Cardiovascular outcomes and safety with linagliptin, a dipeptidyl peptidase‐4 inhibitor, compared with the sulphonylurea glimepiride in older people with type 2 diabetes: A subgroup analysis of the randomized CAROLINA trial

Abstract

Aim To compare the cardiovascular (CV) safety of linagliptin with glimepiride in older and younger participants in the CAROLINA trial in both prespecified and post hoc analyses. Materials and Methods People aged 40 to 85 years with relatively early type 2 diabetes, inadequate glycaemic control and elevated CV risk were randomly assigned to linagliptin 5 mg or glimepiride 1 to 4 mg. The primary endpoint was time to first occurrence of three‐point major adverse CV events (MACE: CV death, non‐fatal myocardial infarction, or non‐fatal stroke). We evaluated clinical and safety outcomes across age groups. Results Of 6033 participants, 50.7% were aged <65 years, 35.3% were aged 65 to 74 years, and 14.0% were aged ≥75 years. During the 6.3‐year median follow‐up, CV/mortality outcomes did not differ between linagliptin and glimepiride overall (hazard ratio [HR] for three‐point MACE 0.98, 95.47% confidence interval [CI] 0.84, 1.14) or across age groups (interaction P >0.05). Between treatment groups, reductions in glycated haemoglobin were comparable across age groups but moderate‐to‐severe hypoglycaemia was markedly reduced with linagliptin (HR 0.18, 95% CI 0.15, 0.21) with no differences among age groups (P = 0.23). Mean weight was −1.54 kg (95% CI –1.80, –1.28) lower for linagliptin versus glimepiride. Adverse events increased with age, but were generally balanced between treatment groups. Significantly fewer falls or fractures occurred with linagliptin. Conclusions Linagliptin and glimepiride were comparable for CV/mortality outcomes across age groups. Linagliptin had significantly lower risk of hypoglycaemia and falls or fractures than glimepiride, including in “older‐old” individuals for whom these are particularly important treatment considerations.

Safety of dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials

“… 34 , 36 , 37 , 39 , 41 , 42 , 47 – 49 Five RCTs compared DPP-4 inhibitor second-line treatment with sulfonylureas. 38 , 40 , 43 – 45 Barzilai et al. 35 and Schweizer et al.…”

“…The screening of full-text publications resulted in 16 RCTs (21 publications) which met all eligibility criteria. 34 – 54 Supplemental Figure 1 shows the study selection according to the updated PRISMA statement 2020. 15 A list of excluded studies with primary reason for exclusion is provided in Supplement III .…”

“…We rated five RCTs to be at low risk of bias. 37 – 39 , 48 , 49 We had some concerns regarding risk of bias for 10 RCTs. 34 , 35 , 40 – 47 One RCT we assessed as being at high risk of bias.…”

“…DPP-4 inhibitors added to standard care may reduce mortality compared with sulfonylureas added to standard care in older type 2 diabetes patients with inadequate glycaemic control. 38 , 40 , 44 , 45 DPP-4 inhibitors probably reduce hypoglycaemia compared with sulfonylureas, but the magnitude of the reduction cannot be reliably quantified because of heterogeneity in effect sizes between studies. 38 , 40 , 43 – 45 DPP-4 inhibitors have no impact on overall adverse events 38 , 40 , 44 , 45 but may reduce discontinuation due to adverse events 38 , 40 , 44 , 45 slightly.…”

Pharmacological treatment of type 2 diabetes in elderly patients with heart failure: randomized trials and beyond

“…The effect of the two treatments was similar on glycemic control, but patients treated with linagliptin experienced fewer moderate to severe hypoglycemic events (HR 0.18, 95% CI 0.15, 0.21) with no difference between age groups (P = 0.23). Significantly fewer falls or fractures occurred with linagliptin[62].…”