Use of DPP4 Inhibitors and GLP-1 Receptor Agonists and Risk of Intestinal Obstruction: Scandinavian Cohort Study.

BACKGROUND & AIMS: Concerns have been raised that the incretin-based diabetes drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists may increase the risk of intestinal obstruction. We aimed to assess the association between use of DPP4 inhibitors and GLP-1 receptor agonists and the risk of intestinal obstruction. METHODS: Using data from nationwide registers in Sweden, Denmark, and Norway, 2013-2021, we conducted 2 cohort studies, one for DPP4 inhibitors and one for GLP-1 receptor agonists, to investigate the risk of intestinal obstruction as compared with an active comparator drug class (sodium-glucose co-transporter 2 [SGLT2] inhibitors). RESULTS: Among 19,0321 new users of DPP4 inhibitors (median (interquartile range [IQR]) follow-up time, 1.3 [0.6-2.6] years) and 139,315 new users of SGLT2 inhibitors (median [IQR] follow-up time, 0.8 [0.4-1.7] years), 919 intestinal obstruction events occurred. Use of DPP4 inhibitors, as compared with SGLT2 inhibitors, was not associated with a statistically significant increase in risk of intestinal obstruction (adjusted incidence rate, 2.0 vs 1.8 per 1000 person-years; hazard ratio, 1.13; 95% confidence interval, 0.96-1.34). Among 121,254 new users of GLP-1 receptor agonists (median [standard deviation] follow-up time, 0.9 [0.4-1.9] years) and 185,027 new users of SGLT2 inhibitors (median [IQR] follow-up time, 0.8 [0.4-1.8] years), 557 intestinal obstruction events occurred. Use of GLP-1 receptor agonists was not associated with a statistically significant increase in risk of intestinal obstruction (adjusted incidence rate, 1.3 vs 1.6 per 1000 person-years; hazard ratio, 0.83; 95% confidence interval, 0.69-1.01). CONCLUSIONS: In this analysis of nationwide data from 3 countries, previous safety signals indicating an increased risk of intestinal obstruction with use of DPP4 inhibitors and GLP-1 receptor agonists were not confirmed.

Incretin drugs effect on epigenetic machinery: New potential therapeutic implications in preventing vascular diabetic complications.

The effect of GLP-1R agonists on DNA methylation levels of NF-κB and SOD2 genes in human aortic endothelial cells exposed to high glucose and in diabetic patients treated and not with incretin-based drugs, was evaluated. Methylation levels, mRNA and protein expression of NF-κB and SOD2 genes were measured in human endothelial cells exposed to high glucose for 7 days and treated with GLP-1R agonists. Methylation status of NF-κB and SOD2 promoter was also analyzed in 128 diabetics and 116 nondiabetics and correlated with intima media thickness (ITM), an early marker of atherosclerotic process. Cells exposed to high glucose showed lower NF-κB and SOD2 methylation levels, increased NF-κB and reduced SOD2 expression compared to normal glucose cells. Co-treatment with GLP-1 agonists prevented methylation and genes expression changes induced by high glucose. Both high glucose and incretins exposure increased DNA methyltransferases and demethylases levels. In diabetics, incretin treatment resulted a significant predictor of NF-κB DNA methylation, independently of age, sex, body mass index (BMI), glucose and plasma lipid levels. NF-κB DNA methylation inversely correlated with IMT after adjusting for multiple covariates. Our results firstly provide new evidences of an additional mechanism by which incretin drugs could prevent vascular diabetic complications.

Impact of early intervention with alogliptin on coronary plaque regression and stabilization in patients with acute coronary syndromes.

