Bryan Cardiology Conference DM2 & Cardiovascular Outcome Trials Shannon Wakeley MD Complete Endocrinology 9/2/2017 Disclosures Speakers Bureau: Astra Zeneca, Sanofi, Abbvie, Boehringer-Ingelheim, Medtronic, Valeritas, Novo Nordisk Research: Medtronic Objectives Review current DM2 guidelines (ADA vs AACE) Review available classes of DM2 meds - highlight most recently approved FDA medications Discuss cardiovascular outcome studies Discuss customization of medication regimen to individual patients. 1
ADA GUIDELINES 2
AACE GUIDELINES New DM2 Medications 12 classes of DM2 meds Since 2010: 18 new FDA approved drugs to treat DM2 3
Victoza (liraglutide);, Approved January 2010 Tradjenta (linagliptin); Approved May 2011 Bydureon (exenatide extended-release for injectable suspension); Approved January 2012 Jentadueto (linagliptin plus metformin hydrochloride); Approved February 2012 Invokana (canagliflozin); Approved April 2013 Nesina (alogliptin); ]Approved January 2013 Afrezza (insulin human) Inhalation Powder; Approved June 2014 Farxiga (dapagliflozin); January of 2014 Jardiance (empagliflozin) ; Approved August 2014 Tanzeum (albiglutide); Approved April 2014 Trulicity (dulaglutide); Approved September 2014 Xigduo XR (dapagliflozin + metformin hydrochloride); Approved October 2014 Synjardy (empagliflozin and metformin hydrochloride) Approved August 2015 Tresiba (insulin degludec injection); Approved September 2015 Adlyxin (lixisenatide);approved July 2016 Soliqua 100/33 (insulin glargine and lixisenatide injection); Approved November 2016 Xultophy 100/3.6 (insulin degludec and liraglutide injection); Approved November 2016 Qtern (dapagliflozin and saxagliptin); Approved February 2017 New Era DM treatment Half of patients are not at goal (A1C <7%) Is step wise approach a treat to fail model? Combine meds to address the physiologic defects present in DM2 Tailor treatment regimen to the patient. 4
8/28/2017 Metformin -Has been used successfully since the 1950s as 1st line therapy for DM2 -Biguanide - decreases blood glucose concentration by enhancing insulin sensitivity, inducing greater peripheral uptake of glucose and decreasing hepatic glucose output. -Lowers A1C by 1.5% -Generally well tolerated with weight gain, most common side effect GI issues -UKPDS demonstrated 36% relative risk reduction in all cause mortality and 39% relative risk reduction in MI 5
8/28/2017 SGLT2 inhibitors (sodium/glucose cotransporter 2) BRAND NAME ACTIVE INGREDIENTS Invokana canagliflozin Invokamet (Invokamet XR) canaglifozin + metformin Farxiga dapagliflozin Xigduo XR dapagliflozin + metformin XR Jardiance empagliflozin Glyxambi empagliflozin + linagliptin Synjardy empagliflozin + metformin DPP4 inhibitors (dipeptidyl peptidase inhibitor) BRAND NAME ACTIVE INGREDIENT Januvia Sitagliptin Janumet Sitagliptin + Metformin Onglyza Saxagliptin Kombiglyze XR Onglyxa + Metformin XR Tradjenta Linagliptin Jentadueto Linagliptin + Metformin Glyxambi Linagliptin + Empagliflozin Nesina Alogliptin Oseni Alogliptin + Pioglitazone 6
8/28/2017 GLP1-Receptor Agonists Generic Dosing Schedule Mixing Required Preinjection Wait Time Dosing Smallest Needle Guage Needles Included Approved with Basal Insulin Auto Injection Exenetide BID 5mcg, 10mcg 32g 4mm Lixisenetide QD No No 10mcg, 20mcg 32g 4mm Exenetide ER Q WEEK 2mg 23g 7mm Albiglutide Q WEEK 15-30 MIN 30mg, 50mg 29g 5mm Dulaglutide Q WEEK 0.75mg 1.5mg 29g 5mm, built in needle, part of the device Liraglutide Q DAY 0.6mg, 1.2mg, 1.8mg 32g 4mm DRUG Byetta Adlyxin Bydureon Pen Tanzeum Trulicity Victoza 7
