Identification of Risk Factors for Gliptin-associated Bullous Pemphigoid among Diabetic Patients.

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008-2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer's disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p < 0.0001 for both). While compared with sitagliptin, exposure to linagliptin and vildagliptin were associated with bullous pemphigoid with an odds ratio of 5.68 and 6.61 (p < 0.0001 for both), respectively. These results suggest gliptins should be prescribed with caution to patients with type 2 diabetes with coexisting Alzheimer's and other dementias, or patients receiving long-term use of thiazides and loop diuretics. The use of sitagliptin over linagliptin and vildagliptin should be preferred in these patients.

Cardiovascular safety of evogliptin dual and triple therapy in patients with type 2 diabetes: a nationwide cohort study.

OBJECTIVE: To investigate the risk of cardiovascular events associated with commonly used dual and triple therapies of evogliptin, a recently introduced dipeptidyl peptidase-4 inhibitor (DPP4i), for managing type 2 diabetes in routine clinical practice. DESIGN: A retrospective cohort study. SETTING: Korean Health Insurance Review and Assessment database. PARTICIPANTS: Patients who initiated metformin-based dual therapy and metformin+sulfonylurea-based triple therapy in South Korea from 2014 to 2018. INTERVENTIONS: Initiation of combination therapy with evogliptin. PRIMARY AND SECONDARY OUTCOME MEASURES: Hazards of cardiovascular events, a composite endpoint of myocardial infarction, heart failure and cerebrovascular events, and its individual components. Cox proportional hazards model with propensity score-based inverse probability of treatment weighting were used to estimate HRs and 95% CIs. RESULTS: From the dual and triple therapy cohorts, 5830 metformin+evogliptin users and 2198 metformin+sulfonylurea+evogliptin users were identified, respectively. Metformin+evogliptin users, as compared with metformin+non-DPP4i, had a 29% reduced risk of cardiovascular events (HR 0.71, 95% CI 0.62 to 0.82); HRs for individual outcomes were cerebrovascular events (0.71, 95% CI 0.53 to 0.95), heart failure (0.70, 95% CI 0.59 to 0.82), myocardial infarction (0.89, 95% CI 0.60 to 1.31). Metformin+sulfonylurea+evogliptin users, compared with metformin+sulfonylurea+non-DPP4i, had a 24% reduced risk of cardiovascular events (0.76, 95% CI 0.59 to 0.97); HRs for individual outcomes were myocardial infarction (0.57, 95% CI 0.27 to 1.19), heart failure (0.74, 95% CI 0.55 to 1.01), cerebrovascular events (0.96, 95% CI 0.61 to 1.51). CONCLUSIONS: These findings suggest that dual or triple therapies of evogliptin for the management of type 2 diabetes in routine clinical practice present no cardiovascular harms, but could alternatively offer cardiovascular benefits in this patient population.

Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modeling of cetagliptin in patients with type 2 diabetes mellitus.

Aims: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cetagliptin (CAS number:2243737-33-7) in Chinese patients with type 2 diabetes mellitus (T2DM). A population PK/PD model was developed to quantify the PK and PD characteristics of cetagliptin in patients. Materials and methods: 32 Chinese adults with T2DM were enrolled in this study. The subjects were randomly assigned to receive either cetagliptin (50 mg or 100 mg), placebo, or sitagliptin (100 mg) once daily for 14 days. Blood samples were collected for PK and PD analysis. Effects on glucose, insulin, C-peptide, and glucagon were evaluated following an oral glucose tolerance test (OGTT) (day15). Effects on HbA1c and glycated albumin (GA), and safety assessments were also conducted. Meanwhile, a population PK/PD model was developed by a sequential two-step analysis approach using Phoenix. Results: Following multiple oral doses, cetagliptin was rapidly absorbed and the mean half-life were 34.9-41.9 h. Steady-state conditions were achieved after 1 week of daily dosing and the accumulation was modest. The intensity and duration of DPP-4 inhibition induced by 50 mg cetagliptin were comparable with those induced by sitagliptin, and 100 mg cetagliptin showed a much longer sustained DPP-4 inhibition (≥80%) than sitagliptin. Compared with placebo group, plasma active GLP-1 AUEC0-24h increased by 2.20- and 3.36-fold in the 50 mg and 100 mg cetagliptin groups. A decrease of plasma glucose and increase of insulin and C-peptide were observed following OGTT in cetagliptin groups. Meanwhile, a tendency of reduced GA was observed, whereas no decreasing trend was observed in HbA1c. All adverse events related to cetagliptin and sitagliptin were assessed as mild. A population PK/PD model was successfully established. The two-compartment model and Sigmoid-Emax model could fit the observed data well. Total bilirubin (TBIL) was a covariate of volume of peripheral compartment distribution (V2), and V2 increased with the increase of TBIL. Conclusions: Cetagliptin was well tolerated, inhibited plasma DPP-4 activity, increased plasma active GLP-1 levels, and exhibited a certain trend of glucose-lowering effect in patients with T2DM. The established population PK/PD model adequately described the PK and PD characteristics of cetagliptin.

