Introduction

Diabetes mellitus (DM) affects more than 23 million adults in the US and is a major risk factor for cardiovascular disease (CVD).¹ Patients with concomitant heart failure (HF) and DM are increasing with the aging population and have worse outcomes than those without comorbid DM.² However, evidence that intensive glucose lower therapy with traditional drugs reduces the incidence of HF, rate of cardiovascular events, and death has not convincingly been shown.^2-4 More so, some hypoglycemic drugs, though lower blood glucose effectively, have been shown to increase adverse cardiovascular (CV) events.^5,6 In response to the concerns of increased CV risk, in 2008 the FDA mandated all new antidiabetic drugs demonstrate CV safety with a minimum of 2-year follow-up data required with independent adjudication of CV outcomes.⁷ As a result of this, there have been several CV safety trials in the past several years in patients with known CVD and some of these trials have inadvertently shown proven CV benefit in patients with DM.⁸

Prior Studies: EMPA-REG OUTCOME Trial

Empagliflozin is a selective inhibitor of sodium-glucose cotransporter-2 (SGLT2) that acts by decreasing renal glucose reabsorption and increasing urinary glucose excretion. Empagliflozin is associated with weight loss, decrease in blood pressure, and favorable effects on markers of arterial stiffness.^9-10 The EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial was the first trial evaluating the CV effects of empagliflozin in addition to standard care in diabetic patients with known CVD.¹¹ A total of 7,020 patients were randomly assigned in a 1:1:1 fashion to receive 10mg or 25mg of empagliflozin versus placebo with the primary composite outcome being death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. The primary composite outcome occurred less frequently with empagliflozin (10.5% vs. 12.1%, p=0.04). This was primarily driven by lower CV death in the treatment group (3.7% vs. 5.9%, p <0.001).

EMPA-REG OUTCOME also showed a significantly lower risk of hospitalization for HF (HHF) (2.7 vs. 4.1%, 35% relative risk reduction; p=0.002). HHF was defined as an event requiring either an inpatient admission or 12-hour emergency department stay as a result of clinical manifestations of new or worsening HF or increased HF therapy. Approximately 10% of patients who received empagliflozin had a prior diagnosis of HF. In a sub-analysis of EMPA-REG OUTCOME, it was shown that HHF were statistically significantly reduced in patients without HF at baseline but not in those with HF [HR 0.59 (0.43-0.82) vs. HR 0.75 (0.48-1.19)].¹² The effect of empagliflozin on HHF and CV death occurred early and overall the mechanism behind these effects remain unknown. However, the potential contributors to CV benefit include increased osmotic diuresis, weight loss, decreased arterial stiffness, and modulation of the cardio-renal axis.

EMPRISE Study Design

The EMPagliflozin comparative effectIveness and SafEty (EMPRISE) study program used two commercial (Optum Clinformatics® and IBM® MarketScan®) databases and one federal (Medicare fee-for-service) database in the US to assess real-word effectiveness, safety, and healthcare utilization of empagliflozin.¹³ EMPRISE consisted of 1:1 propensity-score-matched (PS-matched) patients being initiated on empagliflozin or a comparator over a 5-year period, August 2014 – September 2019, following empagliflozin's approval in the US. Propensity scores were conditional upon 140 pre-defined baseline characteristics. By the time of completion, EMPRISE is expected to include over 200,000 patients and there are four interim analyses and a final analysis planned. In this first interim analysis from EMPRISE, Patorno et al. evaluate the risk of HHF associated with initiation of empagliflozin versus sitagliptin, a commonly prescribed dipeptidyl peptidase 4 inhibitor (DPP-4). Patients ≥18 years old with type 2 DM (T2DM) were entered into the matched cohort when the prescription of either drug was first filled, with 1 year of enrollment prior to drug initiation. Follow-up was until September 2016 or until treatment discontinuation, treatment switch, the occurrence of an outcome, nursing home admission, death, or planned disenrollment. A secondary analysis of the class-specific effect of DPP-4 and SGLT2 was also performed. The primary outcome was defined as a discharge diagnosis of HF in the primary position (HHF-specific). A broader definition of HF discharge diagnosis in any position (HHF-broad) was also assessed.

Primary Results of EMPRISE

Of the 18,880 empagliflozin initiators identified, 87% were successfully matched to the 201,839 sitagliptin initiators, resulting in 16,443 PS-matched patient pairs. There were no significant differences in the baseline characteristics of the PS-matched pairs. Compared to sitagliptin, the initiation of empagliflozin decreased the risk of HHF-specific by 50% [HR=0.5 (0.28-0.91)] and the risk of HHF-broad by 49% [HR=0.51 (0.39-0.68)] over a mean follow-up of 5.3 months. When further stratified by subgroups including CVD history or HF history, only the HHF-broad definition remained significant in all subgroups. High dimensional propensity score matching, performed for enrichment with 100 additional covariates, showed consistent results. These results remained consistent over time, and for both the 10mg and 25mg doses of empagliflozin.

