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Differential cardiovascular outcomes after dipeptidyl peptidase-4 inhibitor, sulfonylurea, and pioglitazone therapy, all in combination with metformin, for type 2 diabetes: a population-based cohort study.

ABSTRACT: BACKGROUND/OBJECTIVES:Data on the comparative effectiveness of oral antidiabetics on cardiovascular outcomes in a clinical practice setting are limited. This study sought to determine whether a differential risk of cardiovascular disease (CVD) exists for the combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor plus metformin versus a sulfonylurea derivative plus metformin or pioglitazone plus metformin. METHODS:We conducted a cohort study of 349,476 patients who received treatment with a DPP-4 inhibitor, sulfonylurea, or pioglitazone plus metformin for type 2 diabetes using the Korean national health insurance claims database. The incidence of total CVD and individual outcomes of myocardial infarction (MI), heart failure (HF), and ischemic stroke (IS) were assessed using the hazard ratios (HRs) estimated from a Cox proportional-hazards model weighted for a propensity score. RESULTS:During follow-up, 3,881 patients developed a CVD, including 428 MIs, 212 HFs, and 1,487 ISs. The adjusted HR with 95% confidence interval (CI) for a sulfonylurea derivative plus metformin compared with a DPP-4 inhibitor plus metformin was 1.20 (1.09-1.32) for total CVD; 1.14 (1.04-1.91) for MI; 1.07 (0.71-1.62) for HF; and 1.51 (1.28-1.79) for IS. The HRs with 95% CI for total CVD, MI, HF, and IS for pioglitazone plus metformin were 0.89 (0.81-0.99), 1.05 (0.76-1.46), 4.81 (3.53-6.56), and 0.81 (0.67-0.99), respectively. CONCLUSIONS:Compared with a DPP-4 inhibitor plus metformin, treatment with a sulfonylurea drug plus metformin was associated with increased risks of total CVD, MI, and IS, whereas the use of pioglitazone plus metformin was associated with decreased total CVD and IS risks.

SUBMITTER: Seong JM

PROVIDER: S-EPMC4439115 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Although patients with type 2 diabetes mellitus (T2DM) may fail to achieve adequate hemoglobin A1c (HbA1c) control despite metformin-sulfonylurea (Met-SU) dual therapy, a third-line glucose-lowering medication-including dipeptidyl peptidase-4 inhibitor (DPP4i), insulin, or thiazolidinedione (TZD)-can be added to achieve this. However, treatment effects of intensification with the medications on the risk of severe hypoglycemia (SH), cardiovascular disease (CVD), and all-cause mortality are uncertain. Study aim was to compare the risks of all-cause mortality, CVD, and SH among patients with T2DM on Met-SU dual therapy intensified with DPP4i, insulin, or TZD. METHODS AND FINDINGS:We analyzed a retrospective cohort data of 17,293 patients with T2DM who were free from CVD and on Met-SU dual therapy and who were intensified with DPP4i (n = 8,248), insulin (n = 6,395), or TZD (n = 2,650) from 2006 to 2017. Propensity-score weighting was used to balance out baseline covariates across groups. Hazard ratios (HRs) for all-cause mortality, CVD, and SH were assessed using Cox proportional hazard models. Mean age of all patients was 58.56 ± 11.41 years. All baseline covariates achieved a balance across the 3 groups. Over a mean follow-up period of 34 months with 49,299 person-years, cumulative incidences of all-cause mortality, SH, and CVD were 0.061, 0.119, and 0.074, respectively. Patients intensified with insulin had higher risk of all-cause mortality (HR = 2.648, 95% confidence interval [CI] 2.367-2.963, p < 0.001; 2.352, 95% CI 2.123-2.605, p < 0.001) than those intensified with TZD and DPP4i, respectively. Insulin users had the greatest risk of SH (HR = 1.198, 95% CI 1.071-1.340, p = 0.002; 1.496, 95% CI 1.342-1.668, p < 0.001) compared with TZD and DPP4i users, respectively. Comparing between TZDs and DPP4i, TZDs were associated with a higher risk of SH (HR = 1.249, 95% CI 1.099-1.419, p < 0.001) but not all-cause mortality (HR = 0.888, 95% CI 0.776-1.016, p = 0.084) or CVD (HR = 1.005, 95% CI 0.915-1.104, p = 0.925). Limitations of this study included the lack of data regarding lifestyle, drug adherence, time-varying factors, patients' motivation, and cost considerations. A limited duration of patients intensifying with TZD might also weaken the strength of study results. CONCLUSIONS:Our results indicated that, for patients with T2DM who are on Met-SU dual therapy, the addition of DPP4i was a preferred third-line medication among 3 options, with the lowest risks of mortality and SH and posing no increased risk for CVD events when compared to insulin and TZD. Intensification with insulin had the greatest risk of mortality and SH events.

Project description:AbstractThe comparative effectiveness of oral hypoglycemic agents on glycemic control and chronic complications in clinical practice is unknown in Korea. This study aimed to compare glycemic control and the incidence of hypoglycemia and chronic complications among adult patients with type 2 diabetes prescribed metformin, dipeptidyl peptidase-4 inhibitors (DPP4I), and sulfonylurea (SU) as monotherapy or dual combination therapy.We retrospectively analyzed propensity-matched cohort data from 3 national university hospitals in Korea. All electronic health records were transformed into a unified Observational Medical Outcomes Partnership Common Data Model and analyzed using ATLAS, an open-source analytical tool, and R software. Glycemic control was assessed as the first observation of a reduction in glycosylated hemoglobin (HbA1c) level below 7% after prescription of the drug. Differences in the incidence of chronic complications were compared based on the first observation of each complication. Glycemic control and chronic complications were evaluated in patients who maintained the same prescription for at least 3 and 12 months, respectively.Patients who received metformin had lower hazard of reaching HbA1c levels below 7% as compared with those who received SU, and had higher hazard compared with those who received DPP4I (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.98; and HR, 1.68; 95% CI, 1.42-1.99, respectively). The incidence of hypoglycemia was significantly higher in the SU group than in the metformin and DPP4I groups (metformin vs SU; HR, 0.30; 95% CI, 0.21-0.43; SU vs DPP4I; HR, 4.42; 95% CI, 2.35-8.31). Metformin + DPP4I had similar hazard of reaching HbA1c levels below 7% compared with metformin + SU (HR, 1.19; 95% CI, 0.99-1.43) and the incidence of hypoglycemia was significantly lower in the metformin + DPP4I group (HR 0.13; 95% CI 0.05-0.30). There was no significant difference in the analysis of the occurrence of chronic complications.SU followed by metformin was effective, and both drugs showed an increased hazard of reaching HbA1c levels below 7% compared with DPP4I. Metformin + DPP4I is comparatively effective for HbA1c level reduction below 7% compared with metformin + SU. Hypoglycemia was high in the SU-containing therapy.

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Differential cardiovascular outcomes after dipeptidyl peptidase-4 inhibitor, sulfonylurea, and pioglitazone therapy, all in combination with metformin, for type 2 diabetes: a population-based cohort study.

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