Use Of Dipeptidyl Peptidase-4 Inhibitors Research Articles

Association of sulfonylureas with the risk of dementia: A population-based cohort study.

Sulfonylureas are oral glucose-lowering medications positioned as a second-line therapy for type 2 diabetes. Evidence relating them to cognitive decline has been mixed. The objective was to determine whether sulfonylurea use was associated with a differential risk of dementia compared with dipeptidyl peptidase-4 (DPP4) inhibitor use. Using administrative data from residents in Ontario, Canada, adults aged ≥66 years who were new users of a sulfonylurea or a DPP4 inhibitor from June 14, 2011, to March 31, 2021 entered this population-based retrospective cohort study. Dementia was ascertained using a validated algorithm for Alzheimer's disease and related dementias. Propensity-score weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and confidence intervals (CI) for time to incident dementia. The observation window started at 1 year after cohort entry to mitigate protopathic bias due to delayed diagnosis. The primary analysis used an intention-to-treat exposure definition. A separate propensity-score weighted analysis was conducted to explore within-class differences in dementia risk among sulfonylurea new users selected from the primary cohort. Among 107,806 DPP4 inhibitor new users and 37,030 sulfonylurea new users, sulfonylureas compared with DPP4 inhibitors were associated with a higher risk of dementia (18.4/1000 person-years; aHR [95% CI] = 1.09 [1.04-1.15]) over a mean follow-up of 4.82 years from cohort entry. Glyburide compared to gliclazide exhibited a higher dementia risk (aHR [95% CI] = 1.17 [1.03-1.32]). New use of a sulfonylurea especially glyburide was associated with a higher dementia risk compared with new use of a DPP4 inhibitor in older adults with diabetes.

Sodium-Glucose Cotransporter 2 Inhibitor Use in Early-Phase Acute Coronary Syndrome with Severe Heart Failure.

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) improves clinical outcomes in patients with heart failure (HF), but has limited evidence of SGLT2i use on early-phase acute coronary syndrome (ACS). We determined association of early SGLT2i use compared with either non-SGLT2i or dipeptidyl peptidase 4 inhibitor (DPP4i) in hospitalized patients with ACS. This retrospective cohort study that used the Japanese nationwide administrative claims database included patients hospitalized with ACS aged≥20 years between April 2014 and March 2021. The primary outcome was a composite of all-cause mortality or HF/ACS rehospitalization. Using 1:1 propensity score matching, the association with outcomes of the early SGLT2i use (≤14 days after admission) compared with non-SGLT2i or DPP4i was determined according to the HF treatment. Among 388185 patients included, 115612 and 272573 with and without severe HF, respectively. Compared to non-SGLT2i users, the SGLT2i users had a lower hazard ratio (HR) with the primary outcome (HR: 0.83, 95% confidence interval [CI]: 0.76-0.91, p<0.001) in the severe HF group; however, there was no significant difference in the non-severe HF group (HR: 0.92, 95% CI: 0.82-1.03, p=0.16). SGLT2i use showed a lower risk of the outcome in patients with severe HF and diabetes compared with DPP4i (HR: 0.83, 95% CI: 0.69-1.00, p=0.049). SGLT2i use in patients with early-phase ACS showed a lower risk of primary outcome in patients with severe HF but the effect was not apparent in patients without severe HF.

Primary Occurrence of Cardiovascular Events After Adding Sodium-Glucose Cotransporter-2 Inhibitors or Glucagon-like Peptide-1 Receptor Agonists Compared With Dipeptidyl Peptidase-4 Inhibitors: A Cohort Study in Veterans With Diabetes.