Clinical Significance of EMPRISE Outcomes

In the first interim analysis of the EMPRISE trial, Patorno et al. have shown that initiation of empagliflozin is superior to sitagliptin in reducing risk of HHF in a real-world setting. These results strengthen the findings of the EMPA-REG OUTCOME trial by comparing empagliflozin to a therapeutic alternative rather than to placebo and including patients with and without CVD. The EMPRISE Trial investigators should be commended on their meticulous attempt to minimize confounding results by using a high-dimensional propensity score matching study design and by eliminating patients who had previously been treated with either SGLT2 or DDP-4 in the prior year. Similar to other large database studies, an important critique is that the primary endpoint of HHF was based on discharge diagnosis and may be subject to inaccuracy.

Though safety outcomes are not yet available from EMPRISE, data from the EMPA-REG OUTCOME trial showed overall similar rate of serious adverse events of empagliflozin compared to placebo. The most common side effects of empagliflozin were urinary tract infection and genital infection in the EMPA-REG OUTCOME trial. Given the overall favorable side-effect profile and positive outcomes, empagliflozin may be advantageous for treatment of T2DM compared to other glucose-lowering therapies including DPP-4.

Future Directions

The current guidelines from the American Diabetes Association (ADA) recommend metformin as the initial pharmacologic agent for treatment of T2DM with early introduction of insulin if DM is significantly uncontrolled.¹⁴ The use of SGLT2 is recommended as an additive therapy in those with established atherosclerotic cardiovascular disease, HF, or at high risk of HF. The results of EMPA-REG OUTCOME and now EMPRISE are promising for the CV outcome benefits in T2DM patients with and without known CVD or HF history, though more longitudinal data including safety outcomes will be needed prior to a major paradigm shift in the treatment algorithm of T2DM. The beneficial effects of empagliflozin and other SGLT2 appear to extend beyond glycemic control to include weight loss, anti-fibrotic effects, and increased natriuresis. There are important ongoing clinical trials of empagliflozin in HF with reduced (HFrEF) and preserved ejection fraction (HFpEF), independent of T2DM diagnosis. The Empagliflozin Outcome Trial in patients with Chronic Heart Failure with Reduced Ejection Fraction (EMPEROR-REDUCED) and the Empagliflozin Outcome Trial in patients with Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-PRESERVED), are double-blinded phase III randomized clinical trials evaluating the efficacy and safety of empagliflozin 10mg compared to placebo in chronic HF patients. EMPERIAL-REDUCED and EMPERIAL-PRESERVED trials will study the effect of empagliflozin on exercise ability including 6MWT in each respective HF phenotype. Given the high burden of HFpEF and no effective medications for improved mortality, investigation of novel therapies that improve quality of life and outcomes in this patient population are desperately needed. Based on the results of EMPRISE, we remain optimistic about the broader use of empagliflozin in the treatment of heart failure.

References

1. Dei Cas A, Khan SS, Butler J et al. Impact of diabetes on epidemiology, treatment, and 0utcomes of patients with heart failure. JACC Heart Failure 2015;3136-45.
2. Palazzuoli A, Ceccarelli E, Ruocco G, Nuti R. Clinical impact of oral antidiabetic medications in heart failure patients. Heart Fail Rev 2018;23:325-35.
3. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-89.
4. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232-42.
5. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 2007;370:1129-36.
6. Komajda M, McMurray JJ, Beck-Nielsen H, et al. Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial. Eur Heart J 2010;31:824-31.
7. Center for Drug Evaluation and Research. Guidance Document: Diabetes Mellitus -- Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes (FDA website). September 19, 2018. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diabetes-mellitus-evaluating-cardiovascular-risk-new-antidiabetic-therapies-treat-type-2-diabetes. Accessed June 24, 2019.
8. Acharya T, Deedwania PC. The Role of Newer Anti-Diabetic Drugs in Cardiovascular Disease (ACC website). May 23, 2018. Available at: https://www.acc.org/latest-in-cardiology/articles/2018/05/22/16/59/the-role-of-newer-anti-diabetic-drugs-in-cv-disease. Accessed June 24, 2019.
9. Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care 2014;38:420-28.
10. Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab 2015;17:1180-93.
11. 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.
12. Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J 2016;37:1526-34.
13. Patorno E, Pawar A, Franklin JM, et al. Empagliflozin and the risk of heart failure hospitalization in routine clinical care. Circulation 2019;139:2822-30.
14. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes -- 2019. Diabetes Care 2019;42:S90–S102

Keywords: Metabolic Syndrome, Hypoglycemic Agents, Dipeptidyl-Peptidase IV Inhibitors, Blood Glucose, Metformin, Diabetes Mellitus, Type 2, Propensity Score, Insulin, Risk Factors, Fee-for-Service Plans, Blood Pressure, Glucose, Weight Loss, Vascular Stiffness, Inpatients, Research Personnel, Follow-Up Studies, Quality of Life, Stroke Volume, Glucosides, Benzhydryl Compounds, Sodium-Glucose Transporter 2, Heart Failure, Stroke, Myocardial Infarction, Myocardial Infarction, Hospitalization, Medicare, Emergency Service, Hospital, Urinary Tract Infections, Algorithms, Phenotype, Cohort Studies

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