Multiple cardiovascular outcomes trials (CVOTs) investigating new glucose-lowering drugs (GLDs) have been completed in recent years with important treatment implications for patients with type 2 diabetes. Furthermore, data from real-life cohorts supporting the findings from CVOTs are now emerging. A recent study by Norhammer et al.¹ verified the results from the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events—Thrombolysis in Myocardial Infarction 58) trial.² Specifically, this study, based on real-life data, evaluated cardiovascular safety and event rates for dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT-2i), versus other GLDs in a Swedish nationwide type 2 diabetes population using the same inclusion criteria as in the DECLARE-TIMI 58 trial.

The main finding was that the results from a real-world dapagliflozin cohort were similar to the results from DECLARE-TIMI 58. Patients who received dapagliflozin versus other GLDs were found to have a 21% lower risk of hospitalization for heart failure (HHF) or cardiovascular mortality (hazard ratio [HR]: 0.79, confidence interval (CI): 0.69-0.92). The respective hazard ratios for HHF and cardiovascular mortality were 0.79 (95% CI 0.67-0.93) and 0.75 (95% CI 0.57-0.97). Inclusion criteria for the study reflected those of the DECLARE-TIMI 58 trial and were ≥40 years of age and established cardiovascular disease or multiple risk factors, defined as men aged ≥55 years and women aged ≥60 years with hypertension or dyslipidemia. New users of dapagliflozin were matched 1:3 to new users of other GLD users using propensity scores, yielding a cohort of 28,408 in the time period 2013 to 2016. Patients were identified from the Swedish nationwide healthcare registries. Outcomes of interest were major adverse cardiovascular events (MACE), which was a composite of cardiovascular-specific mortality, myocardial infarction or ischemic stroke, and the primary outcome in the DECLARE-TIMI 58 trial. Other outcomes were HHF and cardiovascular-specific mortality.

The main difference between the DECLARE-TIMI 58 trial cohort and the Swedish study was that more patients were frail and had a higher mortality rate in the latter. This may explain why the Swedish study was able to detect a significant difference in cardiovascular and all-cause mortality between the dapagliflozin versus other GLD group, which was not the case in the DECLARE-TIMI 58 trial. The Swedish study was, like the DECLARE-TIMI 58, not able to show a significant decrease in MACE with dapagliflozin. In comparison, the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trail in Type 2 Diabetes Mellitus Patients) and CANVAS (CANagliflozin CardioVascular Assessment Study) trial showed significant lowering of the primary MACE endpoint for the respective SGLT-2i versus placebo.^3,4 This may be due to differences in trial design. EMPA-REG included only patients with established cardiovascular disease, CANVAS included 66% with cardiovascular disease, whereas only 41% in the DECLARE-TIMI 58 had cardiovascular disease. In comparison, 35% had established cardiovascular disease in the Swedish study. Hence, the DECLARE-TIMI 58 trial was more representative of the general type 2 diabetes population than the EMPA-REG and CANVAS trial and the lower frequency of established cardiovascular disease in the DECLARE-TIMI 58 trial may explain the inability to detect a lower rate of MACE in patients who received dapagliflozin. Furthermore, the results of the DECLARE-TIMI 58 are likely more generalizable to the general type 2 diabetes population. On the other hand, the impressive results seen in EMPA-REG and CANVAS may reflect that the cardiovascular benefits associated with SGLT-2i may be more pronounced in high-risk patients with type 2 diabetes and established cardiovascular disease. However, all three trials along with the observational study on dapagliflozin showed significant benefits of SGLT-2i in preventing HHF, suggesting a class effect. Both the DECLARE-TIMI 58 trial and the Swedish study found neutral effects in regard to myocardial infarction and ischemic stroke, which is similar to the EMPA-REG and CANVAS trials.

It is still unclear what effects of SGLT-2i contribute most directly to the lowering of cardiovascular risk. SGLT-2i act on the kidney to promote glucose and sodium excretion and exert their effects independent of insulin secretion. Yet, it is clear that the mere effect of glucose lowering is not the main mechanism behind lowering cardiovascular risk, and that a range of protecting effects, including improved hemodynamics, reduction in arterial stiffness and blood pressure levels may be at play. More mechanistic studies are needed to elucidate the favorable effects of SGLT-2i.

Both SGLT-2i and GLP-1 receptor agonists (GLP-1RA) are now highly recommended drugs for all patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) as stated by the 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease.⁵ Furthermore, the 2019 ESC Guidelines now recommend that in drug-naive patients with type 2 diabetes and ASCVD, monotherapy with SGLT-2i or GLP-1RA should be initiated, and metformin can be added if hemoglobin A1c (HbA1c) is not at target.⁶ It is important to note that SGLT-2i and GLP-1RA also are recommended second-line drugs for patients with type 2 diabetes without established ASCVD.⁷ Also, the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease state that in those with type 2 diabetes and additional ASCVD risk factors, addition of SGLT-2i or GLP-1RA may be a reasonable choice.⁸

SGLT-2i is preferred in patients with existing heart failure or chronic kidney disease if estimated glomerular filtration rate is adequate.⁷ The application of SGLT-2i seems to be broadening, and the results of several ongoing trials investigating the effect of SGLT-2i in patients with heart failure and no type 2 diabetes have been greatly anticipated, including the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure), EMPEROR-Preserved (EMPagliflozin outcome tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction), EMPEROR-Reduced (EMPagliflozin outcome tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction), and DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure) trials. DAPA-HF is the first trial shown in which dapagliflozin reduces the risk of the composite endpoint of cardiovascular death or HHF in both patients with and without type 2 diabetes and heart failure with reduced ejection fraction,⁹ adding further evidence that SGLT-2i is a promising drug class in the treatment of heart failure.

Conclusion
The external validity of the DECLARE-TIMI 58 trial findings was demonstrated by a recent Swedish nationwide study on dapagliflozin use. The study design and cohort size make these results reliable and adds to the growing pool of evidence favoring SGLT-2i for protection against cardiovascular events, particularly HHF, in patients with type 2 diabetes. It is important to finally have cardiovascular safety in terms of GLD use. Besides showing cardiovascular safety with few adverse effects, SGLT-2i seems to be an important addition in the armamentarium of cardio-protective drugs for patients with type 2 diabetes.

References

1. Norhammar A, Bodegård J, Nyström T, Thuresson M, , Nathanson D, Eriksson JW. Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE-TIMI 58 trial: a nationwide observational study. Diabetes Obes Metab 2019;21:1136-45.
2. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57.
3. 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.
4. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57.
5. Das SR, Everett BM, Birtcher KK, et al. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease. J Am Coll Cardiol 2018;72:3200–23.
6. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2019;00:1–69.
7. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes - 2019. Diabetes Care 2019;42:S90–S102.
8. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;140:e596-e646.
9. McMurray JJV. Dapagliflozin reduces death and hospitalisation in patients with heart failure: DAPA-HF trial. Presented at 2019 European Society of Cardiology Congress, Paris, France, September 1, 2019.

Keywords: Metabolic Syndrome, Diabetes Mellitus, Diabetes Mellitus, Type 2, Hemoglobin A, Blood Pressure, Risk Factors, Cardiovascular Diseases, Vascular Stiffness, Propensity Score, Glomerular Filtration Rate, Brain Ischemia, Stroke Volume, Stroke, Glucosides, Benzhydryl Compounds, Renal Insufficiency, Chronic, Heart Failure, Hypertension, Myocardial Infarction, Dyslipidemias, Primary Prevention, Hospitalization, Protective Agents, Registries, Sodium-Glucose Transport Proteins, Insulins, Cohort Studies

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