Combination basal insulin +GLP1 RA Soliqua 100/33-100 units glargine u100 (lantus) + 33mcg lixisenatide Xultophy 100/3.6-100 units dulaglutide (tresiba) + 3.6mcg liraglutide (victoza) in each ml - 2 meds in one pen, addressing fasting and postprandial glucose levels. Cardiovascular Disease CVD is the leading cause of morbidity & mortality for those with diabetes. Largest contributor to direct/indirect costs Common conditions coexisting with type 2 diabetes (e.g., hypertension, dyslipidemia) are clear risk factors for ASCVD. Diabetes itself confers independent risk Control individual cardiovascular risk factors to prevent/slow CVD in people with diabetes. Systematically assess all patients with diabetes for cardiovascular risk factors. American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2017; 40 (Suppl. 1): S75-S87 Cardiovascular Outcome Trials (CVOT) FDA mandates all DM meds be tested for adverse CV effects (rosiglitazone) During the quest to ensure no adverse CV outcomes we ve found benefit! EMPA-REG CANVAS LEADER SUSTAIN-6 8
EMPA-REG Multicenter, randomized, double-blind, placebocontrolled trial of >7000 patients from 42 countries with DM2 at high risk for CV events (*established CV disease). Empagliflozin 10mg or 25mg added to standard of care compared with placebo added to standard of care (glucose-lowering agents and CV drugs). Mean age 63 yrs, 57% had DM2 >10 yrs duration, 99% had established CV disease Primary endpoint: time to first occurrence of CV death, non-fatal heart attack or nonfatal stroke EMPA-REG Over 3.1 years, empagliflozin significantly reduced the composite outcome of CV death, MI or stroke by 14% ->10.5% vs. 12.1% (HR 0.86; 95% CI 0.74-0.99; superiority P=0.04, noninferiority P<0.001; NNT 62) Risk of CV death reduced by 38% >3.7% vs. 5.9% (HR 0.62; 95% CI 0.49-0.77; P<0.001; NNT 45) **FDA added new indiction for empagliflozin to reduce the risk of CV death in adults with DM2 and CV disease. 32% reduction in all-cause mortality and 35% reduction in hospitalization for heart failure. ->5.7% vs. 8.3% (HR 0.68; 95% CI 0.57-0.82; P<0.001; NNT 38) HF hospitalization or CV mortality excluding fatal stroke ->5.7% vs. 8.5% (HR 0.66; 95% CI 0.55-0.79; P<0.001; NNT 36) No difference between 10mg and 25mg dose 9
8/28/2017 June 12, 2017 CANVAS Mean age 63 y/o, DM2 duration 13.5 yrs, 65% with CV disease. primary outcome: composite of death from CV disease, MI or stroke Primary outcome was 14% lower with canagliflozin (26.9 vs 31.5 pts/1000 pt years, HR 0.86, CI 0.75-0.97, P<0.02 Although not statistically significant, realists showed a possible benefit with respect to progression of albuminuria and composite outcome of a sustained 40% reduction in egfr, the need for renalreplacement therapy or death from renal causes. canagliflozin showed increased risk of amputation, primarily at level of the toe or metatarsal (6.3 vs 3.4 participants/1000 pt years, HR 1.987, CI 1.41-2.75) *Amputation 6.3 (canagliflozin) vs 3.4 (placebo) /1000 pt yrs 10
What s driving the CV benefits? Unclear, there are several theories (and studies underway to better define the physiology) Theories - pleiotropic effects have been inferred.. improved glucose control, lowering of BP, decrease in intraglomerular pressure, reunion in albuminuria and amelioration of volume overload are all plausible protective mechanisms. SGLT2i: glucosuria & natriuresis - cause weight loss, amelioration of volume overload shift from glucose to lipid metabolism - increase FFA, taken up by liver, more metabolism of FFA to B-OHB ketone bodies In the fasted state the human heart utilizes B-OHB. B-OHB is an efficient fuel source - cardiomyocytes metabolize ketones more easily thereby reducing oxygen demand. In setting of stress and hypoxia the relative volume depletion results in elevated Hct - thereby allowing more oxygen to be transported to cells LEADER Multicenter, double-blind, placebo-controlled trial at 410 sites in 32 countries. 9340 high-risk adults with DM2 followed for 3.5-5 years, randomly assigned to receive 1.8mg liraglutide daily vs placebo Mean age 64 years, DM2 duration ~13 yrs, >80% had established CV disease Primary endo point was time to first occurrence of the 3-point major adverse cardiac event (MACE) components: CV death, nonfatal MI, or nonfatal stroke 11