Efficacy and Safety of Omarigliptin, a Novel Once-Weekly Dipeptidyl Peptidase-4 Inhibitor, in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

BACKGRUOUND: No recent meta-analysis has holistically analyzed and summarized the efficacy and safety of omarigliptin in type 2 diabetes mellitus (T2DM). We conducted a meta-analysis to address this knowledge gap. METHODS: Electronic databases were searched to identify randomized controlled trials (RCTs) that included patients with T2DM who received omarigliptin in the intervention arm. The control arm consisted of either a placebo (passive control group [PCG]) or an active comparator (active control group [ACG]). The primary outcome assessed was changes in hemoglobin A1c (HbA1c), while secondary outcomes included variations in glucose levels, achievement of glycemic targets, adverse events (AEs), and hypoglycemic events. RESULTS: From 332 initially screened articles, data from 16 RCTs involving 8,804 subjects were analyzed. Omarigliptin demonstrated superiority over placebo in reducing HbA1c levels (mean difference, -0.58%; 95% confidence interval, -0.75 to -0.40; P<0.00001; I2=91%). Additionally, omarigliptin outperformed placebo in lowering fasting plasma glucose, 2-hour postprandial glucose, and in the percentage of participants achieving HbA1c levels below 7.0% and 6.5%. The glycemic efficacy of omarigliptin was similar to that of the ACG across all measures. Although the omarigliptin group experienced a higher incidence of hypoglycemic events compared to the PCG, the overall AEs, serious AEs, hypoglycemia, and severe hypoglycemia were comparable between the omarigliptin and control groups (PCG and ACG). CONCLUSION: Omarigliptin has a favorable glycemic efficacy and safety profile for managing T2DM.

Time-dependent risk of fracture in adults with type 2 diabetes receiving anti-diabetic drug: A one-stage network meta-analysis.

AIMS: To assess the time-dependent risk of fracture in adults with type 2 diabetes receiving anti-diabetic drugs. MATERIALS AND METHODS: We searched MEDLINE, EMBASE, and Cochrane Library up to 18 November 2021, for randomized controlled trials (RCTs) and propensity-score-matched non-randomized studies (NRSs) comparing all anti-diabetic drugs with standard treatment or with each other on fracture in adults with type 2 diabetes. The study performed a one-stage network meta-analysis using discrete-time hazard regression with reconstructed individual time-to-event data. RESULTS: This network meta-analysis involved seven RCTs (65,051 adults with type 2 diabetes) with a median follow-up of 36 months and three propensity-score-based NRSs (17,954 participants) with a median follow-up of 27.3 months. Among anti-diabetic drugs, thiazolidinediones increased the overall hazard of fracture by 42% (95% credible interval [CrI], 3%-97%) and almost tripled the risk after 4 years (hazard ratio [HR], 2.74; 95% CrI, 1.53-4.80). Credible subgroup analysis suggested that thiazolidinediones increased the hazard of fracture only in females (HR, 2.19; 95% CrI, 1.26-3.74) but not among males (HR, 0.81; 95% CrI, 0.45-1.40). Moderate certainty evidence established that thiazolidinediones increase 92 fractures in five years per 1000 female patients. We did not find the risk of fractures with other anti-diabetic drugs including metformin, sulfonylureas, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors. CONCLUSIONS: Long-term use of thiazolidinediones elevates the risk of fracture among females with type 2 diabetes. There is no evidence eliciting fracture risk associated with other anti-diabetic drugs.

