Liraglutide improves memory in obese patients with prediabetes or early type 2 diabetes: a randomized, controlled study

Vadini, Francesco; Simeone, Paola; Boccatonda, Andrea; Guagnano, Maria Teresa; Liani, Rossella; Tripaldi, Romina; Castelnuovo, Augusto Di; Cipollone, Francesco; Consoli, Agostino; Santilli, Francesca

doi:10.1038/s41366-020-0535-5

Cited by 67 publications

(49 citation statements)

References 42 publications

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“…In Alzheimer's disease, the most prevalent form of dementia, animal studies have shown the positive effects of GLP-1 RAs on cognitive impairment [ 222 , 223 ]. In a clinical trial of patients with prediabetes and type 2 diabetes, memory function improved after 4 months of liraglutide administration [ 224 ]. However, there was no placebo control.…”

Section: Opportunities For Future Development Of Glp-1 Rasmentioning

confidence: 99%

GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art

Nauck

Quast

Wefers

2021

Molecular Metabolism

741

570

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Background GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). Scope of review To summarize current knowledge about GLP-1 receptor agonist. Major conclusions At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA 1c , both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA 1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal comp...

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Section: Opportunities For Future Development Of Glp-1 Rasmentioning

confidence: 99%

GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art

Nauck

Quast

Wefers

2021

Molecular Metabolism

741

570

View full text Add to dashboard Cite

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“…Stimulation of the GLP-1 receptor could attenuate neuroinflammation and enhance neurogenesis in diabetes-induced dementia, in animal models [27,28]. The concept was supported by a small randomized, controlled study in humans, which showed that liraglutide therapy improved memory function in obese patients with prediabetes or early type 2 diabetes, independently of weight loss and the glycemic lowering effect [29]. Therefore, increased circulating GLP 1 concentrations from DPP-4i therapy may have a neuroprotective role in the treatment of dementia.…”

Section: Discussionmentioning

confidence: 98%

Association between the Use of Dipeptidyl Peptidase 4 Inhibitors and the Risk of Dementia among Patients with Type 2 Diabetes in Taiwan

Chen

Chung

et al. 2020

JCM

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Study Objectives: Diabetes mellitus per se and its related therapy have been frequently associated with an increased risk of developing dementia. However, studies that explored the risk of dementia from the use of the novel oral antidiabetic medication dipeptidyl peptidase 4 inhibitor (DPP-4i) have been limited, especially in Asian populations. The present study aimed to determine the effect of DPP-4i on the subsequent risk of dementia among patients with type 2 diabetes (T2D) in Taiwan. Methods: This study utilized data from the Longitudinal Health Insurance Database between 2008 and 2015. We enrolled 2903 patients aged ≥50 years, who were on DPP-4i for a diagnosis of T2D and had no dementia. A total of 11,612 subjects were included and compared with a propensity score-matched control group who did not use DPP-4i (non-DPP-4i group). Survival analysis was performed to estimate and compare the risk of dementia—including Alzheimer’s disease, vascular dementia, and other dementia types—between the two groups. Results: Both groups had a mean age of 68 years, had a preponderance of women (61.8%), and were followed up for a mean duration of 7 years. The risk of all-cause dementia was significantly lower in the DPP-4i group than in the non-DPP-4i group (hazard ratio (HR) 0.798; 95% confidence interval (CI) 0.681–0.883; p < 0.001), with a class effect. This trend was particularly observed for vascular dementia (HR 0.575; 95% CI 0.404–0.681; p < 0.001), but not in Alzheimer’s disease (HR 0.891; 95% CI 0.712–1.265; p = 0.297). The Kaplan–Meier analysis showed that the preventive effect on dementia was positively correlated with the cumulative dose of DPP-4i. Conclusions: DPP-4i decreased the risk of dementia with a class effect, especially vascular dementia, but not in Alzheimer’s disease. Our results provide important information on the drug choice when managing patients with T2D in clinical practice.

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“…One further approach for the treatment of cognitive impairments has recently gained growing interestglucagon-like peptide-1 (GLP-1) receptor agonists. 31 33 These drugs showed first beneficial effect in recent pilot trials [34][35][36] and larger trials are ongoing. 31 33 Of note, animal studies indicate a close interaction between GLP-1 receptor and insulin receptor signaling in the brain.…”

Section: Discussionmentioning

confidence: 99%

Insulin sensitivity predicts cognitive decline in individuals with prediabetes

Willmann

Brockmann

Wagner

et al. 2020

BMJ Open Diab Res Care

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IntroductionEpidemiological studies indicate an association between type 2 diabetes and cognitive dysfunction that appear to start already in the prediabetic state. Although cross-sectional studies have linked insulin resistance to impaired cognition, the potential predictive value of insulin resistance has not yet been sufficiently studied longitudinally without confounding by overt diabetes (and its pharmacological treatment).Research design and methodsWe investigated longitudinal data from participants of the ‘Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration’ Study. Subjects underwent a neurocognitive assessment battery (CERAD Plus battery; Consortium to Establish a Registry for Alzheimer’s Disease) at baseline and followed every 2 years (median follow-up 4.0 Q1–3: 2.2–4.3 years). Subjects within a pre-diabetic glycated hemoglobin range of 5.6%–6.5% underwent 5-point 75 g oral glucose tolerance tests (OGTTs) with assessment of insulin sensitivity and insulin secretion (n=175). Subjects with newly diagnosed diabetes mellitus or with major depressivity (Beck Depression Inventory >20) were excluded (n=15). Data were analyzed by mixed models using sex, age and glycemic trait as fixed effects. Subject and time since first measurement were used as random effects.ResultsInsulin sensitivity was positively associated with the CERAD sum score (higher is better) in a time-dependent manner (p=0.0057). This result is mainly driven by a steeper decrease in the memory domain associated with lower insulin sensitivity (p=0.029). The interaction between age and insulin sensitivity was independent of glycemia (p=0.02). There was also no association between insulin secretion and cognition.ConclusionsInsulin resistance rather than sole elevation of blood glucose predicts cognitive decline, specifically in the memory domain, in persons with prediabetes. Treatments of diabetes that improve insulin sensitivity might therefore have the potential to postpone or even prevent cognitive decline in patients with diabetes.

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Liraglutide improves memory in obese patients with prediabetes or early type 2 diabetes: a randomized, controlled study

Cited by 67 publications

References 42 publications

GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art

GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art

Association between the Use of Dipeptidyl Peptidase 4 Inhibitors and the Risk of Dementia among Patients with Type 2 Diabetes in Taiwan

Insulin sensitivity predicts cognitive decline in individuals with prediabetes

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