The effectiveness of glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in preventing major adverse cardiac events (MACE) is uncertain for those without preexisting cardiovascular disease. To test the hypothesis that MACE incidence was lower with the addition of GLP1RA or SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i) for primary cardiovascular prevention. Retrospective cohort study of U.S. veterans from 2001 to 2019. Veterans aged 18 years or older receiving care from the Veterans Health Administration, with data linkage to Medicare, Medicaid, and the National Death Index. Veterans adding GLP1RA, SGLT2i, or DPP4i onto metformin, sulfonylurea, or insulin treatment alone or in combination. Episodes were stratified by history of cardiovascular disease. Study outcomes were MACE (acute myocardial infarction, stroke, or cardiovascular death) and heart failure (HF) hospitalization. Cox models compared the outcome between medication groups using pairwise comparisons in a weighted cohort adjusted for covariates. The cohort included 28 759 GLP1RA versus 28 628 DPP4i weighted pairs and 21 200 SGLT2i versus 21 170 DPP4i weighted pairs. Median age was 67 years, and diabetes duration was 8.5 years. Glucagon-like peptide-1 receptor agonists were associated with lower MACE and HF versus DPP4i (adjusted hazard ratio [aHR], 0.82 [95% CI, 0.72 to 0.94]), yielding an adjusted risk difference (aRD) of 3.2 events (CI, 1.1 to 5.0) per 1000 person-years. Sodium-glucose cotransporter-2 inhibitors were not associated with MACE and HF (aHR, 0.91 [CI, 0.78 to 1.08]; aRD, 1.28 [-1.12 to 3.32]) compared with DPP4i. Residual confounding; use of DPP4i, GLP1RA, and SGLT2i as first-line therapies were not examined. The addition of GLP1RA was associated with primary reductions of MACE and HF hospitalization compared with DPP4i use; SGLT2i addition was not associated with primary MACE prevention. VA Clinical Science Research and Development and supported in part by the Centers for Diabetes Translation Research.

Sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors on new-onset overall cancer in Type 2 diabetes mellitus: A population-based study.

Cancer is currently the second leading cause of death globally. There is much uncertainty regarding the comparative risks of new-onset overall cancer and pre-specified cancer for Type 2 diabetes mellitus (T2DM) patients on sodium-glucose cotransporter 2 inhibitors (SGLT2I) versus DPP4I. This population-based cohort study patients included patients who were diagnosed with T2DM and administered either SGLT2 or DPP4 inhibitors between 1 January 2015 and 31 December 2020 in public hospitals of Hong Kong. This study included 60,112 T2DM patients (mean baseline age: 62.1 ± 12.4 years, male: 56.36%), of which 18,167 patients were SGLT2I users and 41,945 patients were dipeptidyl peptidase 4 inhibitor (DPP4I) users. Multivariable Cox regression found that SGLT2I use was associated with lower risks of all-cause mortality (HR: 0.92; 95% CI: 0.84-0.99; p= 0.04), cancer-related mortality (HR: 0.58; 95% CI: 0.42-0.80; p ≤ 0.001) and new diagnoses of any cancer (HR: 0.70; 95% CI: 0.59-0.84; p ≤ 0.001). SGLT2I use was associated with a lower risk of new-onset breast cancer (HR: 0.51; 95% CI: 0.32-0.80; p ≤ 0.001), but not of other malignancies. Subgroup analysis on the type of SGLT2I, dapagliflozin (HR: 0.78; 95% CI: 0.64-0.95; p = 0.01) and ertugliflozin (HR: 0.65; 95% CI: 0.43-0.98; p = 0.04) use was associated with lower risks of new cancer diagnosis. Dapagliflozin use was also linked to lower risks of breast cancer (HR: 0.48; 95% CI: 0.27-0.83; p = 0.001). Sodium-glucose cotransporter 2 inhibitor use was associated with lower risks of all-cause mortality, cancer-related mortality and new-onset overall cancer compared to DPP4I use after propensity score matching and multivariable adjustment.

Bullous pemphigoid and dipeptidyl peptidase-4 inhibitors: Evaluation of the clinical course and treatment response.

Dipeptidyl peptidase-4 inhibitors (DPP4is), drugs used to treat type 2 diabetes mellitus (DM2), show a significant association with bullous pemphigoid (BP) development. In this retrospective cohort study, we evaluated the clinical course and development of BP among patients with DM2 treated with DPP4is. This retrospective cohort study included all the patients with BP and comorbid DM2 who visited Sheba hospital during 2015-2020. Among 338 patients with BP, 153 were included in our study. In 92 patients, BP diagnosis was attributed to the use of DPP4is. DPP4i-associated BP patients had fewer neurological and cardiovascular comorbidities and higher blistered body surface area (BSA) at first presentation, with noticeable upper and lower limb involvement. These patients were younger and more responsive to treatment, with a greater reduction in the BSA score after two months of treatment. The clinical features of patients with BP treated with DPP4is were initially more severe; however, during follow-up, a marked clinical improvement was noticed, especially among patients who had ceased the drug. Therefore, although withdrawal of the drug may not impose disease remission, it can alleviate the disease course and avert the need for treatment escalation.