BACKGROUND AND AIMS: Anti-atherosclerotic effects of early intervention with dipeptidyl peptidase-4 inhibitors remain poorly defined. METHODS: In a prospective, single-center, randomized trial, 66 patients with acute coronary syndrome (ACS) and mild dysglycemia (HbA1c 6.0 (5.7, 6.3)%, 58% of impaired glucose tolerance) were randomly assigned to receive alogliptin (n = 33) or placebo (n = 33) in addition to standard treatments. Serial intravascular ultrasound (IVUS) was performed at baseline and 10 months to evaluate changes in coronary percent plaque volumes (%PV) and plaque tissue components of non-culprit lesions (NCLs). RESULTS: Baseline clinical and IVUS characteristics, as well as decreases in HbA1c and lipid variables during 10 months, did not differ significantly between the 2 groups. In contrast, with respect to vascular responses, the alogliptin group showed significantly greater decreases in plaque volumes (-0.3 ± 0.6 vs. -0.04 ± 0.7 mm3/mm, p = 0.03) and %PV (-0.9 ± 2.8 vs. 1.2 ± 3.6%, p = 0.01), with a tendency toward smaller lumen loss (-0.1 ± 0.7 vs. -0.4 ± 0.8 mm3/mm, p = 0.07) compared with the placebo group. Significantly decreased percent necrotic volumes (%NV) (-1.9 ± 3.8 vs. 0.3 ± 3.7%, p = 0.03) and increased fibrotic volumes (2.5 ± 5.0 vs. -0.3 ± 5.3%, p = 0.05) were or tended to be seen in alogliptin versus placebo groups at 10 months. In multiple regression analysis, alogliptin use was a statistically significant determinant of changes in %PV (ß = -0.33, p = 0.004) and %NV (ß = -0.28, p = 0.03) at 10 months. CONCLUSIONS: Alogliptin treatment, independently of glycemic and lipid status, resulted in significant plaque regression and stabilization in NCLs in patients with ACS and mild dysglycemia, suggesting the potential utility of early intervention with incretin-based treatments for this patients' subset.

Nonalcoholic Steatohepatitis (NASH) and Atherosclerosis: Explaining Their Pathophysiology, Association and the Role of Incretin-Based Drugs.

Nonalcoholic steatohepatitis (NASH) is the most severe manifestation of nonalcoholic fatty liver disease (NAFLD), a common complication of type 2 diabetes, and may lead to cirrhosis and hepatocellular carcinoma. Oxidative stress and liver cell damage are the major triggers of the severe hepatic inflammation that characterizes NASH, which is highly correlated with atherosclerosis and coronary artery disease. Regarding drug therapy, research on the role of GLP-1 analogues and DPP4 inhibitors, novel classes of antidiabetic drugs, is growing. In this review, we outline the association between NASH and atherosclerosis, the underlying molecular mechanisms, and the effects of incretin-based drugs, especially GLP-1 RAs, for the therapeutic management of these conditions.

Incretin-based drugs and intestinal obstruction: A pharmacovigilance study.

AIMS: To investigate the risk of intestinal obstruction associated with incretin-based drugs by performing a disproportionality analysis of adverse reaction reports in a global pharmacovigilance database. METHODS: We conducted a case/non-case analysis using VigiBase, the World Health Organization's adverse drug reactions (ADR) database, to assess intestinal obstruction reporting associated with incretin-based drugs (glucagon-like peptide 1 analogues [GLP-1a] and dipeptidyl peptidase 4 inhibitors [DPP-4i]. Cases were defined as reports of gastrointestinal stenosis and obstruction (MedDRA High Level Group Term) and non-cases were all other reactions recorded. Disproportionality analysis were performed by computing reporting odds ratios (ROR) with their 95% confidence interval (95%CI) within all ADR reports concerning diabetes drugs from January 2007 to January 2018 and in a restricted sample including only serious reports. RESULTS: A total of 501,244 ADR with diabetes drugs were reported in VigiBase during the study period. We identified 452 intestinal obstructions involving an incretin-based drug. In disproportionality analyses, intestinal obstructions were more than 4.5 times more frequently reported with incretin-based drugs than with other diabetes drugs (ROR 4.52, 95% CI: 3.87-5.28) with a higher signal for serious cases and for DPP-4i (ROR 8.66, 95% CI: 7.27-10.32) compared to GLP-1a (ROR 3.05, 95% CI: 2.54-3.66). CONCLUSIONS: We identified a pharmacovigilance signal that suggests a risk of potentially serious intestinal obstruction associated with incretin-based drugs, as a class and with a greater signal for DPP4-i. Other studies are needed to confirm and better understand the potential risk of intestinal obstruction associated with incretin-based drugs.

Augmentation of glucagon-like peptide-1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure.

Augmentation of glucagon-like peptide-1 (GLP-1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP-1 and long-acting GLP-1 receptor analogues are degraded not only by dipeptidyl peptidase-4, but also by neprilysin. This observation raises the possibilities that endogenous GLP-1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin-based drugs may experience important drug-drug interactions. Specifically, potentiation of GLP-1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long-acting GLP-1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP-1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP-1 analogues, the action of neprilysin to enhance the effects of GLP-1 may be particularly relevant in the brain, where augmentation of GLP-1 and other endogenous peptides may act to inhibit amyloid-induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP-1 and GLP-1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP-1 and long-acting GLP-1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes.

