Medical World News: Clinical Updates, December 2018

Analysis Estimates Empagliflozin Will Add Years to Life for Those With Type 2 Diabetes

Results derived from the cardiovascular outcomes trial for empagliflozin (EMPA-REG OUTCOME) suggest that the drug could extend life for individuals with type 2 diabetes (T2D), with greater benefits for those who start taking the drug at younger ages. The survival estimate analysis appears in the journal Circulation, the official journal of the American Heart Association.¹ Empagliflozin is sold as Jardiance by Boehringer-Ingelheim and Eli Lilly, which funded the study.

Using actuarial methods and assuming the benefits of empagliflozin remain constant, the team, led by Harvard biostatistician Brian Claggett, PhD, estimated that the therapy could extend life by between 1 and 4.5 years. They made their calculations based on data gathered from 7020 people who took part in EMPA-REG OUTCOME, the first trial that showed a T2D therapy was not simply safe, but also had cardiovascular benefits.²

The trial showed a 38% relative risk reduction in cardiovascular death and a 32% risk reduction in all-cause mortality among those with T2D and cardiovascular disease. Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and since the publication of EMPA-REG OUTCOME, competitors in the class have reported cardiovascular benefits.

In this new analysis, the survival benefit was greater for younger patients and diminished, compared with placebo, as the study patients aged. The mean differences between patients taking empagliflozin and those taking placebo were 4.5 years at age 45, 3.1 years at age 50, 2.5 years at age 60, 2.0 years at age 70, and 1 year at age 80.

“For a 60-year-old living with type 2 diabetes, who has already had a cardio- vascular event, previous studies estimate that life expectancy could be reduced by up to 12 years compared with someone of the same age without these conditions,” Claggett said in a statement.³ “This latest analysis estimates that empagliflozin could prolong such a person’s life span by, on average, 2.5 years.”

The findings came as an FDA advisory committee voted 10-9 to continue large cardiovascular outcomes trials like EMPA-REG OUTCOME (See Cover), which were required after concerns over the safety of rosiglitazone.

A report in Diabetes Care, whose authors included some of the leading scientists who worked on these trials, notes that although the round of trials have revealed unanticipated benefits, the high costs involved must be considered.⁴

References:

1. Claggett B, Lachin JM, Hantel S, et al. Long-term benefit of empagliflozin on life expectancy in patients with type 2 diabetes mellitus and established cardiovascular disease. Circulation. 2018;138(15):1599-1601. doi: 10.1161/ CIRCULATIONAHA.118.033810.
2. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.
3. New analysis estimates the positive impact of Jardiance on life expectancy in adults with type 2 diabetes and established cardiovascular disease [press release]. Ridgefield, CT, and Indianapolis, IN: Boehringer Ingelheim, Lilly; October 10, 2018. prnewswire.com/news-releases/new-analysis-estimates-the-positive-impact-of-jardi- ance-on-life-expectancy-in-adults-with-type-2-diabetes-and-established-cardiovascular-disease-300728200. html. Accessed October 13, 2018.
4. Cefalu WT, Kaul S, Gerstein HC, et al. Cardiovascular outcomes trials in type 2 diabetes: where do we go from here? Reflections from a Diabetes Care editors’ expert forum. Diabetes Care. 2018;41(1):14-31. doi: 10.2337/dci17-0057.

Cardiovascular Results for Dapagliflozin Point to SGLT2 Use to Prevent Heart Failure

Results from the 17,000-patient cardiovascular outcomes trial for dapagliflozin, the sodium-glucose cotransporter 2 (SGLT2) inhibitor sold as Farxiga (AstraZeneca), DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events), presented November 10, 2018, at the American Heart Association (AHA) annual meeting in Chicago, show the type 2 diabetes (T2D) drug safely controls blood glucose, significantly reduces hospitalization for heart failure, and may slow the loss of kidney function. The drug did not produce the same mortality benefits seen with competitors in the class. Results were simultaneously published in the New England Journal of Medicine.¹

The big news, however, is what heart failure specialists have wondered about for some time: that dapagliflozin, and perhaps the entire SGLT2 class, might someday be used to prevent heart failure among a much larger group of T2D patients who are at risk but have not become seriously ill. In the United States, 30 million individuals have diabetes; all but 1.25 million have T2D.² About 5.7 million people have heart failure, and diabetes is a leading cause. About half of those with heart failure die within 5 years of diagnosis.³

“The SGLT2 inhibitor benefits for heart failure and renal dysfunction were quite consistent for all populations of patients, with or without pre-existing atherosclerotic cardiovascular disease [(ASCVD)],” and with and without pre-existing heart failure or kidney disease, said lead study author Stephen D. Wiviott, MD, FACC, of Brigham and Women’s Hospital, in an interview with Evidence-Based Diabetes Management^TM prior to the AHA annual meeting.

