Effects on the glucagon response to hypoglycaemia during <scp>DPP</scp>‐4 inhibition in elderly subjects with type 2 diabetes: <scp>A</scp> randomized, placebo‐controlled study

Farngren, Johan; Persson, Margaretha; Åhrén, Bo

doi:10.1111/dom.13316

Cited by 5 publications

(10 citation statements)

References 39 publications

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“…Briefly, these studies were all RCTs including T2DM patients which were published between 2007 and 2018. Seven of them were crossover studies ( 20 , 24 , 25 , 27 , 31 , 37 , 45 ), whilst the remaining studies were parallel-group RCTs. The mean ages of the patients varied between 51 and 74 years.…”

Section: Resultsmentioning

confidence: 99%

Effect of dipeptidyl peptidase-4 inhibitors on postprandial glucagon level in patients with type 2 diabetes mellitus: A systemic review and meta-analysis

Chai¹,

Zhang²,

Zhang³

et al. 2022

Front. Endocrinol.

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AimsHyperglucagonemia occurs in the pathogenesis of type 2 diabetes mellitus (T2DM). In this meta-analysis, we summarized the effects of DPP4 inhibitors on glucagon levels in patients with T2DM.Materials and methodsRandomized controlled trials (RCTs) comparing the influence of DPP4 inhibitors on circulating glucagon levels with placebo or other oral antidiabetic drugs (OADs) in patients with T2DM were identified by searches of Medline (PubMed), Embase (Ovid), and CENTER (Cochrane Library). Only studies reporting changes in glucagon level presented as total area under the curve (AUCglucagon) using a meal or oral glucose tolerance test were included. Results were combined using a random-effects model that incorporated potential heterogeneity among the included studies.ResultsA total of 36 RCTs with moderate to high quality were included. Overall, the numbers of T2DM patients included for the meta-analyses comparing DPP4 inhibitors with placebo and other OADs were 4266 and 1652, respectively. Compared to placebo, DPP4 inhibitors significantly reduced circulating glucagon levels (standard mean difference [SMD]: -0.32, 95% CI: -0.40 to -0.24, P<0.001; I2 = 28%). Analysis of subgroups revealed that study characteristics had no significant effect on results, such as study design (parallel group or crossover), number of patients, mean patient age, proportion of men, baseline HbA1c, duration of diabetes, background therapy, treatment duration, or methods for glucagon measurement (all P for subgroup differences >0.05). Moreover, DPP4 inhibitors significantly reduced glucagon levels compared to other OADs (SMD: -0.35, 95% CI: -0.53 to -0.16, P<0.001; I2 = 66%), and the reduction in glucagon was greater in comparison with insulin secretagogues than in comparison with non-insulin secretagogues (P for subgroup difference =0.03).Systematic review registrationhttps://inplasy.com/, identifier INPLASY202280104.ConclusionsDPP4 inhibitors are effective at reducing the circulating postprandial glucagon level in T2DM patients.

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Section: Resultsmentioning

confidence: 99%

Effect of dipeptidyl peptidase-4 inhibitors on postprandial glucagon level in patients with type 2 diabetes mellitus: A systemic review and meta-analysis

Chai¹,

Zhang²,

Zhang³

et al. 2022

Front. Endocrinol.

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“…Whether glucagon counter-regulation to hypoglycemia is affected during DPP-4 inhibition in type 2 diabetes has been studied in drug-naïve subjects (138), in subjects when a DPP-4 inhibition was added on to insulin therapy (139), and in elderly subjects with metformin-treated type 2 diabetes (140). These studies have used the hyperinsulinemic, hypoglycemic clamp technique and have determined glucagon counter regulation.…”

Section: Low Risk Of Hypoglycemiamentioning

confidence: 99%

“…Results showed that glucagon counter-regulation during hypoglycemia is sustained during DPP-4 inhibition. Figure 10 shows results from the study in elderly subjects (140). The study examined the counter-regulation to hypoglycaemia in 28 elderly subjects (65–84 years) with metformin-treated type 2 diabetes after addition of sitagliptin or placebo for 4 weeks in a cross-over design.…”

Section: Low Risk Of Hypoglycemiamentioning

confidence: 99%

DPP-4 Inhibition and the Path to Clinical Proof

Åhrén

2019

Front. Endocrinol.

