Dataset Information

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.

SUBMITTER: Espeland MA

PROVIDER: S-EPMC7839453 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

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.

Espeland Mark A MA Pratley Richard E RE Rosenstock Julio J Kadowaki Takashi T Seino Yutaka Y Zinman Bernard B Marx Nikolaus N McGuire Darren K DK Andersen Knut Robert KR Mattheus Michaela M Keller Annett A Weber Maria M Johansen Odd Erik OE

Diabetes, obesity & metabolism 20201206 2

<h4>Aim</h4>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.<h4>Materials and methods</h4>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 d ...[more]

PMID: 33185002

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Project description:AimTo determine the effect of the dipeptidyl peptidase-4 inhibitor linagliptin on postprandial glomerular hyperfiltration compared with the sulphonylurea glimepiride in adults with type 2 diabetes (T2D).Materials and methodsIn this predefined substudy within a randomized, double-blind, parallel-group, intervention trial, overweight people with T2D without renal impairment were treated with once-daily linagliptin 5 mg (N = 10) or glimepiride 1 mg (N = 13) as an add-on to metformin for 8 weeks. After a standardized liquid protein-rich meal, the glomerular filtration rate (GFR) and effective renal plasma flow were determined by inulin and para-aminohippuric acid clearance, respectively, based on timed urine sampling. Intrarenal haemodynamics were estimated using the Gomez equations. Glucoregulatory/vasoactive hormones, urinary pH and fractional excretions (FE) of sodium, potassium and urea were measured.ResultsCompared with glimepiride, linagliptin increased the postprandial filtration fraction (FF; mean difference 2.1%-point; P = .016) and estimated glomerular hydraulic pressure (mean difference 3.0 mmHg; P = .050), and tended to increase GFR (P = .08) and estimated efferent renal arteriolar resistance (RE ; P = .08) from baseline to week 8. No differences in FE were noted. Glimepiride reduced HbA1c more than linagliptin (mean difference -0.40%; P = .004), without between-group differences in time-averaged postprandial glucose levels. In the linagliptin group, change in FF correlated with change in mean arterial pressure (R = 0.807; P = .009) and time-averaged mean glucagon (R = 0.782; P = .008), but not with changes in glucose, insulin, intact glucagon-like peptide-1, renin or FENa . Change in glucagon was associated with change in RE (R = 0.830; P = .003).ConclusionsIn contrast to our hypothesis, compared with glimepiride, linagliptin does not reduce postprandial hyperfiltration, yet appears to increase FF after meal ingestion by increasing blood pressure or RE .

Project description:ImportanceType 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator.ObjectiveThis trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease.Design, setting, and participantsRandomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5% to 8.5%, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August 2018.InterventionsPatients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need.Main outcomes and measuresThe primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3.ResultsOf 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P < .001 for noninferiority), meeting the noninferiority criterion but not superiority (P = .76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]).Conclusions and relevanceAmong adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome.Trial registrationClinicalTrials.gov Identifier: NCT01243424.

Project description:Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors used to treat type 2 diabetes may have nephroprotective effects beyond the reduced renal risk conferred by glycemic control. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. The kidneys contain the highest levels of DPP-4, which is increased in diabetic nephropathy. DPP-4 inhibitors are a chemically heterogeneous class of drugs with important pharmacological differences. Of the globally marketed DPP-4 inhibitors, linagliptin is of particular interest for diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine. Linagliptin is also the most potent DPP-4 inhibitor, has the highest affinity for this protein, and has the largest volume of distribution; these properties allow linagliptin to penetrate kidney tissue and tightly bind resident DPP-4. In animal models of kidney disease, linagliptin elicited multiple renoprotective effects, including reducing albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis, independent of changes in glucagon-like peptide-1 (GLP-1) and glucose levels. At the molecular level, linagliptin prevented the pro-fibrotic endothelial-to-mesenchymal transition by disrupting the interaction between membrane-bound DPP-4 and integrin β1 that enhances signaling by transforming growth factor-β1 and vascular endothelial growth factor receptor-1. Linagliptin also increased stromal cell derived factor-1 levels, ameliorated endothelial dysfunction, and displayed unique antioxidant effects. Although the nephroprotective effects of linagliptin are yet to be translated to the clinical setting, the ongoing Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA®) study will definitively assess the renal effects of this DPP-4 inhibitor. CARMELINA® is the only clinical trial of a DPP-4 inhibitor powered to evaluate kidney outcomes.

Dataset Information

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.

Aim

Materials and methods

Results

Conclusions

Publications

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.

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