Incretin-based drugs and hospitalization for heart failure in the clinical practice: A nested case-control study.

BACKGROUND AND AIMS: There are concerns that incretin-based antidiabetic drugs - including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists - increase the risk of hospitalization for heart failure (HF). To further analyse this issue, we conducted a nested case-control study within a cohort of antidiabetic users in a real world setting. METHODS AND RESULTS: Within a cohort of 133,639 subjects with a first prescription of an antidiabetic drug (new-users) between 2010 and 2016 in Lombardy, Italy, and were followed-up to 2016, we identified 4057 subjects with a first hospitalization for HF and 80,450 controls matched on sex, age, and date of cohort-entry. The multivariate odds ratios (ORs) of HF in relation to current use of incretin-based drugs as compared to current use of two or more oral antidiabetics was 1.06 (95% confidence interval, CI, 0.83-1.35), with no evidence of a trend in risk with increasing duration of use. The corresponding ORs were 1.10 (95% CI 0.85-1.41) for DPP-4 inhibitors and 0.84 (95% CI 0.48-1.47) for GLP-1 receptor agonists. Estimates were consistent in various sensitivity analyses. CONCLUSIONS: This study indicates that incretin-based drugs are not associated with an increased risk of hospitalization for HF, thus providing further reassurance on the cardiovascular safety of these antidiabetic drugs in the clinical practice.

Signals of gastroesophageal reflux disease caused by incretin-based drugs: a disproportionality analysis using the Japanese adverse drug event report database.

BACKGROUND: Incretin-based drugs are important in the treatment of type 2 diabetes. However, among the incretin-based drugs, glucagon-like peptide-1 receptor agonists (GLP-1-RAs) have been reported to cause gastroesophageal reflux disease (GERD)-like symptoms making it difficult to continue treatment. Therefore, with the aim of clarifying the relationship between incretin-based drugs and GERD-like symptoms, we conducted a pharmacoepidemiological study using the Japanese adverse drug event report database (JADER). METHODS: Dipeptidyl peptidase-4 inhibitors (DPP-4-Is) and GLP-1-RAs were set as the incretin-based target drugs. The reporting odds ratio (ROR) and the information component (IC) was used for the detection of quantitative signals. Furthermore, we also compared the time to onset of GERD-like symptoms by log-rank test. RESULTS: GERD-like symptoms were reported in 36 GLP-1-RAs cases (ROR: 5.61, 95% confidence interval (95% CI): 3.95-7.96 and IC: 2.17, 95% CI: 1.66-2.67) and GLP-1-RAs were detected in the signal. In contrast, DPP-4-Is were not detected in the signal.There was no sex difference with regard to the expression time of GERD-like symptoms by GLP-1-RAs (log-rank test, p = 0.5381). However, the expression time of GERD-like symptoms from GLP-1-RAs was shorter in patients older than 70 years of age than that in those younger than 70 years of age (log-rank test, p < 0.0001). CONCLUSIONS: The administration of GLP-1-RA had a higher incidence of GERD-like symptoms earlier than the administration of DPP-4-Is. In this study, although we think that further investigation is necessary, and suggest that patients older than 70 years of age who have been administered GLP-1-RAs need earlier attention to address GERD-like symptoms than younger patients.

Adverse events associated with incretin-based drugs in Japanese spontaneous reports: a mixed effects logistic regression model.