Comparison between sodium-glucose cotransporter 2 inhibitors and dipeptidyl peptidase 4 inhibitors on the risk of incident cancer in patients with diabetes mellitus: A real-world evidence study.

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) have been demonstrated to be associated with cancer cell mechanisms. However, whether they increase the risk of cancer remains unclear. Thus, this study aimed to determine the association between SGLT-2i use and the incidence of cancer in patients with diabetes mellitus (DM) in Taiwan. MATERIALS AND METHODS: This retrospective cohort study was based on the Taiwan National Health Insurance database. The study population comprised patients with DM, and those who first used SGLT-2is during 2016-2018 were assigned to the study group. Greedy propensity score matching was performed to select patients who first used dipeptidyl peptidase 4 inhibitors (DPP-4is), and these patients were assigned to the control group. A Cox proportional hazards model was used to estimate the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for cancer risk in the study and control groups; this model was adjusted for demographic characteristics, DM severity, comorbidities and concomitant medication use. RESULTS: After controlling for relevant variables, the SGLT-2i cohort (aHR = 0.90, 95% CI = 0.87-0.93) had a significantly lower risk of developing cancer than the DPP-4i cohort, particularly when the SGLT-2i was dapagliflozin (aHR = 0.91, 95% CI = 0.87-0.95) or empagliflozin (aHR = 0.90, 95% CI = 0.86-0.94). Regarding cancer type, the SGLT-2i cohort's risk of cancer was significantly lower than that of the DPP-4i cohort for leukaemia, oesophageal, colorectal, liver, pancreatic, lung, skin and bladder cancer. CONCLUSIONS: SGLT-2i use was associated with a significantly lower risk of cancer than DPP-4i use.

Exploring nontraditional cardiorenal advantages of SGLT-2 inhibitors and GLP-1 receptor agonists.

This commentary provides an analysis of the study by Fu et al. in Kidney International, which employs 3 administrative databases to investigate the hyperkalemia protective effects of sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors. It emphasizes the methodological approach, notably the use of a fixed-effect model to aggregate pairwise comparisons from 3 data sets. In addition, we explored the broader cardiorenal and potential nonrenal benefits of these drug classes, underscoring the imperative for continued research in this domain.

Two years with GIOIA 'Effects of gliflozins and gliptins on markers of cardiovascular damage in type 2 diabetes': A prospective, multicentre, quasi-experimental study on sodium-glucose cotransporter 2 and dipeptidyl peptidase-4 inhibitors in diabetes clinical practice.

AIM: To assess and compare the metabolic and vascular effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i) in the clinical practice of patients with type 2 diabetes in Italy. MATERIALS AND METHODS: GIOIA is a 2-year prospective, multicentre, quasi-experimental study that enrolled patients with type 2 diabetes initiating SGLT-2i or DPP-4i for inadequate glycaemic control [glycated haemoglobin (HbA1c) >7%] between March 2018 and March 2021. The primary endpoints were changes in markers of organ damage [carotid intima-media thickness (CIMT), albuminuria, myocardial function] and HbA1c from baseline to year 2. RESULTS: In total, 1150 patients were enrolled in the study (SGLT-2i n = 580, DPP-4i n = 570). Patients initiated on SGLT-2i were younger (about 6 years) and heavier (about 11 kg), had higher HbA1c level (1% more), more albuminuria and cardiovascular events (16% more) than patients initiated on DPP-4i. CIMT and echocardiographic parameters were not significantly different. Propensity score matching yielded two groups, each consisting of 155 patients with diabetes with similar baseline characteristics. Despite a significant similar reduction in HbA1c levels in both groups (-0.8%), more patients on SGLT-2i had regression of CIMT and albuminuria (22% and 10%, respectively, p < .001 vs. DPP-4i); more patients on DPP-4i had progression of CIMT and albuminuria (23% and 28%, respectively, p < .001 vs. SGLT-2i). Left ventricular ejection fraction improved slightly (3%, p = .043) on SGLT-2i only. CONCLUSIONS: In a real-world setting, both SGLT-2i and DPP-4i improve glycaemic control persisting after 2 years of treatment, with a robust effect on both CIMT and albuminuria regression for SGLT-2i as compared with DPP-4i in the propensity score matching.

Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes and mild/moderate chronic kidney disease.

AIM: To determine the comparative effectiveness regarding major cardiovascular events of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). MATERIALS AND METHODS: We assembled a cohort of commercially insured adult patients with T2DM in the United States (derived from Optum Clinformatics DataMart 2003-2021) who were new users of GLP-1 receptor agonists or SGLT-2 inhibitors. We compared risks of non-fatal myocardial infarction or stroke in patients with and without CKD, and further categorized by CKD stage: stages G1 or G2 [estimated glomerular filtration rate (eGFR) ≥60 ml/min] and A2 (urine albumin to creatinine ratio 30 to <300 mg/g) or A3 (urine albumin to creatinine ratio ≥300 mg/g), stage G3a (eGFR 45 to <60 ml/min/1.73 m2 ) and stage G3b (eGFR 30 to <45 ml/min/1.73 m2 ). We used proportional hazards regression after inverse probability of treatment weighting to compute hazard ratios and 95% confidence intervals. RESULTS: After accounting for the probability of treatment, patients with T2DM and CKD treated with SGLT-2 inhibitors experienced a 14% lower risk of non-fatal myocardial infarction or stroke (hazard ratio 0.86, 95% confidence interval 0.78-0.94) relative to those treated with GLP-1 receptor agonists. CONCLUSIONS: Recognizing the potential for residual confounding, selection bias and immortal time bias, commercially insured patients in the United States with T2DM and CKD treated with SGLT-2 inhibitors experienced significantly lower risks of non-fatal myocardial infarction or stroke relative to those treated with GLP-1 receptor agonists.

Effect of Teneligliptin 20 mg Twice Daily on Glucagon-Like Peptide-1 Levels and Its Influence on Non-Glycemic Components in Non-Diabetic Obese Individuals.

Background and Aims: Teneligliptin is an oral antidiabetic agent, it can persevere glucagon-like peptide-1 (GLP-1) by inhibiting dipeptidyl peptidase enzyme. In addition, it has rare incidence of hypoglycemia. Hence, this study aimed to test the effect of teneligliptin 20 mg twice daily along with low carbohydrate diet and physical exercise on change of body weight and insulin resistance in nondiabetic obese subjects. Materials and Methods: It is a prospective, randomized, double-blind, placebo-controlled, parallel group study carried out at outpatient department of an endocrinology hospital over the period of 48 weeks. Teneligliptin 20 mg twice daily 30 min before food (low carbohydrate diet [LCD]) with regular physical exercise, and control group was kept with placebo twice daily 30 min before food LCD with regular physical exercise. This study was registered in clinical trial registry of India [CTRI/2020/02/023329]. Results: A total of 150 nondiabetic obese subjects were randomized into test (n = 75) and control groups (n = 75). At the end of 48 weeks there was significant improvement in GLP-1, simplified nutrition assessment questionnaire (SNAQ) score, homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides (TG), and body weight. The mean difference and 95% confidence interval of GLP-1 (pg/mL) was 76.42 (44.42-148.41) (P = 0.37); SNAQ score, -1.64 (-2.48 to -0.81) (P = 0.000); HOMA-IR, -0.9 (-0.59 to -0.38) (P = 0.000); TG (mg/dL) -29.37 (-44.46 to -14.07) (P = 0.000); reduction of body weight (kilograms) -3.09 (-6.11 to -0.07) (P = 0.043). Conclusion: Findings of this study reveals that teneligliptin-treated group showed significant improvement in GLP-1 levels, reduced insulin resistance, body weight, TG, appetite, and metabolic syndrome. Teneligliptin is well tolerated, except in upper respiratory tract infections. CTR number: CTRI/2020/02/023329.

