Effect of SGLT-2 Inhibitors on the Heart. Robert Zimmerman MD Vice Chairman Endocrinology Director Diabetes Center Cleveland Clinic

Transcription

1 Effect of SGLT-2 Inhibitors on the Heart Robert Zimmerman MD Vice Chairman Endocrinology Director Diabetes Center Cleveland Clinic

2 Disclosures Speaker - Johnson and Johnson - Merck Research - Merck - Novo Nordisk

3 n engl j med 373;22 November 26, 2015

4 Empa-Reg Patients randomly assigned to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. n engl j med 373;22 November 26, 2015

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9 Cardiovascular Outcomes in Empa Reg n engl j med 373;22 November 26, 2015

10 Cardiovascular Outcomes in Empa Reg

11 Adverse Events n engl j med 373;22 November 26, 2015

12 Adverse Events Cont. n engl j med 373;22 November 26, 2015 n engl j med June DOI: /NEJMoa

13 n engl j med June DOI: /NEJMoa

14 N Engl J Med 2017; 377:

15 Canvas Cardiovascular Outcomes N Engl J Med 2017; 377:

16 Canvas Cardiovascular and Renal Outcomes N Engl J Med 2017; 377:

17 Selected Adverse Events Canvas N Engl J Med 2017; 377:

18 CVD REAL All Cause Death sglt-2 vs OGLD Circulation. 2017;136:

19 Diabetes Obes Metab. 2018;1 13.

20 Hospitalization for Heart Failure Cana vs non-sglt2i Diabetes Obes Metab. 2018;1 13.

21 Risk of BKLE amputation Canagliflozin vs other SGLT-2 Inhibitors Diabetes Obes Metab. 2018;1 13.

22 Circulation. 2017;137:

23 EASEL A population-based cohort study among patients with type 2 diabetes mellitus with established cardiovascular disease newly initiated on anti hyperglycemic agents within the US Department of Defense Military Health System between April 1, 2013, and December 31, Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite end point of all-cause mortality and hospitalization for heart failure event, major adverse cardiovascular events (defined as all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke), and individual end points were evaluated using conditional Cox models comparing new SGLT2i users with other anti hyperglycemic agents. The exploratory safety end point was below-knee lower extremity amputation. Intent-to-treat and on treatment analyses were performed. After propensity matching, patients were followed for a median of 1.6 years.

24 Circulation. 2017;137:

25 Conclusion Treatment with empagliflozin caused a lower rate of the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke There was a significant reduction in death from cardiovascular causes, with no significant between-group difference in the risk of myocardial infarction or stroke Patients in the empagliflozin group had significantly lower risks of death from any cause and for hospitalization for heart failure Empagliflozin rx had a lower risk of progression of kidney disease (as defined by incident or worsening nephropathy a significantly lower risk of renal outcomes, such as a doubling of the serum creatinine level and initiation of renal-replacement therapy

26 Conclusion CANVAS demonstrated that canagliflozin significant improvement in combined cardiovascular outcomes and marked improvement in renal Outcomes CANVAS did not show significant reduction in cardiovascular mortality or all cause mortality CANVAS demonstrated significant increases in lower extremity amputations and fractures

27 Summary CVD REAL demonstrated in a lower risk population and an international population that SGLT-2 Inhibitors (primarily dapagliflozin and Canagliflozin) decreases the risk of hospitalization for heart failure, and all cause mortality CVD Real -2 demonstrated that MI and CVA were reduced in a large population of patients on SGLT-2 inhibitors CVD REAL-2 also demonstrated that reduction in all of the cardiovascular events occurred in both patients without prior CVD and patients with prior CVD

28 Summary Cont CANVAS was a prospective cardiac safety trial that showed that Canagliflozin increased the risk of below the Knee amputations OBSERVE-4D was a retrospective study of 4 data bases that found that canagliflozin and other SGLT-2 inhibitors decreased the risk of hospitalization for heart failure compared to OGLD OBSERVE 4-D did not find that canagliflozin increased risk of below the knee amputations compared to OGLD or other SGLT-2 inhibitors Compared with the CANVAS Program, this study had a lower event rate (1-5 events per 1000 person-years, on-treatment and in the overall population) and a shorter follow-up time (median, days ontreatment). Therefore, OBSERVE- 4D had limited statistical power to detect differences in the 6 to 12-month period, the time at which amputation risk began to emerge in the CANVAS Program, particularly in patients with established cardiovascular disease.

29 Summary cont The fact that EASEL corroborated the increased risk of amputation seen in CANVAS and had a longer follow-up than OBSERVE-4D and was mainly evaluating canagliflozin, lends support to the concept that OBSERVE 4D may not have had enough drug exposure time to assess the amputation risk.