Hypoglycemic Therapy and the Course of Post-Covid Syndrome, is There a Connection?

Diabetes mellitus (both type 1 and type 2) is considered one of the risk factors for severe COVID-19 and death from this infection. Past infection with COVID-19 leads to deterioration in the control of existing diabetes mellitus, progression of pre-diabetes to diabetes, an increase in the number of new cases of diabetes and an increase in the proportion of glucocorticoid-induced diabetes, which significantly aggravates the course of post-COVID syndrome for this category of patients. Antihyperglycemic drugs may influence the pathogenesis of COVID-19, which may be of relevance for the treatment of patients with type 2 diabetes mellitus and post-COVID syndrome. The review also presents our own data on the effect of various regimens of oral hypoglycemic agents on post-COVID syndrome in people with type 2 diabetes mellitus. The observation showed that the use of dipeptidyl peptidase-4 inhibitors as part of a treatment strategy in patients with type 2 diabetes mellitus with a past COVID-19 infection was associated with a decrease in the duration and severity of post-COVID symptoms.

Hyperamylasemia is not Associated with Dipeptidyl Peptidase 4 Inhibitors in South Indian Adults with Type 2 Diabetes Mellitus.

Although not definitive, there is small increased risk of acute pancreatitis with the use of dipeptidyl peptidase 4 inhibitors (DPP4i). Hence, there is an interest in the elevation of pancreatic enzymes among type 2 diabetes mellitus (T2DM) patients using DPP4i. However, the studies regarding their association are limited and provide conflicting results. Moreover, there are no such studies among South Indian T2DM patients. Hence, we evaluated the prevalence of hyperamylasemia among South Indian T2DM patients and its association with DPP4i use. This cross-sectional study was conducted at a tertiary health care center from South India. Adult T2DM patients on stable doses of antidiabetic medications for at least previous 3 months were included in the study. Patients with other types of diabetes mellitus, gall stones, diabetic ketoacidosis, acute illness, chronic kidney disease and untreated hypothyroidism were excluded from the study. All participants were evaluated with glycemic parameters, serum creatinine and serum amylase. Hyperamylasemia was defined as serum amylase ≥220 U/L. A total of 200 participants were included in the study among whom 93 patients were not on DPP4i whereas 107 were on DPP4i including 41 (38.32%) each on teneligliptin and sitagliptin. Baseline characteristics including glycemic measures were comparable between DPP4i users and nonusers. A total of 14 patients (7%) had hyperamylasemia but the prevalence of hyperamylasemia did not differ between DPP4i users and nonuser (6/107 vs. 8/93, P = 0.42). Asymptomatic hyperamylasemia is not uncommon in South Indian T2DM patients but is not associated with the use of DPP4i.

Comparing sodium-glucose cotransporter 2 inhibitors and dipeptidyl peptidase-4 inhibitors on new-onset depression: a propensity score-matched study in Hong Kong

IntroductionThe risk of new onset depression associated with sodium-glucose co-transporter 2 inhibitor (SGLT2I) use in patients with type 2 diabetes mellitus (T2DM) remains unclear. This study investigated the risk of new onset depression between SGLT2I and dipeptidyl peptidase 4 inhibitor (DPP4I) users.MethodsThis was a population-based cohort study of T2DM patients in Hong Kong between January 1st, 2015, and December 31st, 2019. T2DM patients over 18 with either SGLT2I or DPP4I use were included. 1:1 propensity-score matching using the nearest-neighbour method was conducted based on demographics, past comorbidities and non-DPP4I/SGLT2I medication use. Cox regression analysis models were used to identify significant predictors for new onset depression.ResultsThe study cohort included a total of 18,309 SGLT2I users and 37,269 DPP4I users (55.57% male, mean age: 63.5 ± 12.9 years) with a median follow-up duration of 5.56 (IQR: 5.23–5.8) years. After propensity score matching, SGLT2I use was associated with a lower risk of new onset depression compared to DPP4I use (HR: 0.52, 95% CI: [0.35, 0.77], P = 0.0011). These findings were confirmed by Cox multivariable analysis and sensitive analyses.ConclusionSGLT2I use is associated with significantly lower risk of depression compared to DPP4 use in T2DM patients using propensity score matching and Cox regression analyses.