BACKGROUND: Spontaneous Reporting Systems (SRSs) are passive systems composed of reports of suspected Adverse Drug Events (ADEs), and are used for Pharmacovigilance (PhV), namely, drug safety surveillance. Exploration of analytical methodologies to enhance SRS-based discovery will contribute to more effective PhV. In this study, we proposed a statistical modeling approach for SRS data to address heterogeneity by a reporting time point. Furthermore, we applied this approach to analyze ADEs of incretin-based drugs such as DPP-4 inhibitors and GLP-1 receptor agonists, which are widely used to treat type 2 diabetes. METHODS: SRS data were obtained from the Japanese Adverse Drug Event Report (JADER) database. Reported adverse events were classified according to the MedDRA High Level Terms (HLTs). A mixed effects logistic regression model was used to analyze the occurrence of each HLT. The model treated DPP-4 inhibitors, GLP-1 receptor agonists, hypoglycemic drugs, concomitant suspected drugs, age, and sex as fixed effects, while the quarterly period of reporting was treated as a random effect. Before application of the model, Fisher's exact tests were performed for all drug-HLT combinations. Mixed effects logistic regressions were performed for the HLTs that were found to be associated with incretin-based drugs. Statistical significance was determined by a two-sided p-value <0.01 or a 99% two-sided confidence interval. Finally, the models with and without the random effect were compared based on Akaike's Information Criteria (AIC), in which a model with a smaller AIC was considered satisfactory. RESULTS: The analysis included 187,181 cases reported from January 2010 to March 2015. It showed that 33 HLTs, including pancreatic, gastrointestinal, and cholecystic events, were significantly associated with DPP-4 inhibitors or GLP-1 receptor agonists. In the AIC comparison, half of the HLTs reported with incretin-based drugs favored the random effect, whereas HLTs reported frequently tended to favor the mixed model. CONCLUSION: The model with the random effect was appropriate for analyzing frequently reported ADEs; however, further exploration is required to improve the model. The core concept of the model is to introduce a random effect of time. Modeling the random effect of time is widely applicable to various SRS data and will improve future SRS data analyses.

Incretin-based drugs and risk of acute pancreatitis: A nested-case control study within a healthcare database.

To assess the association between use of incretin-based drugs for diabetes mellitus and the occurrence of acute pancreatitis. A population-based, nested case-control study was performed within a cohort of 166,591 patients from the Lombardy region (Italy) aged 40 years or older who were newly treated with oral antihyperglycaemic agents between 2004 and 2007. Cases were 666 patients who experienced acute pancreatitis from April 1, 2008 until December 31, 2012. For each case patient, up to 20 controls were randomly selected from the cohort and matched on gender, age at cohort entry, and date of index prescription. Conditional logistic regression was used to model the risk of acute pancreatitis associated with use of incretin-based drugs within 30 days before hospitalization, after adjustment for several risk factors, including the use of other antihyperglycaemic agents. Sensitivity analyses were performed in order to account for possible sources of systematic uncertainty. Use of incretin-based drugs within 30 days was reported by 17 (2.6%) cases of acute pancreatitis versus 193 (1.5%) controls. The corresponding multivariate odds ratio was 1.75 (95% confidence interval, 1.02 to 2.99). Slightly lower and no significant excess risks were observed by shortening (15 days) and increasing (60 and 90 days) the time-window at risk. This study supports a possible increased risk of acute pancreatitis in relation to use of incretin-based drugs reported in a few previous studies. However, given the potential for bias and the inconsistency with other studies, additional investigations are needed to clarify the safety of incretin-based-drugs.

Studying pancreatic risks caused by incretin-based therapies: is it a game? It's not a game!

A manuscript published recently on histological changes induced in the pancreas by incretin-based medications has been widely criticized because of ill-matched groups treated with incretin-based versus non-incretin-based medications and because of methodological problems identifying glucagon-producing cells. Now a study making use of the same tissue bank is available, and does not easily confirm the bulk of findings originally reported. This is an important opportunity to discuss the responsibility of authors to publish results potentially reproducible by other scientists as an important quality criterion, and the responsibility of reviewers and editors in handling such manuscripts. The main conclusion is that attempts to reproduce controversial findings are a necessity if finally the essence of novel results is at stake.

[Important epidemiological features of the treatment of type 2 diabetes]. / Aspectos epidemiológicos relevantes del tratamiento de la diabetes tipo 2.

According to the various clinical practice guidelines, the recommendations for the treatment of type 2 diabetes are well-established, thus leading to homogenization of clinical practice and avoiding variability. However, it is well known that, depending on factors such as effectiveness, physiopathology, cost, adverse effects, preferences, and comorbidities, each patient will, in the long-term, receive different treatment of type 2 diabetes. The consensus document published last year and approved by the American Diabetes Association and the European Association for the Study of Diabetes recommends distinct targets for each patient with type 2 diabetes and argues for the individualization of the management and treatment of this disease. In other words, the document advocates a patient-centered approach, in which the various therapeutic alternatives are related mainly to distinct physiopathological factors, adverse effects, and the patient's comorbidities, as well as the patient's preferences.