Liver, renal, genitourinary and diabetic ketoacidosis risks among new users of empagliflozin versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: Post-authorization safety study based on multinational cohorts.

AIM: To estimate risks of diabetic ketoacidosis (DKA), acute liver injury (ALI), acute kidney injury (AKI), chronic kidney disease (CKD), severe complications of urinary tract infection (UTI) and genital infection (GI) among patients with type 2 diabetes initiating empagliflozin versus those initiating a dipeptidyl peptidase-4 (DPP-4) inhibitor. MATERIALS AND METHODS: In this large multinational, observational, new-user cohort study in UK, Danish and US healthcare data sources, patients initiated empagliflozin or a DPP-4 inhibitor between August 2014 and August 2019, were aged ≥18 years, and had ≥12 months' continuous health plan enrolment. Incidence rates by exposure and incidence rate ratios, adjusted for propensity-score deciles, were calculated. RESULTS: In total, 64 599 empagliflozin initiators and 203 315 DPP-4 inhibitor initiators were included. There was an increased risk [pooled adjusted incidence rate ratios (95% confidence interval)] of DKA [2.19 (1.74-2.76)] and decreased risks of ALI [0.77 (0.50-1.19) in patients without predisposing conditions of liver disease; 0.70 (0.56-0.88) in all patients] and AKI [0.54 (0.41-0.73)]. In the UK data, there was an increased risk of GI [males: 4.04 (3.46-4.71); females: 3.24 (2.81-3.74)] and decreased risks of CKD [0.53 (0.43-0.65)] and severe complications of UTI [0.51 (0.37-0.72)]. The results were generally consistent in subgroup and sensitivity analyses. CONCLUSIONS: Compared with DDP-4 inhibitor use, empagliflozin use was associated with increased risks of DKA and GI and decreased risks of ALI, AKI, CKD and severe complications of UTI. These associations are consistent with previous studies and known class effects of sodium-glucose cotransporter 2 inhibitors, including renoprotective effects and beneficial effects on alanine aminotransferase levels.

Sodium-Glucose Cotransporter 2 Inhibitors and Nephrolithiasis Risk in Patients With Type 2 Diabetes.

Importance: Type 2 diabetes (T2D) is associated with an increased risk of kidney stones. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) might lower the risk of nephrolithiasis by altering urine composition. However, no studies have investigated the association between SGLT2i use and nephrolithiasis risk in patients receiving routine care in the US. Objective: To investigate the association between SGLT2i use and nephrolithiasis risk in clinical practice. Design, Setting, and Participants: This new-user, active comparator cohort study used data from commercially insured adults (aged ≥18 years) with T2D who initiated treatment with SGLT2is, glucagon-like peptide 1 receptor agonists (GLP-1RAs), or dipeptidyl peptidase 4 inhibitors (DPP4is) between April 1, 2013, and December 31, 2020. The data were analyzed from July 2021 through June 2023. Exposure: New initiation of an SGLT2i, GLP-1RA, or DPP4i. Main Outcomes and Measures: The primary outcome was nephrolithiasis diagnosed by International Classification of Diseases codes in the inpatient or outpatient setting. New SGLT2i users were 1:1 propensity score matched to new users of a GLP-1RA or DPP4i in pairwise comparisons. Incidence rates, rate differences (RDs), and estimated hazard ratios (HRs) with 95% CIs were calculated. Results: After 1:1 propensity score matching, a total of 716 406 adults with T2D (358 203 pairs) initiating an SGLT2i or a GLP-1RA (mean [SD] age, 61.4 [9.7] years for both groups; 51.4% vs 51.2% female; 48.6% vs 48.5% male) and 662 056 adults (331 028 pairs) initiating an SGLT2i or a DPP4i (mean [SD] age, 61.8 [9.3] vs 61.7 [10.1] years; 47.4% vs 47.3% female; 52.6% vs 52.7% male) were included. Over a median follow-up of 192 (IQR, 88-409) days, the risk of nephrolithiasis was lower in patients initiating an SGLT2i than among those initiating a GLP-1RA (14.9 vs 21.3 events per 1000 person-years; HR, 0.69 [95% CI, 0.67-0.72]; RD, -6.4 [95% CI, -7.1 to -5.7]) or a DPP4i (14.6 vs 19.9 events per 1000 person-years; HR, 0.74 [95% CI, 0.71-0.77]; RD, -5.3 [95% CI, -6.0 to -4.6]). The association between SGLT2i use and nephrolithiasis risk was similar by sex, race and ethnicity, history of chronic kidney disease, and obesity. The magnitude of the risk reduction with SGLT2i use was larger among adults aged younger than 70 years vs aged 70 years or older (HR, 0.85 [95% CI, 0.79-0.91]; RD, -3.46 [95% CI, -4.87 to -2.05] per 1000 person-years; P for interaction <.001). Conclusions and Relevance: These findings suggest that in adults with T2D, SGLT2i use may lower the risk of nephrolithiasis compared with GLP-1RAs or DPP4is and could help to inform decision-making when prescribing glucose-lowering agents for patients who may be at risk for developing nephrolithiasis.