Linagliptin exacerbates heart failure due to energy deficiency via downregulation of glucose utilization and absorption in a mouse model

Use of dipeptidyl peptidase-4 (DPP4) inhibitor in some clinical trials might have caused heart failure (HF), leading to increased hospitalizations. The aim of the present study was to determine whether linagliptin has any effect on chronic dilated HF, and its underlying mechanisms. Physiologic and pathologic studies were conducted on heart/muscle-specific manganese superoxide dismutase-deficient mice, which exhibited dilated cardiomyopathy, and were randomized to receive a low dose (1 mg/kg, HF-L group) or high dose (10 mg/kg, HF–H group) mixed with food, or normal food (HF group), for 8 weeks. Linagliptin increased mortality and heart/body weight ratio in mice with HF. Cardiac contractility and fibrosis worsened, whereas hepatic glycogen content and individual carbohydrate consumption decreased significantly in the HF–H group, when compared with the HF control group. Therefore, we performed a complementary experiment by supplementing glucose to the mice treated with high-dose linagliptin (HF-HG group). Adequate glucose supplementation reduced heart/body weight ratio and cardiac fibrosis, and improved cardiac contractility, without changing mortality. Following oral administration of 13C glucose, the respiratory 13C decreased in the HF–H and HF-HG groups, when compared with that in the HF group; the fecal 13C increased, suggesting that linagliptin inhibited glucose absorbance in the intestine. In addition, the expression of GLUT2, a glucose transporter was downregulated in the small intestine. Linagliptin treatment exacerbated HF, which increased mortality, cardiac function, and fibrosis. DPP4 inhibitors might boost cardiac cachexia and exacerbate HF, at least in part, through the modification of glucose utilization and absorption.

Prevalence of diabetes mellitus in bullous pemphigoid patients in the absence of dipeptidyl peptidase-4 inhibitors: a systematic review and meta-analysis.

Bullous pemphigoid (BP) has been associated with dipeptidyl peptidase-4 inhibitor (DDP-4i) use in patients with diabetes mellitus (DM). The prevalence and association of DM in BP patients independent of DPP-4i use has not been investigated by meta-analysis. To perform a systematic review and meta-analysis on the association between diabetes and bullous pemphigoid. The goal was to determine the prevalence and pooled odds ratio of BP patients with DM in the absence of DDP-4i use compared to the general population prevalence of diabetes mellitus. OVID Medline, EMBASE, Cochrane Central and Web of Science were searched for relevant studies published from inception to April 2020. Case-control, case-series, cohort, and cross-sectional studies that included the association of BP and DM without DDP-4i's, in any language. PRISMA guidelines were followed for data extraction and the Newcastle-Ottawa Scale for risk of bias evaluation. Three reviewers independently performed data extraction. Pooled odds ratio and prevalence were calculated using the random effects model. The odds ratio and prevalence of BP patients with DM. Overall, 8 studies out of 856 identified publications through data base searches were included. The pooled prevalence of diabetes in patients with BP was 20.0% [95% CI 14%-26%; p = 0.00]. Within the comparative non-BP control population, 13% had diabetes. BP patients were more likely to have diabetes compared to a control population without BP [OR 2.10, 95% CI 1.22-3.60; p = 0.01]. This study found that twice the number of BP patients have DM (20%) compared to the general population reported as 10.5%, warranting monitoring of blood glucose levels in BP patients who may have yet undeclared or undiagnosed DM when initiating systemic steroids.

DPP4 Inhibitors: Could they be One of the Solutions for COVID-19 Patients with Prediabetes?

Recent reports suggest that prediabetes is a risk factor for developing severe COVID-19 complications through underlying mechanisms involving undiagnosed sub-clinical inflammation. However, we remain without a clinical approach for managing COVID-19 in prediabetic cases. The subclinical inflammation in prediabetes is associated with elevated DPP4 levels and activity. DPP4 has pleiotropic actions, including glycaemia regulation and immuno-modulation. Recently, DPP4 has been recognised as a co-receptor for COVID-19 for entering host cells. In addition to improving glycaemia, DPP4 inhibition is associated with reduced inflammation. In this submission, we explore the potential use of DPP4 inhibitors as therapeutic agents for prediabetic patients in managing the deleterious effects of COVID-19. DPP4 inhibitors (gliptins), such as linagliptin and sitagliptin, have therapeutic effects, which have been shown to extend beyond glycaemic control with no risk of hypoglycaemia. By the nature of their mechanism of action, gliptins are not associated with hypoglycaemia, unlike their anti-glycaemic counterparts, as they mainly target postprandial glycaemia. Moreover, DPP4 inhibitors may represent a safer option for prediabetic individuals in managing prediabetes either as a prophylactic or curative treatment for COVID-19. We envisage that beyond improved glycaemic control, the use of DPP4 inhibitors would also alleviate the cytokine storm, resulting in a reduction in the severity of COVID-19 symptoms and consequently reducing the morbidity and mortality in prediabetic COVID- 19 patients.