Previous cardiovascular outcomes trials for the SGLT2 inhibitors empagliflozin (Jardiance, Eli Lilly/Boehringer Ingelheim) and canagliflozin (Invokana, Janssen) prompted the American Diabetes Association and the European Society of Cardiology to revise guidelines for patients with established cardiovascular disease. DECLARE-TIMI 58 was designed differently from those trials, however, and included more than 10,000 patients who had risk factors for ASCVD but had not developed the disease.

The results of this study offer the strongest evidence to date that treating healthier patients with T2D using SGLT2 inhibitors can prevent heart failure among those at risk for this condition, a finding that could have enormous impact on managed care. The Framingham Heart Study⁴ has found that women with diabetes are 5 times more likely to develop heart failure, and men are 2.4 times more likely to develop it. Patients with heart failure are among the sickest in the health system, with total costs of $30 billion a year, according to the CDC.³

“These new data suggest that in patients without established atherosclerotic cardiovascular disease, SGLT2 inhibition can prevent serious clinical events, particularly hospitalization for heart failure, and possibly reduce the likelihood of progression of renal disease,” Wiviott et al wrote in their findings.

A meta-analysis of the 3 major cardiovascular outcomes trials involving SGLT2 inhibitors, appearing in The Lancet less than an hour after presentation of the DECLARE-TIMI 58 results, found that drugs in this class appear to be producing modest results in reducing heart attacks and strokes, but “robust” outcomes in reducing hospitalization for heart failure and progression of renal disease.⁵

Under a 2008 FDA guidance, the makers of all T2D therapies were required to conduct large cardiovascular outcomes trials to ensure that the drugs did not cause heart attacks, strokes, or early cardiovascular death. The diabetes community was stunned in September 2015 when results from EMPA-REG OUTCOME⁶ showed that empagliflozin was not only safe, but also produced a 38% reduction in cardiovascular deaths and a 32% reduction in deaths from any cause, in addition to a 35% reduction in hospitalization for heart failure.

Canagliflozin followed in June 2017 with results from CANVAS,⁷ which found a 14% reduction in a composite outcome of reduction in death from cardiovascular causes, myocardial infarction, and stroke, but an increased risk of lower extremity amputation (primarily at the toe or metatarsal). The CANVAS results also showed a delay in loss of renal function and a reduction in hospitalization for heart failure; although the reduction was greater for those with established heart failure (39% vs 13%), CANVAS also hinted at a protective benefit⁸ that should be confirmed in other trials.

After the EMPA-REG OUTCOME results were announced, the DECLARE- TIMI 58 investigators decided to include 2 primary efficacy outcomes: (1) major adverse cardiovascular events, or MACEs; and (2) a composite of cardiovascular death and hospitalization for heart failure. AstraZeneca had previously announced topline results for DECLARE-TIMI 58. Complete results of 17,160 patients who were followed for a median of 4.2 years found:

• Dapagliflozin was noninferior to placebo with respect to the primary safety outcome (95% CI, <1.3; P <.001 for noninferiority).
• For the first primary efficacy endpoint, dapagliflozin did not result in a lower rate of major adverse cardiovascular events (MACE) (8.8% for the MACE group vs 9.4% in the placebo group; hazard ratio [HR], 0.93; 95% CI, 0.84-1.03; P = .017).
• For the second primary efficacy endpoint, dapagliflozin resulted in a lower composite rate of cardiovascular death and hospitalization for heart failure (HHF) (4.9% vs 5.8% for placebo), for a reduction of 17% (composite HR, 0.83; 95% CI, 0.73-0.95; P = .005). This was driven by the reduction in HHF; there were no between-group differences in cardiovascular death. The HR for HHF was 0.73; 95% CI, 0.61 to 0.88).

The study authors say that, although they cannot rule out that the differences between the drugs themselves account for the lack of a mortality benefit in DECLARE-TIMI 58, they speculated that trial design may account for this, given the drug’s mechanism of action. They note the trial had a “more restrictive exclusion of patients according to creatinine clearance” that could account for the difference; mortality rates were lower in the placebo group than in EMPA-REG OUTCOME, suggesting population differences.

SGLT2 inhibitors have a mechanism of action that involves blocking a protein that normally allows the body to reabsorb glucose; instead, the body discharges excess glucose through the urine, offering those with T2D glycemic control, as well as reduced blood pressure and modest weight loss. Wiviott said in the interview that besides the renal benefits, DECLARE-TIMI 58 showed no evidence of early concerns about bladder cancer—in fact, the treatment group had lower rates.

