Effects of linagliptin vs glimepiride on cognitive performance in type 2 diabetes: results of the randomised double-blind, active-controlled CAROLINA-COGNITION study

Abstract

Aims/hypothesis Type 2 diabetes, particularly with concomitant CVD, is associated with an increased risk of cognitive impairment. We assessed the effect on accelerated cognitive decline (ACD) of the DPP-4 inhibitor linagliptin vs the sulfonylurea glimepiride in individuals with type 2 diabetes. Methods The CAROLINA-COGNITION study was part of the randomised, double-blind, active-controlled CAROLINA trial that evaluated the cardiovascular safety of linagliptin vs glimepiride in individuals with age ≥40 and ≤85 years and HbA1c 48–69 mmol/mol (6.5–8.5%) receiving standard care, excluding insulin therapy. Participants were randomised 1:1 using an interactive telephone- and web-based system and treatment assignment was determined by a computer-generated random sequence with stratification by center. The primary cognitive outcome was occurrence of ACD at end of follow-up, defined as a regression-based index score ≤16th percentile on either the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning, in participants with a baseline MMSE score ≥24. Prespecified additional analyses included effects on ACD at week 160, in subgroups (sex, age, race, ethnicity, depressive symptoms, cardiovascular risk, duration of type 2 diabetes, albuminuria), and absolute changes in cognitive performance. Participants, caregivers, and people involved in measurements, examinations or adjudication, were all masked to treatment assignment. Results Of 6033 participants recruited from hospital and primary care sites, 3163 (38.0% female, mean age/diabetes duration 64/7.6 years, MMSE score 28.5, HbA1c 54 mmol/mol [7.1%]) represent the CAROLINA-COGNITION cohort. Over median 6.1 years, ACD occurred in 27.8% (449/1618, linagliptin) vs 27.6% (426/1545, glimepiride), OR 1.01 (95% CI 0.86, 1.18). Also, no differences in ACD were observed at week 160 (OR 1.07 [0.91, 1.25]), between treatments across subgroups, or for absolute cognitive changes. Conclusions/interpretation In a large, international outcome trial in people with relatively early type 2 diabetes at elevated cardiovascular risk, no difference in risk for ACD was observed between linagliptin and glimepiride over 6.1 years. Funding This study was sponsored by Boehringer Ingelheim. Trial registration ClinicalTrials.gov NCT01243424. Graphical abstract

Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer’s disease risk in the general population: a Mendelian randomization study

“…By reviewing existing clinical trial and/or MR studies of medication treatment and/or drug repurposing on Alzheimer’s disease, we found that cholinesterase inhibitors and NMDA receptor antagonist were the two most widely used anti-dementia medications 42,43 , which were recommended by the current National Institute for Health and Care Excellence (NICE) guidance for people with Alzheimer’s disease (https://www.nice.org.uk/guidance/cg42). We also found some evidence to support the role of liraglutide (one GLP-1 inhibitor) and most of the anti-hypertensive drugs on preventing/delaying cognitive impairment 37,38,39,40,41 . The level of prevention of liraglutide was similar to the effect estimate we observed on metformin targets (14%) 37 .…”

“…By reviewing existing clinical trial and/or MR studies of drug repurposing on Alzheimer's disease, we found some evidence to support the role of liraglutide (one GLP-1 inhibitor) and most of the anti-hypertensive drugs on preventing/delaying cognitive impairment 37,38,39,40,41 .…”

Diabetes, Albuminuria and the Kidney—Brain Axis

“…Experimental evidence also supports the use of dipeptidyl peptidase-4 inhibitors or gliptins as potential drugs to prevent cognitive impairment through the preservation of Glucagon-like peptide 1 (GLP-1) function and increasing neurogenesis, among many other mechanisms [ 90 ]. However, the translation into clinical trials has failed, as has been shown recently [ 91 ]. In the CAROLINA-COGNITION study [ 91 ], 3163 diabetic participants (40 to 85 years old; HbA1c range of 48–69 mmol/mol (6.5–8.5%) and who received standard care, excluding insulin therapy) were randomized to linagliptin versus glimepiride and followed-up for a mean duration of 6.1 years.…”

“…However, the translation into clinical trials has failed, as has been shown recently [ 91 ]. In the CAROLINA-COGNITION study [ 91 ], 3163 diabetic participants (40 to 85 years old; HbA1c range of 48–69 mmol/mol (6.5–8.5%) and who received standard care, excluding insulin therapy) were randomized to linagliptin versus glimepiride and followed-up for a mean duration of 6.1 years. The study assessed the effect of linagliptin and glimepiride on accelerated cognitive decline in participants with a baseline MMSE score ≥24.…”

The Effectiveness of Antidiabetic Drugs in Treating Dementia: A Peek into Pharmacological and Pharmacokinetic Properties

“…Moreover, in a Bayesian network meta-analysis, the use of DPP-4 inhibitors was associated with a lower risk of dementia than no treatment with antidiabetic drugs, and DDP-4 inhibitors were the most effective antidiabetic drugs for dementia [ 19 ]. In contrast, two randomized controlled trials of linagliptin [ 78 , 79 ], a non-BBB-penetrating DPP-4 inhibitor, found no association between linagliptin use and maintenance of cognitive function. Unfortunately, there is no randomized controlled trial of BBB-penetrating DPP-4 inhibitors such as omarigliptin.…”