascular death or hospitalization for heart failure McGuire et al JAMA Cardiol. 2016;1:126-35. More questions than answers? Is the increase in heart failure hospitalization with saxagliptin real or spurious? What about alogliptin? If the effect in SAVOR-TIMI-53 is real, is it a drug- specific effect? How likely is it that one (or two) drugs in a class are different than the others? If it is real, why does it occur? No plausible explanation to date. Potential CV actions of DDP-4 inhibitors Oyama & Node Circ J. 2014;78(4):819-24. New approaches to reducing blood glucose Inhibit gastro- GLP-1 agonists/analogues intestinal absorption e.g. exenatide (α-glucosidase inhib’s) Stimulate insulin Incretins release Reduce •(GIP) blood glucose •GLP-1 Inhibit glucagon DPP4 release Breakdown Inhibit renal products DPP4 inhibitors re-absorption (“gliptins”) (SGLT2 inhibitors) Major CV outcome trials in type 2 diabetes SAVOR- Omarigliptin¶ : DPP4i TIMI 53 CAROLINA (n = 4000) (n = 16,492) N = 6041 Q42017 : SGLT2i 1222 MACE3 MACE4 ? MACE4 : GLP1 EXAMINE CARMELINA TECOS (n = 5380) N = 8300 (n = 14,723) 621 MACE3 MACE4 1300 MACE4 2012 2013 2014 2015 2016 2017 2018 2019 Ertugliflozin REWIND# ELIXA* CVOT LEADER† EXSCEL§ (n = 9622) (n = 6000) (n = 3900) (n = 9341) (n = 14000) FREEDOM§ MACE3 *lixisenatide (Sanofi, post-ACS). 844 MACE4 611 MACE3 MACE3 (n = 4000) MACE3 †liraglutide (Novo Nordisk). ? MACE4 ‡semaglutide (Novo Nordisk). CREDENCE DECLARE- §exenatide (Amylin). (n = 3627) TIMI 58 §§albiglutide (GSK) CANVAS-R Cardiorenal SUSTAIN-6‡ (n = 5700) (n = 27,000) ¶once-weekly DPP4i (Merck). EMPA-REG (n = 3260) Alb.uria MACE3 #dulaglutide (Eli Lilly). OUTCOME MACE3 N = 7034 CANVAS HARMONY §§ MACE3 (n = 4339) (n = 9400) MACE3 MACE3 ACS, acute coronary syndrome; CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP1, glucagon-like peptide 1; HR, hazard ratio; SGLT2i, sodium glucose cotransporter 2 inhibitor; UL, upper limit. Major GLP-1 RA CV outcome trials 1 2 3 4 5 REWIND 6 7 ITCA 650/ GLP-1 RA Lixisenatide Liraglutide Semaglutide Exenatide Dulaglutide Albiglutide exenatide Comparator Placebo Placebo Placebo Placebo Placebo Placebo Placebo No. of 6068 9340 3297 ~14000 ~4000 ~9600 ~9400 patients Trial initiation/ June 2010 Sept. 2010 Feb. 2013 June 2010 March 2013 July 2011 June 2015 completion April 2015 Oct. 2015 Jan. 2016 April 2018 July 2018 April 2019 Aug. 2019 Excluded DPP-4i DPP-4i DPP-4i GLP-1 - ? - therapy pramlintide pramlintide pramlintide agonists CVD/
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