Concomitant Use of Sodium-Glucose Cotransporter 2 Inhibitors and Overactive Bladder Drugs and the Risk of Urinary Tract Infection.

Concomitant use of sodium glucose cotransporter-2 inhibitors (SGLT-2i) and overactive bladder (OAB) drugs potentially poses a risk of urinary tract infections (UTIs) due to the urinary retention of highly concentrated glucose in the urine. Thus, this study aimed to investigate the risk of UTIs among patients who initiated SGLT-2i treatment while taking OAB drugs. This population-based cohort study included new-users of SGLT-2i or comparator antidiabetics (dipeptidyl peptidase-4 inhibitor (DPP-4i); glucagon-like peptide-1 receptor agonist (GLP-1RA)) with OAB drugs between 2014 and 2020 using claim data from Korea. Primary outcome was a composite UTI event composite end point comprising pyelonephritis, cystitis, and urethritis, using both inpatient and outpatient diagnoses. Propensity score fine stratification was used to adjust for potential confounding factors. Weighted hazard ratios (HR) were calculated using the Cox proportional hazards model. In the first cohort, 796 and 9,181 new-users of SGLT-2i and DPP-4i with OAB drugs were identified, respectively. This study found a similar risk of UTIs in concomitant users of SGLT-2i and DPP-4i (weighted HR 1.08, 95% confidence interval: 0.88-1.32) with OAB drugs. In the second cohort, 2,387 and 280 new-users of SGLT-2i and GLP-1RA with OAB drugs were identified, respectively. Initiation of SGLT-2i while on OAB treatment was not associated with increased risk of UTI (0.89, 0.50-1.60), compared with initiation of GLP-1RA. These results show that the concomitant use of SGLT-2i with OAB drugs was not associated with an increased risk of UTI compared with the concomitant use of DPP-4i or GLP-1RA with OAB drugs.

Diabetes, antidiabetic medications and risk of dementia: A systematic umbrella review and meta-analysis.

AIMS: The objective of this umbrella review and meta-analysis was to evaluate the effect of diabetes on risk of dementia, as well as the mitigating effect of antidiabetic treatments. MATERIALS AND METHODS: We conducted a systematic umbrella review on diabetes and its treatment, and a meta-analysis focusing on treatment. We searched MEDLINE/PubMed, Embase, PsycINFO, CINAHL and the Cochrane Library for systematic reviews and meta-analyses assessing the risk of cognitive decline/dementia in individuals with diabetes until 2 July 2023. We conducted random-effects meta-analyses to obtain risk ratios and 95% confidence intervals estimating the association of metformin, thiazolidinediones, pioglitazone, dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, meglitinides, insulin, sulphonylureas, glucagon-like peptide-1 receptor agonists (GLP1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) with risk of dementia from cohort/case-control studies. The subgroups analysed included country and world region. Risk of bias was assessed with the AMSTAR tool and Newcastle-Ottawa Scale. RESULTS: We included 100 reviews and 27 cohort/case-control studies (N = 3 046 661). Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia. When studies examining metformin were divided by country, the only significant effect was for the United States. Moreover, the effect of metformin was significant in Western but not Eastern populations. No significant effect was observed for dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, or insulin, while meglitinides and sulphonylureas were associated with increased risk. CONCLUSIONS: Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with reduced risk of dementia. More longitudinal studies aimed at determining their relative benefit in different populations should be conducted.