LEADER 13% risk reduction for MACE in liraglutide group(608 of 4668 patients taken liraglutide) vs 14.9% in placebo (694 of 4672 taking placebo), including a 22% lower rate of CV death (4.7 vs 6.0%, p=.007) Time-to-event analysis of death from cardiovascular from causes, nonfatal (including silent) myocardial infarction, or nonfatal stroke.hazard ratio 0.87; 95% CI, 0.78-0.97; P<0.001, NNT=53 Death from any cause: Hazard ratio 0.85; 95% CI, 0.74-0.97; P=0.02, NNT=71 12
SUSTAIN-6 SUSTAIN-6: The culmination of a global phase 3 clinical development program for semaglutide injection (once weekly GLP1), comprising six trials and encompassing more than 7000 people with type 2 diabetes. In the trial, approximately 3,300 people with type 2 diabetes were treated for 104 weeks. The primary endpoint of the study was defined as the composite outcome of the first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. The trial achieved its primary endpoint of showing non-inferiority of major cardiovascular events (MACE) with semaglutide compared with placebo, as well as a statistically significant reduction in stroke. Mean age 63, DM2 x 13.9 yrs, mean A1C 8.7% *Currently not approved anywhere.working on oral version. GLP1RA studies LEADER (Victoza) SUSTAIN-6 (Semaglutide) Patients (N) 9341 3297 Study Design: Primary Prevention Secondary Prevention No(19%) N (17%) Yes (81%) Yes (83%) Available Data June 2016 Sept 2016 Outcome Inclusion in Label 3-point MACE Driving FActor Expected 2H2017 HR, 0.87 p=0.01 (for superiority) Reduction in CV Death by 22% Expected 2H2017 HR, 0.74 p=0.02 (for superiority) Reduction in nonfatal stroke by 39% SGLT2i studies CANVAS/CANVAS-R (Invokana) EMPA-REG (Jardiance) DECLARE (Farxiga) Patients (N) 10,039 7034 17,150 Study Design: Primary Prevention Secondary Prevention Yes No Yes Yes Yes (99%) Yes Outcome Available Data 2017 Sept 2015 Inclusion in Label 3-point MACE Driving FActor Pending 2018 HR 0.86 p=0.02 (for superiority) Composite CV death, MI, stroke Expected 4Q2016 HR, 0.86 p=0.04 (for superiority) Reduction in CV Death by 38% Interim analysis 1Q20-17 Full Readout: 2019 Pending 2020 Pending 13
New Recommendation: Pharmacologic Therapy For T2DM In patients with long-standing suboptimally controlled type 2 diabetes and established atherosclerotic cardiovascular disease, empagliflozin or liraglutide should be considered as they have been shown to reduce cardiovascular and all-cause mortality when added to standard care. Ongoing studies are investigating the cardiovascular benefits of other agents in these drug classes. B American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74 What about my patients? Tailor to their needs, their comorbidities, GFR, tolerability, lifestyle Avoid meds contraindicated in certain clinical scenarios (recurrent UTI s, GMI, gastroparesis, renal impairment, hx pancreatitis, MTC/MEN2) Multiple options - use to patient s advantage Your own comfort level $$ 14
Summary CV safety studies showing positive outcomes - shaping current guidelines Refer to AACE & ADA guidelines; Central to both - individualization of therapy (goal A1C, efficacy, side effects ~positive & negative, renal function, comorbid conditions, cost, coverage, Future treatments oral GLP1RA, the race to the artificial pancreas, CGM coverage. References Garber et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2017 Executive summary. Endocrine Practice Vol 23 No. 2 February 2017 Holman R Metformin as first choice in oral diabetes treatment: the UKPDS experience Journ Annu Diabetol Hotel Dieu 2007:13-20, Marso SP, Daniels GH, Buse JB, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:312-322 Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patiets with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247-57. Zinman B, Wanner C Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28. Standards of Medical Care in Diabetes - 2017. Diabetes Care 2017;40(Suppl. 1):S1 S2 Neal et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes, N Engl J Med 2017;376:1-10. 15