LATE BREAKING STUDIES IN DM AND CAD. Will this change the guidelines?

Transcription

1 LATE BREAKING STUDIES IN DM AND CAD Will this change the guidelines?

2 Objectives 1. Discuss current guidelines for prevention of CHD in diabetes. 2. Discuss the FDA Guidance for Industry regarding evaluating cardiovascular risk with new antidiabetes medications. 3. Review recent cardiovascular outcome studies for antidiabetic agents will this change the guidelines? Conflicts: Speaker for Novo Nordisk and Janssen

3 DIABETES MELLITUS A Global Epidemic

4 Background - Diabetes a Global Epidemic 2016 WHO Report of Diabetes estimated a worldwide adult diabetes prevalence in 415 million individuals (8.4% in 2015). This is an increase in the previous estimate of 4.7% in Highest increment in middle and low-income countries

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6 DIABETES MELLITUS Cardiovascular Risk

7 T2DM and Macrovascular Disease Type 2 diabetes mellitus (T2DM) 2 fold increase in risk of coronary heart disease 1.5 to 2.3 fold increase in CVA.

8 CHD Risk in T2 DM The Lancet, Volume 375, Issue 9733, June 2010

9 CHD Risk in T2DM The Lancet, Volume 375, Issue 9733, June 2010

10 CHD Risk in T2DM 5 mmol/l = 90mg/dl The Lancet, Volume 375, Issue 9733, June 2010

11 T2DM = Prior MI for CHD risk (2003) N Engl J Med 1998 Jul 23;339(4):

12 Current Concept: More nuanced CHD risk in patients with T2DM is highly heterogeneous. T2DM CHD risk non-dm pt with MI

13 T2DM alone compared with prior MI alone Bulugahapitiya U, et al. Diabet Med. 2009;26:

14 T2DM and MI as predictors of future CHD Rana, J.S., Liu, J.Y., Moffet, H.H. et al. J GEN INTERN MED (2016) 31: 387

15 Risk of CHD by duration of T2DM vs prior CHD Rana, J.S., Liu, J.Y., Moffet, H.H. et al. J GEN INTERN MED (2016) 31: 387

16 DIABETES MELLITUS Evaluating cardiovascular risk in New Antidiabetic Therapies FDA Guidance for Industry

17 Thalizolidinedione - Rosiglitazone In a meta-analysis of 42 randomized trials, many of which were unpublished clinical trial registry data, rosiglitazone was associated with a significant increase in the risk of MI (OR 1.43, 95% CI , p = 0.03) and a nonsignificant trend for increased cardiovascular mortality (OR 1.64, 95% CI , p = 0.06) (SE Nissen, M.D st al. N Engl J Med 2007; 356: ) This highly-publicized study resulted in a black boxed warning for myocardial ischemia for rosiglitazone in 2007.

18 FDA Guidance For Industry Diabetes Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes Sponsors should establish an independent cardiovascular endpoints committee to prospectively adjudicate, in a blinded fashion, cardiovascular events during all phase 2 and phase 3 trials. These events should include cardiovascular mortality, myocardial infarction, and stroke, and can include hospitalization for acute coronary syndrome, urgent revascularization procedures, and possibly other endpoints Sponsors should ensure that phase 2 and phase 3 clinical trials are appropriately designed and conducted so that a meta-analysis can be performed at the time of completion Sponsors also should provide a protocol describing the statistical methods for the proposed meta-analysis Sponsors should perform a meta-analysis of the important cardiovascular events across phase 2 and phase 3 controlled clinical trials and explore similarities and/or differences in subgroups (e.g., age, sex, race), if possible

19 Thalizolidinedione - Rosiglitazone Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial was published in (N Engl J Med 2007; 357:28-38) The final analysis showed that after a mean follow up of 5.5 years, rosiglitazone was non-inferior to a combination of metformin and sulfonylurea with regards to the primary endpoint of cardiovascular hospitalization or cardiovascular death (HR 0 99, 95% CI ), but its effect on MI was inconclusive due to small number of events (HR 1 14, 95% CI ) Black Box warning removed in 2010.

20 Thalizolidinedione - Pioglitazone Pioglitazone was compared with placebo in the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE) study, which randomized 5238 T2DM patients at high risk for macrovascular complications. (Lancet 366: 9493, p , 8 October 2005) The trial was terminated prematurely after an average follow up of 34.5 months due to significant reduction in the main secondary composite endpoint of all-cause mortality, non-fatal MI, and stroke in the pioglitazone group (HR 0 84, 95% CI , p = 0 027).