Association of Dipeptidyl Peptidase-4 Inhibitors Use with Reduced Risk of Hepatocellular Carcinoma in Type 2 Diabetes Patients with Chronic HBV Infection

Previous studies have indicated that HBV infection and T2DM are the factors that increase the risk of developing HCC. The experimental evidence has shown that antiglycemic agents may reduce the risk of HCC. However, the effect of dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) on the risk of HCC in T2DM patients with chronic HBV infection remains unclear. In this retrospective cohort study, we extracted patients with T2DM and chronic HBV infection from the National Health Insurance Research Database (NHIRD) in Taiwan. The cases were divided into DPP-4 inhibitors use and non-use groups, according to whether they received DPP-4 inhibitors treatment, and the risk of HCC was compared between the two groups. At the end of the follow-up, approximately 2.33% of DPP-4 inhibitors users had received an HCC diagnosis compared with 3.33% of non-DPP-4 inhibitors users (p < 0.0001). After multivariate adjustment, DPP-4 inhibitors users showed a significant reduction in HCC risk (adjusted hazard ratios (aHRs): 0.53; 95% confidence intervals (CIs): 0.44-0.65). In conclusion, this population-based retrospective cohort study indicated that, in T2DM patients with chronic HBV infection, the use of DPP-4 inhibitors significantly reduced the risk of developing HCC compared with non-DPP-4 inhibitors use.

Beneficial Effects of Dipeptidyl Peptidase-4 Inhibitors on HeartFailureWith Preserved EjectionFraction and Diabetes.

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to exert pleiotropic effects on heart failure (HF) in animal experiments. This study sought to investigate the impact of DPP-4 inhibitors on HF patients with diabetes mellitus (DM). We analyzed hospitalized patients with HF and DM enrolled in the JROADHF (Japanese Registry Of Acute Decompensated HeartFailure) registry, a nationwide registry of acute decompensated HF. Primary exposure was the use of a DPP-4 inhibitor. The primary outcome was a composite of cardiovascular death or HF hospitalization during the median follow-up of 3.6 years according to left ventricular ejection fraction. Out of 2,999 eligible patients, 1,130 had heart failure with preserved ejection fraction (HFpEF), 572 had heart failure with midrange ejection fraction (HFmrEF), and 1,297 had heart failure with reduced ejection fraction (HFrEF). In each cohort, 444, 232, and 574 patients received a DPP-4 inhibitor, respectively. A multivariable Cox regression model showed that DPP-4 inhibitor use was associated with a lower composite of cardiovascular death or HF hospitalization in HFpEF (HR: 0.69; 95%CI: 0.55-0.87; P = 0.002) but not in HFmrEF and HFrEF. Restricted cubic spline analysis demonstrated that DPP-4 inhibitors were beneficial in patients with higher left ventricular ejection fraction. In HFpEF cohort, propensity score matching yielded 263 pairs. DPP-4 inhibitor use was associated with a lower incidence rate of the composite of cardiovascular death or HF hospitalization (19.2 vs 25.9 events per 100 patient-years; rate ratio: 0.74; 95%CI: 0.57-0.97; P = 0.027) in matched patients. DPP-4 inhibitor use was associated with better long-term outcomes in HFpEF patients with DM.

Empagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in routine care in East Asia: Results from the EMPRISE study.