“These positive results are clinically relevant to the 425 million people worldwide living with diabetes, of whom those with type 2 diabetes have a 2 to 5 times greater risk of heart failure along with an increased risk of a heart attack or stroke. Heart failure survival rates are only 50% after 5 years from diagnosis, which is why these new findings are so important in broadening our understanding of how to go beyond blood glucose so we may better address this serious and often overlooked cardiovascular complication,” said Elizabeth Bjork, vice president, head of Cardiovascular, Renal and Metabolism, Global Medicines, Development for AstraZeneca, in a statement.⁹

The FDA recently held a 2-day hearing on the future of the cardiovascular outcomes trials; these studies generated the unexpected results in EMPA-REG OUTCOME and have produced the consistent results suggesting a new way forward to prevent heart failure. Asked to reflect on the value of these trials, Wiviott said, based on the changes to clinical guidelines the trials have already produced, it would be hard to imagine a major new class of diabetes drugs reaching the market without demonstrating cardiovascular benefits.

“It will be sorted out by the clinical community and by the market, in a sense,” he said. “One of my take-home messages about this whole area and what’s happening is that we are really moving to a place where it’s not enough to lower blood sugar—it’s how you lower it&mdash;by choosing the right agents as opposed to simply getting to a specific hemoglobin A1C target.”

When asked about the managed care benefits of using SGLT2 inhibitors, and dapagliflozin in particular, to prevent heart failure, Wiviott said that cost-benefit analyses are still needed. However, with an aging population and the prospect for more patients with diabetes and congestive heart failure, he said, “there’s no question that it is important to find ways to reduce the long-term costs of these conditions.”

“The concept of preventing events does have some real economic merit,” he said. “Most of the heart failure drugs we use are for treating patients with established heart failure.” Preventing heart failure in patients who do not realize they are at risk for the disease would be a different concept, Wiviott said.

Some heart failure specialists called for greater focus on this area a decade ago when cardiovascular outcomes trials began. They argued that the FDA should be equally focused on heart failure and not just on events like heart attacks and strokes. In an interview with EBDM in 2017, Brigham and Women’s Eldrin F. Lewis, MD, MPH, said that with diabetes being the number 2 risk factor for heart disease, it is essential to find ways to prevent heart failure in the T2D population.¹⁰

“Especially in patients who have what I call the trifecta—hypertension, diabetes, and pre-existing atherosclerotic cardiovascular disease&mdash;those are very high-risk populations,” he said in the interview. “Lipid lowering is important, as well, in these patients, but we need some type of precision medicine approach to managing the prevention of heart failure.”

References:

1. Wiviott SD, Raz I, Bonaca MP et al; DECLARE—TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes [published online November 10, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1812389.
2. National Diabetes Statistics Report, 2017. CDC website. cdc.gov/diabetes/pdfs/data/statistics/national-diabetesstatistics-report.pdf. Published and accessed July 18, 2017.
3. Heart failure fact sheet. CDC website. cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm. Published June 16, 2016. Accessed December 7, 2018.
4. Papadaki M, Holewinski RJ, Beck Previs S, et al. Diabetes with heart failure increases methylglyoxal modifications in the sarcomere, which inhibit function [published online October 18, 2018]. J Clin Invest. 2018;3(20):e121264.
5. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials [published online November 9, 2018]. Lancet. 2018. doi: 10.1016/S0140-6736(18)32590-X.
6. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.
7. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925.
8. CANVAS suggests canagliflozin reduces CV death, heart failure hospitalization risk. American College of Cardiology website. acc.org/latest-in-cardiology/articles/2018/03/07/15/08/sun-445pm-canvas-canagliflozin-for-prevention-of-hf-in-type-2-diabetes-acc-2018. Published March 11, 2018. Accessed November 10, 2018.
9. Farxiga significantly reduced hospitalisation for heart failure or CV death in a broad patient population with type-2 diabetes in the landmark DECLARE-TIMI 58 trial [press release]. Chicago, IL: AstraZeneca; November 12, 2018. astrazeneca.com/media-centre/press-releases/2018/farxiga-significantly-reduced-hospitalisation-for- heart-failure-or-cv-death-in-a-broad-patient-population-with-type-2-diabetes-in-the-landmark-declare-timi- 58-trial.html. Accessed December 7, 2018.
10. Lewis EF, Caffrey M. Eldr in F. Lewis, MD, MPH, on heart failure’s place in diabetes drug trials, and the promise of SGLT2s in prevention. Am J Manag Care. 2017;23(SP14):SP576-SP577.

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