21 ORIGIN trial - baseline characteristics N Engl J Med 2012; 367:

22 ORIGIN trial CVD outcomes with Glargine N Engl J Med 2012; 367: July 2012

23 ORIGIN trial all outcomes N Engl J Med 2012; 367:

24 DEVOTE Trial - Degludec vs Glargine N Engl J Med 2017;377:

25 DEVOTE trial Degludec vs Glargine N Engl J Med 2017;377:

26 Glycemic control and CVD risk Type 1 diabetes Epidemiology of Diabetes Interventions and Complications (EDIC) study,8 the long-term follow-up study of the Diabetes Control and Complications Trial (DCCT). After a mean 18 years of follow-up from the start of the DCCT, previously intensively controlled patients had a 42% reduction in the primary cardiovascular disease outcome (major nonfatal and fatal cardiovascular disease events, angina, or revascularization) and a 57% reduction in fatal and nonfatal MI, and stroke

27 Glycemic control and CVD risk Type 2 diabetes The United Kingdom Prospective Diabetes Study (UKPDS) was the first study to investigate the effects of intensive diabetes management on complications in patients with type 2 diabetes. a non-significant 16% (P=0.052) decrease in fatal and nonfatal MI, and a non-significant 6% (P=0.44) decrease in all cause mortality. 10 years post-trial conclusion revealed significant cardiovascular disease reduction. Intensive therapy led to 15% reduction in MI, and all cause mortality was reduced by 13%. Only the metformin group had significant reductions in MI (39%) and all cause mortality (36%)

28 ANTI-DIABETIC MEDICATIONS AND CARDIOVASCULAR RISK

29 Tolbutamide (SU s) and UGPD Sulfonylurea medications have a black box warning about the cardiovascular risk associated with the medications. The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a longterm prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with noninsulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes 19 (supp. 2): , 1970)

30 SU s and cardiovascular outcome The impact of sulfonylureas on cardiovascular outcomes may not be a class effect. There is evidence that whilst first-generation sulfonylureas were associated with increased cardiovascular mortality compared to placebo (RR 2.63, 95% CI , p = 0.006), no difference was found for second-generation agents. The newer sulfonylureas (gliclazide and glimepiride) may have a more favorable cardiovascular effect profile than older agents and should be the preferred agents in this class.

31 Metformin UKPDS The UKPDS showed that metformin monotherapy in obese newly diagnosed T2DM patients was associated with a 32% reduction in the aggregate diabetes-related endpoint, including sudden death and myocardial infarction (MI) (p = 0.011), and 36% reduction in all-cause mortality (p = Meta-anaylsis Overall, metformin was not associated with significant harm or benefit on cardiovascular events (MH-OR 0.94[ ], p = 0.34).

32 DPP-4 Inhibitors There have been several post-marketing RCT s evaluating cardiovascular safety with 2 drugs in the class and they were non-inferior to placebo regarding cardiovasular safety The clinical significance of the finding of an early increased hospitalization for heart failure with saxagliptin in the SAVOR study is unclear, although it is unlikely to be a class effect. The FDA safety review recommends considering discontinuation of specifically saxagliptin or alogliptin in patients who develops heart failure

33 SGLT-2 Inhibitors Dapagliflozin, canagliflozin, and empagliflozin The first cardiovascular outcomes trial of SGLT-2 inhibitors was EMPAgliflozin Cardiovascular outcome event trial in type 2 diabetes mellitus patients (EMPA-REG OUTCOME) patients with T2DM and established cardiovascular disease placebo controlled RCT. After 3.1 years, empagliflozin was associated with a reduction in the primary composite endpoint of cardiovascular mortality, non-fatal MI, or non-fatal stroke compared with placebo (10.5 vs 12.1%, HR 0.86, 95% CI , p = 0.04 for superiority, NNT 62).

34 EMPA-REG (Empagliflozin) N Engl J Med 2015; 373:

35 EMPA-REG (Empagliflozin) N Engl J Med 2015; 373:

36 EMPA-REG (Empagliflozin) N Engl J Med 2015; 373:

37 CANVAS (Canagliflozin) N Engl J Med 2017; 377: June 2017

38 CANVAS (Canagliflozin) N Engl J Med 2017; 377: June 2017

39 CANVAS N Engl J Med 2017; 377: June 2017

40 GLP-1 RA class The cardioprotective effects of GLP-1 agonists have been well documented in pre-clinical studies In the Liraglutide Effect And Action In Diabetes: Evaluation Of Cardiovascular Outcome Results (LEADER) trial, which randomized 9340 T2DM patients with high cardiovascular risk, liraglutide reduced the primary composite endpoint of cardiovascular death, non-fatal MI or non-fatal stroke compared to placebo after a median follow-up of 3.8 years (13 vs 14.9%, HR 0.8, 95% CI , p < for non-inferiority; p = 0.01 for superiority).

41 LEADER (Liraglutide) N Engl J Med 2016; 375:

42 WHAT ARE THE CURRENT GUIDELINES? AACE comprehensive guidelines

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