Comparative cardiovascular outcomes and safety of hypoglycemic drug classes in patients with type 2 diabetes and hypertension: a multicenter cohort analysis

Abstract

Background: Patients with type 2 diabetes (T2D) and hypertension are at increased risk of adverse cardiovascular (CV) events. However, real-world evidence comparing the CV effectiveness and safety of major hypoglycemic drug classes remains limited in this population. This multicenter pooled analysis aims to directly compare the CV outcomes and safety profiles of these key agents in patients with T2D and hypertension.

Methods: We analyzed electronic health records from two databases in a cohort study of T2D patients with hypertension who had initiated metformin as first-line therapy. Propensity score matching (PSM) and Cox proportional hazards models were used to compare the risks of 3-/4-point major adverse cardiovascular events (MACE) and safety outcomes across drug classes added to metformin: insulin, sulfonylureas (SUs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 inhibitors (DPP4is), glinides, acarbose, and sodium-glucose transporter 2 inhibitors (SGLT2is).

Results: Compared with insulin, GLP-1 RAs, DPP4is, and glinides were associated with a lower risk of 3-point MACE (HR: 0.48 [0.31-0.76], 0.70 [0.57-0.85], and 0.70 [0.52-0.94], respectively). SUs were associated with a higher risk of 3-point MACE compared with DPP4is (HR: 1.30 [1.06-1.59]). DPP4is, GLP-1 RAs, and glinides showed a lower risk of 3-point MACE compared with acarbose (HR: 0.62 [0.51-0.76], 0.47 [0.29-0.75], and 0.59 [0.43-0.81], respectively). Similar patterns were observed for 4-point MACE. For safety outcomes, DPP4is were associated with a reduced risk of chronic kidney disease, while insulin use was associated with reduced risks of inflammatory polyarthritis and insomnia. However, DPP4is were associated with higher risks of coronary atherosclerotic diseases and hypertensive heart disease.

Conclusions: This study highlights the differential cardiovascular effectiveness and safety profiles of hypoglycemic therapies in real-world settings, providing valuable insights for optimizing T2D management, particularly in patients with comorbid hypertension.

Keywords: Cardiovascular safety; Hypertension; Major adverse cardiovascular events (MACE); Real-world evidence; Retrospective study; Type 2 diabetes.

Fig. 1

Demographic characteristics for hypoglycemic drug comparison before and after adjustment using PSM and IPTW methods across JSPH and FAHZU databases. This figure presents the comparisons of MetAcarbose (metformin combined with acarbose) versus MetDPP4is (metformin combined with dipeptidyl peptidase-4 inhibitors) in the upper panel and MetGlinides (metformin combined with glinides) versus MetInsulin (metformin combined with insulin) in the lower panel, with results from both PSM and IPTW methods across JSPH and FAHZU databases. Group differences were assessed using SMD, with an SMD value of <  ± 0.1 considered indicative of balance. An SMD > 0 indicates that the characteristic is higher in the target drug class (first), while an SMD < 0 indicates that it is higher in the comparator drug class (second)

Fig. 2

Comparative effectiveness of seven hypoglycemic drug classes on 3-point and 4-point MACE using PSM method in JSPH, FAHZU, and Pooled analysis. Seven hypoglycemic drug classes (MetInsulin [metformin combined with insulin], MetSUs [metformin combined with sulfonylureas], MetAcarbose [metformin combined with acarbose], MetSGLT2is [metformin combined with sodium-glucose cotransporter-2 inhibitors], MetGLP-1 RAs [metformin combined with glucagon-like peptide-1 receptor agonists], MetGlinides [metformin combined with glinides], and MetDPP4is [metformin combined with dipeptidyl peptidase-4 inhibitors]) were compared across JSPH and FAHZU databases, with results combined through pooled analysis. Squares represent results from JSPH, circles from FAHZU, and diamonds from pooled analysis. Red and blue shaded areas indicate results for 3-point MACE and 4-point MACE, respectively. For each drug comparison, the target drug class is in the row, while the comparator drug class is in the column. Points report HR estimates, with lines marking their 95% CIs. An HR > 1 indicates that the risk is higher in the target drug class, while an HR < 1 indicates that it is higher in the comparator drug class. Comparisons were considered statistically significant if the 95% CI did not overlap 1

Fig. 3

Comparative safety profiles of seven hypoglycemic drug classes across ten outcomes using PSM method in JSPH, FAHZU, and Pooled analysis. Seven hypoglycemic drug classes (MetInsulin [metformin combined with insulin], MetSUs [metformin combined with sulfonylureas], MetAcarbose [metformin combined with acarbose], MetSGLT2is [metformin combined with sodium-glucose cotransporter-2 inhibitors], MetGLP-1 RAs [metformin combined with glucagon-like peptide-1 receptor agonists], MetGlinides [metformin combined with glinides], and MetDPP4is [metformin combined with dipeptidyl peptidase-4 inhibitors]) were compared across JSPH and FAHZU databases, with results combined through pooled analysis. Squares represent results from JSPH, circles from FAHZU, and diamonds from pooled analysis. Different colored bands represent the ten outcomes. For each drug comparison, the target drug class is in the row, while the comparator drug class is in the column. Points report HR estimates, with lines marking their 95% CIs. An HR > 1 indicates that the risk is higher in the target drug class, while an HR < 1 indicates that it is higher in the comparator drug class. Comparisons were considered statistically significant if the 95% CI did not overlap 1