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In the 1990s it was discovered that the enzyme dipeptidyl peptidase-4 (DPP-4) inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibition results in raised levels of the two incretin hormones which in turn result in lowering of circulating glucose through stimulation of insulin secretion and inhibition of glucagon secretion. Since then, several small orally available molecules have been developed with DPP-4 inhibitory action. Early studies in the 1990s showed that the DPP-4 inhibitors improve glycemia in animals. Subsequent clinical studies during the 2000s showed a glucose-lowering action of DPP-4 inhibitors also in human subjects with type 2 diabetes. This action was seen when DPP-4 inhibitors were used both as monotherapy and as add-on to other therapies, i.e., metformin, sulfonylureas, tiazolidinediones or exogenous insulin. The DPP-4 inhibitors were also found to have a low risk of adverse events, including hypoglycemia. Five of the DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, saxagliptin and linagliptin) were approved by regulatory authorities and entered the market between 2006 and 2013. DPP-4 inhibitors have thereafter undergone long-term cardiovascular outcome trials, showing non-inferiority for risk of major acute cardiovascular endpoints. Also the risk of other potential adverse events is low in these long-term studies. DPP-4 inhibitors are at present included in guidelines as a glucose-lowering concept both as monotherapy and in combination therapies. This article summarizes the development of the DPP-4 inhibition concept from its early stages in the 1990s. The article underscores that the development has its basis in scientific studies on pathophysiology of type 2 diabetes and the importance of targeting the islet dysfunction, that the development has been made possible through academic science in collaboration with the research-oriented pharmaceutical industry, and that the development of a novel concept takes time and requires focused efforts, persistence and long-term perserverance.

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“…2,[26][27][28][29][30] DPP4Is and SUs may differentially affect cognitive and physical functioning through their effects on hypoglycaemia and hyperglycaemia. [28][29][30][31] SUs are associated with a greater risk of hypoglycaemia than DPP4Is. 25,[28][29][30] The use of DPP4Is may also reduce amyloid beta accumulation in the brain, which could further help to maintain or slow cognitive decline.…”

Section: Introductionmentioning

confidence: 99%

“…These oral glucose‐lowering agents may improve cognition and the ability to perform activities of daily living by improving blood glucose control, potentially even reversing impaired neuromotor function 2,26–30 . DPP4Is and SUs may differentially affect cognitive and physical functioning through their effects on hypoglycaemia and hyperglycaemia 28–31 . SUs are associated with a greater risk of hypoglycaemia than DPP4Is 25,28–30 .…”

Section: Introductionmentioning

confidence: 99%

Effects of dipeptidyl peptidase‐4 inhibitors and sulphonylureas on cognitive and physical function in nursing home residents

Zullo

Duprey

Smith

et al. 2021

Diabetes Obesity Metabolism

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Aims Dipeptidyl peptidase‐4 inhibitors (DPP4Is) may mitigate hypoglycaemia‐mediated declines in cognitive and physical functioning compared with sulphonylureas (SUs), yet comparative studies are unavailable among older adults, particularly nursing home (NH) residents. We evaluated the effects of DPP4Is versus SUs on cognitive and physical functioning among NH residents. Materials and Methods This new‐user cohort study included long‐stay NH residents aged ≥65 years from the 2007‐2010 national US Minimum Data Set (MDS) clinical assessments and linked Medicare claims. We measured cognitive decline from the validated 6‐point MDS Cognitive Performance Scale, functional decline from the validated 28‐point MDS Activities of Daily Living scale, and hospitalizations or emergency department visits for altered mental status from Medicare claims. We compared 180‐day outcomes in residents who initiated a DPP4I versus SU after 1:1 propensity score matching using Cox regression models. Results The matched cohort (N = 1784) had a mean ± SD age of 80 ± 8 years and 73% were women. Approximately 46% had no or mild cognitive impairment and 35% had no or mild functional impairment before treatment initiation. Compared with SU users, DPP4I users had lower 180‐day rates of cognitive decline [hazard ratio (HR) = 0.61, 95% confidence interval (CI) 0.31‐1.19], altered mental status events (HR = 0.71, 95% CI 0.39‐1.27), and functional decline (HR = 0.89, 95% CI 0.51‐1.56), but estimates were imprecise. Conclusions Rates of cognitive and functional decline may be reduced among older NH residents using DPP4Is compared with SUs, but larger studies with greater statistical power should resolve the remaining uncertainty by providing more precise effect estimates.

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Effects on the glucagon response to hypoglycaemia during DPP‐4 inhibition in elderly subjects with type 2 diabetes: A randomized, placebo‐controlled study

Cited by 5 publications

References 39 publications

Effect of dipeptidyl peptidase-4 inhibitors on postprandial glucagon level in patients with type 2 diabetes mellitus: A systemic review and meta-analysis

Effect of dipeptidyl peptidase-4 inhibitors on postprandial glucagon level in patients with type 2 diabetes mellitus: A systemic review and meta-analysis

DPP-4 Inhibition and the Path to Clinical Proof

Effects of dipeptidyl peptidase‐4 inhibitors and sulphonylureas on cognitive and physical function in nursing home residents

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