Risk of hyperkalaemia in patients with type 2 diabetes mellitus prescribed with SGLT2 versus DPP-4 inhibitors.

AIMS: To investigate the risk of hyperkalaemia in new users of sodium-glucose cotransporter 2 (SGLT2) inhibitors vs. dipeptidyl peptidase-4 (DPP-4) inhibitors among patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: Patients with T2DM who commenced treatment with an SGLT2 or a DPP-4 inhibitor between 2015 and 2019 were collected. A multivariable Cox proportional hazards analysis was applied to compare the risk of central laboratory-determined severe hyperkalaemia, hyperkalaemia, hypokalaemia (serum potassium ≥6.0, ≥5.5, and <3.5 mmol/L, respectively), and initiation of a potassium binder in patients newly prescribed an SGLT2 or a DPP-4 inhibitor. A total of 28 599 patients (mean age 60 ± 11 years, 60.9% male) were included after 1:2 propensity score matching, of whom 10 586 were new users of SGLT2 inhibitors and 18 013 of DPP-4 inhibitors. During a 2-year follow-up, severe hyperkalaemia developed in 122 SGLT2 inhibitor users and 325 DPP-4 inhibitor users. Use of SGLT2 inhibitors was associated with a 29% reduction in incident severe hyperkalaemia [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.58-0.88] compared with DPP-4 inhibitors. Risk of hyperkalaemia (HR 0.81, 95% CI 0.71-0.92) and prescription of a potassium binder (HR 0.74, 95% CI 0.67-0.82) were likewise decreased with SGLT2 inhibitors compared with DPP-4 inhibitors. Occurrence of incident hypokalaemia was nonetheless similar between those prescribed an SGLT2 inhibitor and those prescribed a DPP-4 inhibitor (HR 0.90, 95% CI 0.81-1.01). CONCLUSION: Our study provides real-world evidence that compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with lower risk of hyperkalaemia and did not increase the incidence of hypokalaemia in patients with T2DM.

A model-informed approach to accelerate the clinical development of cofrogliptin (HSK7653), a novel ultralong-acting dipeptidyl peptidase-4 inhibitor.

AIM: To employ a model-informed drug development approach in facilitating decision making and expediting the clinical progress of cofrogliptin (HSK7653), a novel ultralong-acting dipeptidyl peptidase-4 (DPP-4) inhibitor, for the treatment of type 2 diabetes (T2D) via a biweekly dosing regimen. METHODS: Firstly, a population pharmacokinetics and pharmacodynamics (PopPKPD) model was developed using PK and PD data from a single ascending dose study to simulate the PK and PD time profiles of HSK7653 after multiple doses. Secondly, model-based meta-analysis (MBMA) was performed on published clinical studies of Eastern Asian subjects for all DPP-4 inhibitors. We hypothesized a consistent relationship between PK and DPP-4 inhibition in both healthy individuals and in those with T2D, establishing a quantitative correlation between DPP-4 inhibition and HbA1c. Finally, the predicted PK/DPP-4 inhibition/HbA1c profiles were validated by T2D patients in late clinical trials. RESULTS: The PK/DPP-4 inhibition/HbA1c profiles of T2D patients treated with HSK7653 matched the modelled data. Our PopPKPD and MBMA models predict multiple ascending dosing PK and PD characteristics from single ascending dosing data, as well as the long-term efficacy in T2D patients, based on healthy subjects. CONCLUSIONS: Successful waiver approval for the phase 2b dose-finding study was achieved through model-informed recommendations, facilitating the clinical development of HSK7653 and other DPP-4 inhibitors.