Coadministration of DPP-4 inhibitor and insulin therapy does not further reduce the risk of cardiovascular events compared with DPP-4 inhibitor therapy in diabetic foot patients: a nationwide population-based study

Lee

Huang

et al. 2021

BMJ Open Diab Res Care

Self Cite

IntroductionTherapeutic efficiency of glucagon-like peptide-1 (GLP-1) analog is about 50%–70% in type 2 diabetes mellitus (T2DM). Discovery of potential genetic biomarkers for prediction of treatment efficiency of GLP-1 analog before therapy is still necessary. We assess whether DNA methylation was associated with glycemic response to GLP-1 analog therapy in patients with poorly controlled T2DM.Research design and methodsGenomic DNA was extracted from the peripheral blood of training (n=10) and validation (n=128) groups of patients with T2DM receiving GLP-1 analogs. DNA methylome was analyzed using Infinium Human Methylation EPIC Bead Chip in the training group. The candidate genes were examined using a pyrosequencing platform in the validation group. The association between DNA methylation status and glycemic response to GLP-1 was analyzed in these patients.ResultsThe most differential methylation region between those with a good (responsive) and poor (unresponsive) glycemic response to GLP-1 analog therapy was located on chromosome 5q31.1 (135415693 to 135416613), the promoter of VTRNA2-1 in the training group. The methylation status of the VTRNA2-1 promoter was examined in the validation group via pyrosequencing reaction, and the hypomethylation of VTRNA2-1 (<40% methylation) was significantly associated with poor glycemic response to GLP-1 treatment (OR 2.757, 95% CI 1.240 to 6.130, p=0.011). Since the VTRNA2-1 promoter region was previously reported maternal imprinting extended to the adjacent centromeric CCCTC-binding factor site that contained an A/C polymorphism (rs2346018), which was associated with methylation density of VTRNA2-1, this A/C polymorphism was also integrated to analyze association with glycemic response to GLP-1 analog therapy. In patients with the A allele of rs2346018 and hypomethylation (<40%) on the VTRNA2-1 promoter, the OR increased to 4.048 (95% CI 1.438 to 11.389, p=0.007).ConclusionsThe glycemic response to GLP-1 analog treatment is associated with the methylation status of the VTRNA2-1 promoter and polymorphism of rs2346018.

Section: Discussionmentioning

confidence: 59%

Methylation status of vault RNA 2-1 promoter is a predictor of glycemic response to glucagon-like peptide-1 analog therapy in type 2 diabetes mellitus

Lee

Huang

et al. 2021

BMJ Open Diab Res Care

Self Cite

“…As mentioned above, DPP4-inhibitors maintained their effectiveness in diabetic patients with renal impairment and even ESRD [7,10,47]. Some studies indicated that specific DPP4-inhibitors may lead to adverse cardiovascular events, such as recurrent myocardial infarction and hospitalization, due to heart failure in selected populations [39,48], while the others take a positive attitude among cardiovascular outcome in patients with ESRD [14,49]. Overall, DPP4-inhibitors are thought to be neutral with regard to the cardiovascular events in DM population [12,50].…”

Section: Discussionmentioning

confidence: 95%

Pioglitazone Is Associated with Lower Major Adverse Cardiovascular and Cerebrovascular Events than DPP4-Inhibitors in Diabetic Patients with End-Stage Renal Disease: A Taiwan Nationwide Cohort Study, 2006–2016

Yang

Yen

et al. 2020

JCM

While pioglitazone reduces insulin resistance and hepatic gluconeogenesis effectively in patients with type 2 diabetes mellitus (T2DM), these benefits remained controversial in patients with end stage renal disease (ESRD). We compared major adverse cardiac cerebrovascular events (MACCEs) and mortality (overall, infection-related, and MACCE-related) of pioglitazone to that of dipeptidyl peptidase 4 inhibitors (DPP4-inhibitors) in patients with T2DM and ESRD. From Taiwan’s national health insurance research database (NHIRD), 647 pioglitazone users and 6080 DPP4-inhibitors users between 1 April 2006 and 31 December 2016 were followed from the 91th date after the ESRD certification until the study outcomes, independently; withdraw from the NHI program, death, or 31 December 2017, whichever came first. After weighting, risks of MACCEs (10.48% vs. 12.62% per person-years, hazard ratio (HR): 0.85, 95% (CI): 0.729–0.985) and all-cause mortality (12.86% vs. 13.22% per person-years, (HR): 0.88, 95% (CI): 0.771–0.995) are significantly lower in pioglitazone group. Subgroup analysis found lower MACCEs risk in the pioglitazone users without insulin therapy (6.44% vs. 10.04% (HR): 0.59, 95% (CI): 0.42–0.82) and lower MACCEs related death (2.76% vs. 3.84% (HR): 0.61, 95% (CI): 0.40–0.95) in the pioglitazone group with dyslipidemia, when comparing with DPP4-inhibitors users. Pioglitazone is associated with lower all-cause mortality and MACCEs in diabetic patients with ESRD, compared to DPP4-inhibitors. These benefits were even more significant in the non-insulin users and patients with dyslipidemia.

“…As mentioned above, DPP4-inhibitors maintained its capacity in diabetic patients with renal impairment and even ESRD [7,10,45]. Some studies indicated that specific DPP4-inhibitors may lead to adverse cardiovascular events such as recurrent myocardial infarction and hospitalization due to heart failure in selected populations [46][47][48], while the others take a positive attitude among cardiovascular outcome in patients with ESRD [14,49]. Overall, DPP4-inhibitors is thought to be safe with regard to the cardiovascular events in DM population [12,50].…”

Section: Discussionmentioning

confidence: 96%

Pioglitazone is Associated with Lower Major Adverse Cardiovascular and Cerebrovascular Events than DPP4-Inhibitors in Diabetic Patients with End-Stage Renal Disease: A Taiwan Nationwide Cohort Study, 2006-2016

Yang

Yen

et al. 2020

Preprint

While pioglitazone reduces insulin resistance and hepatic gluconeogenesis effectively in patients with T2DM, these benefits remained controversial in patients with ESRD. We compared MACCEs and mortality (overall, infection-related, and MACCE-related) of pioglitazone to that of DPP4-inhibitors in patients with T2DM and ESRD. From Taiwan’s national health insurance database, 647 pioglitazone users and 6080 DPP4-inhibitors users between April 1st, 2006 and December 31th, 2016 were followed from the 91th date after the ESRD certification till study outcomes, independently; withdraw from the NHI program, death, or Dec. 31th, 2017. After weighting, risks of MACCEs (10.48% vs 12.62% per person-years, [HR]: 0.85, 95% [CI]: 0.729–0.985) and all-cause mortality (12.86% vs 13.22% per person-years, [HR]: 0.88, 95% [CI]: 0.771–0.995) are significantly lower in pioglitazone group. Subgroup analysis found lower MACCEs risk in the pioglitazone users without insulin therapy (6.44% vs 10.04% [HR]: 0.59, 95% [CI]: 0.42–0.82) and lower MACCEs related death (2.76% vs 3.84% [HR]: 0.61, 95% [CI]: 0.40–0.95) in the pioglitazone group with dyslipidemia, when comparing with DPP4-inhibitors users. Pioglitazone is associated with lower all-cause mortality and MACCEs in diabetic patients with ESRD, compared to DPP4-inhibitors. These benefits were further significant in the non-insulin users and patients with dyslipidemia.