The Dapagliflozin Heart Failure Trial (DAPA-HF): The Patients Without Diabetes

Educational Objectives

After completing the activity, the clinician will be better able to summarize the results of DAPA-HF comparing dapagliflozin to placebo in patients with or without type 2 diabetes mellitus at baseline.

Summary

Interviewer: W. Douglas Weaver, MD MACC

Take-home Messages:

• Sodium-glucose co-transporter 2 (SGLT2) inhibitors prevent the development of heart failure (HF) in patients with type 2 diabetes mellitus (T2DM). Now there is evidence that one of these agents, dapagliflozin, reduces the rates of cardiovascular (CV) death and worsening HF in patients without T2DM and is effective regardless of the level of symptomatic impairment at baseline.
• The relative and absolute risk reductions in death and HF hospitalizations were substantial, clinically important, and consistent in patients with and without T2DM.
• Active therapy also improved symptom burden, physical function, and quality of life (QOL) The improvements were sustained and amplified over time, with the beneficial effects independent of baseline diabetes status.

One of the top stories of 2019 was that a new class of drugs designed to treat diabetes turned out to be even better at reducing the risk of heart and kidney disease. Indeed, at this point, it seems that these drugs make up a new class of CV agents that also happen to reduce glucose in patients with diabetes.

In EMPA-REG, for example, empagliflozin lowered the composite CV endpoint, but what was remarkable for a diabetes trial was that the benefit was driven by reductions in hospitalization for HF and CV mortality. Moreover, empagliflozin appeared to slow deterioration in renal function, and the HF benefits persisted in the presence of renal dysfunction.

These early HF observations were extended and confirmed in 2 subsequent trials of SGLT2 inhibitors in patients with type 2 diabetes: CANVAS (canagliflozin) and DECLARE–TIMI 58 (dapagliflozin).

The studies established a role for SGLT2 inhibitors to prevent HF in patients with T2DM. However, now one of these agents, dapagliflozin, has reduced death and HF hospitalization across a wide range of patients, including those without diabetes. The drug also improved HF symptom burden, functional status, and quality of life in patients with HF with reduced ejection fraction (HFrEF). The results may mark the beginning of a new era in treating heart failure.

DAPA-HF

Investigators tested dapagliflozin, 10 mg once daily, versus placebo added to standard therapy in patients with HFrEF. For the overall trial, the primary composite outcome of worsening HF (hospitalization or an urgent visit resulting in intravenous therapy for HF) or death from CV causes was reduced 26% with active therapy. Specifically, it occurred in 386 patients (16.3%) in the dapagliflozin group, compared with 502 patients (21.2%) in the placebo group (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.65 to 0.85; p < 0.001).

At AHA.19, John J.V. McMurray, MD (University of Glasgow), presented the data comparing the outcomes based on the presence (n = 2,139) or absence (n = 2,605) of T2DM at baseline. Over a median of 18.2 months, the risk of the primary composite outcome showed a 27% relative risk reduction (RRR) in the group without T2DM with active therapy — nearly identical to the 25% RRR seen in the dapagliflozin group of patients with diabetes (Table).¹

Regardless of baseline diabetes status, each of the 3 components of the composite outcome was less common in the dapagliflozin group, as were the total numbers of hospitalizations for HF and deaths from CV causes. The rates of RRR were consistent regardless of patient subgroup analyzed, including subgroups across the spectrum of age, as well as in patients with both HF and chronic kidney disease.

Overall, active treatment with dapagliflozin:

• Reduced the rate of CV death or worsening HF (Table) regardless of the level of symptomatic impairment at baseline;
• Led to relative and absolute risk reductions in death and hospitalization that were substantial, clinically important, and consistent in patients with and without T2DM;
• Improved symptom burden, physical function, and QOL that were sustained and even amplified over time (results published separately²); and
• Significantly increased the proportion of patients experiencing at small, moderate and large improvements in health status, all of which were clinically important.

DAPA-HF: Hazard Ratio for Dapagliflozin vs. Placebo in Patients with HFrEF

	Diabetes (n = 2,139) HR (95% CI)	No Diabetes (n = 2,605) HR (95% CI)
Primary composite outcome*	0.75 (0.63-0.90)	0.73 (0.60-0.88)
Components of primary outcome
CV death	0.79 (0.63-1.01)	0.85 (0.66-1.10)
Worsening HF event	0.77 (0.61-0.95)	0.62 (0.48-0.80)
Secondary outcomes
CV death or HF hospitalization	0.75 (0.63-0.90)	0.73 (0.60-0.89)
Total HF hospitalizations and CV death†	0.77 (0.63-0.94)	0.73 (0.59-0.91)

 

*CV death, HF hospitalization, urgent HF visit.

†Including first and repeat hospitalizations.

CI = confidence interval; CV = cardiovascular; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; HR = hazard ratio.

Most patients on active therapy saw a clinically meaningful improvement (≥5 points) in symptoms as assessed by the Kansas City Cardiomyopathy Questionnaire score. Moreover, there were significantly more patients in the dapagliflozin groups compared to placebo with KCCQ score improvements ≥10 or ≥15, representing a level of symptom improvement Dr. McMurray has never seen before.³

Dr. McMurray said, “I have done a lot of heart failure trials with a lot of, sometimes, very good drugs but we have not seen the same benefits in quality of life — and that was true, once again, irrespective of whether people did or did not have diabetes at baseline.”

Dapagliflozin was well tolerated, and the rate of treatment discontinuation was low in patients with (4.0%) and without (5.3%) T2DM. It was similar to treatment discontinuation in patients randomized to placebo (5.4% and 4.5%, respectively).

In an accompanying editorial,⁴ Subodh Verma, MD, PhD (University of Toronto), wrote, “While we may not have all the mechanistic answers, the data are compelling and actionable. To that end, clinicians need to overcome inertia and integrate this new and life-saving therapy as part of the armamentarium in the war against heart failure.”

References:

1. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 2019;381:1995-2008.
2. Kosiborod MN, Jhund P, Docherty KF, et al. Effects of Dapagliflozin on Symptoms, Function and Quality of Life in Patients with Heart Failure and Reduced Ejection Fraction: Results from the DAPA-HF Trial. Circulation 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044138. [Epub ahead of print]
3. Kosiborod MN, Jhund PS, Docherty KF, et al. Effects of Dapagliflozin on Symptoms, Function, and Quality of Life in Patients with Heart Failure and Reduced Ejection Fraction: Results From the DAPA-HF Trial. Circulation 2020;141:90-9.
4. Verma S. The DAPA-HF trial marks the beginning of a new era in the treatment of heart failure with reduced ejection fraction. Cardiovasc Res 2020;116:e8-e10.

Readings

Disclosures

John J.V. McMurray, MD, FACC, Glasgow, United Kingdom

Astra Zeneca (A,G)

Interviewer: W. Douglas Weaver, MD MACC

This author has nothing to disclose.

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

AC520303

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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