Fixed-Dose Combination Lowers Rates of Heart Failure for Patients With Type 2 Diabetes

Fixed-dose combination therapy resulted in lower rates of heart failure for patients with type 2 diabetes (T2D), particularly for older adults. Further, higher medication adherence appeared to be associated with half of the lower rates, according to the study results published in Cardiovascular Diabetology.¹

Investigators examine the effects of combination therapy with metformin combined with sodium-glucose cotransporter-2 inhibitors, a dipeptidyl peptidase-4 inhibitors, or thiazolidinediones. | Image Credit: Sherry Young - stock.adobe.com

“In this real-world cohort study of people with type 2 diabetes who initiated treatment with metformin, the use of FDCs was associated with a modestly lower rate of heart failure than the LDC regimen was, and 47% of this was mediated by medication adherence,” the study authors said.¹

In a review published in the Journal of Family Medicine and Primary Care, experts in a panel noted that fixed-dose combinations improved patient adherence, reduced cost, and provided glycemic control. As for the cardiovascular effects, investigators in another study noted that metformin was favorable for reducing all-cause mortality, cardiovascular death, and myocardial infarction. They stated that metformin monotherapy is safe, but there is still some uncertainty about the effects in cardiovascular health.^2,3

The study authors acknowledged the 2024 and 2025 American Diabetes Association Standards of Care in Diabetes recommending early combination for patients with T2D. Although guidelines do promote early initiation of combination therapy, the authors stated that the guidelines do not specify the optimal formulation, such as fixed-dose combination and loose-dose combination. Investigators aimed to determine if fixed-dose combinations compared with loose-dose combinations could be associated with lower risk of cardiovascular and kidney outcomes.¹

Investigators included patients with T2D who initiated metformin monotherapy between July 1, 2005, and September 30, 2021, from the Swedish Prescribed Drug Register. Patients included for the fixed-dose combination had prescriptions for metformin and either a sodium-glucose cotransporter-2 inhibitor (SGLT2i), a dipeptidyl peptidase-4 inhibitor (DPP4i), or a thiazolidinedione. The loose-dose combination group included patients receiving metformin and an add-on drug concurrently, which emulated the exposure of the fixed-dose group and did not have to be started within a fixed number of days. The primary outcome included the first incidence of cardiovascular or kidney outcomes during follow-up. The secondary outcome included kidney impairment, according to the study authors.¹

There were 51,019 people included in the loose-dose combination group and 14,286 in the fixed-dose group prior to matching. Regardless of group, investigators noted that patients with an SGLT2i prescription had a higher prevalence of angina, ischemic heart disease, myocardial infarction, and recent cardiovascular events. After matching 1:1, both groups had 13,883 individuals, with a mean age of 61.8 years in the loose-dose group and 62 years in the fixed-dose group. In both groups, approximately 67% of patients were male.¹

In both the unmatched and matched populations, heart failure was the most common cardiovascular outcome, followed by unstable angina and acute myocardial infarction, according to the study authors. In the matched population, the outcomes were similar, except for heart failure, which was more common in the loose-dose combination group at 9.2 per 1000 person-years compared with 8.1 per 1000 person-years in the fixed-dose combination group. Investigators noted that medication adherence seemed to mediate 47% of the association.¹

For drug classes, patients in the fixed-dose combination group who used metformin and DPP4i did not have significant differences in heart failure compared with loose-dose combination users. There were also no differences in other cardiovascular outcomes. As for kidney outcomes, approximately 51.8% of the unmatched population did not have creatinine data available, but the rates were similar for loose-dose combination and fixed-dose combination. In the matched population, the mean estimated glomerular filtration rate using creatinine was 91 ml/min/1.73 m² for both groups. In a median follow-up of 3.8 years, the incidence rate was 2.8 cases per 1000 person-years, according to the study authors. There was no association between the fixed-dose combination and kidney events.¹

“This study contributes to the clinical management of type 2 diabetes by examining the role of FDCs in combination therapy, thereby clarifying a previously ambiguous area within current guidelines,” the study authors said.¹ “To our knowledge, this is the first study that has specifically examined cardiorenal endpoints for FDC versus LDC therapy in type 2 diabetes using real-world data.”

READ MORE: Diabetes Resource Center

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REFERENCES

1. Liu Q, Welsh P, Celis-Morales C, Lees JS, Mark PB, Pazzagli L. Fixed-dose vs loose-dose combination antidiabetic therapy and cardiorenal outcomes in type 2 diabetes: a nationwide comparative effectiveness study. Cardiovasc Diabetol. 2025;24(1):365. Published 2025 Sep 23. doi:10.1186/s12933-025-02936-w

2. Kalra S, Das AK, Priya G, et al. Fixed-dose combination in management of type 2 diabetes mellitus: Expert opinion from an international panel. J Family Med Prim Care. 2020;9(11):5450-5457. Published 2020 Nov 30. doi:10.4103/jfmpc.jfmpc_843_20

3. Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017;60(9):1620-1629. doi:10.1007/s00125-017-4337-9