The EMPA-REG OUTCOME® trial demonstrated benefits of empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), on cardiovascular, renal outcomes and all-cause mortality in patients with type 2 diabetes and established cardiovascular disease. The EMPRISE study program evaluates how these effects translate in a broad population of patients with type 2 diabetes in routine clinical care across countries. The study included patients ≥18 years with type 2 diabetes initiating empagliflozin or any dipeptidyl peptidase-4 inhibitors (DPP-4i) from large administrative databases in Japan, South Korea, and Taiwan. Propensity score-matched (1:1) 'as-treated' analyses comparing the risk of cardiovascular outcomes and all-cause mortality between empagliflozin and DPP-4i use were performed in each country. Pooled hazard ratios (pHR) with 95% confidence intervals (CI) were computed using random effects meta-analysis models comparing both empagliflozin and SGLT2i with DPP-4i use, respectively. Intention-to-treat and subgroup analyses in patients with/without cardiovascular disease and in patients receiving 10 mg empagliflozin were performed. The study included 28,712 and 70,233 matched patient pairs for empagliflozin/DPP-4i and SGLT2i/DPP-4i analyses, respectively. The risk of composite outcomes including (i) hospitalization for heart failure (HHF) and all-cause mortality was lower with empagliflozin (pHR 0.76, 95% CI 0.67-0.86) and SGLT2i (0.71, 0.65-0.77); (ii) combined myocardial infarction, stroke, and all-cause mortality was also lower with empagliflozin (0.74, 0.61-0.88) and SGLT2i (0.69, 0.60-0.78) compared to DPP-4i. The intention-to-treat and three subgroup analyses were consistent with results of the main analyses. The results suggest that both empagliflozin and SGLT2i compared with DPP-4i are associated with a lower risk of cardiovascular events and all-cause mortality in routine clinical care in East Asia.

DOP57 GLP-1 based therapies and risk of Inflammatory Bowel Disease: real world evidence from a nationwide cohort study

Abstract Background Glucagon-like peptide-1 (GLP-1) based therapies, including GLP-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP4i), are incretin therapies used to treat type 2 diabetes. In addition to incretin effects, GLP-1 based therapies exhibit anti-inflammatory effects. Nevertheless, a previous study reported increased risk of inflammatory bowel disease (IBD) associated with DPP4i use, while two other studies reported no altered risk. No previous studies have investigated the use of GLP-1RA and risk of IBD. In this study we investigated whether use of GLP-1 based therapies alters the risk of developing IBD among individuals with type 2 diabetes. Methods In the setting of a prospective Danish nationwide cohort study (January 1, 2007 - December 31, 2018), we applied a new user active comparator design to compare the risk of IBD in users of GLP-1 based therapies with users of other glucose-lowering drugs. Considering exposure to GLP-1 based therapies as a time-varying covariate, we used a Cox proportional hazards model adjusted for sex, age, socio-economic status, urbanisation, and metformin use to estimate hazard ratios (HRs) of IBD. Results Among 177,950 new users of glucose-lowering drugs, 412 individuals developed IBD during a median follow-up period of 4.84 (95% CI 4.82 to 4.87) years. We found no altered risk of IBD associated with the use of GLP-1 based therapies with an adjusted HR of 0.96 (95% CI 0.72 to 1.27). Adjusted HRs of IBD were 1.30 (95% CI 0.86 to 1.96) for new users of GLP-1RA and 0.84 (95% CI 0.59 to 1.19) for new users of DPP4i compared to new users of other glucose lowering drugs. Findings were consistent in all analyses, including separate analyses of Crohn’s disease and ulcerative colitis. Conclusion In a population-based cohort of individuals with type 2 diabetes, we did not find an altered risk of IBD associated with the overall use of GLP-1 based therapies. Specifically, we did not confirm the previously reported increased risk of IBD associated with DPP4i. The influence of GLP-1RA on IBD needs further examination.

Noninsulin-based antihyperglycemic medications in patients with diabetes and COVID-19: A systematic review and meta-analysis.

Patients with diabetes are more likely to suffer COVID-19 complications. Using noninsulin antihyperglycemic medications (AGMs) during COVID-19 infection has proved challenging. In this study, we evaluate different noninsulin AGMs in patients with COVID-19. We searched Medline, Embase, Web of Science, and Cochrane on 24 January 2022. We used the following keywords (COVID-19) AND (diabetes mellitus) AND (antihyperglycemic agent). The inclusion criteria were studies reporting one or more of the outcomes. We excluded non-English articles, case reports, and literature reviews. Study outcomes were mortality, hospitalization, and intensive care unit (ICU) admission. The use of metformin rather than other glucose-lowering medications was associated with statistically significant lower mortality (risk ratio [RR]: 0.60, 95% confidence interval [CI]: 0.47, 0.77, p< .001). Dipeptidyl peptidase-4 inhibitor (DPP-4i) use was associated with statistically significantly higher hospitalization risk (RR: 1.44, 95% CI: 1.23, 1.68, p< .001) and higher risk of ICU admissions and/or mechanical ventilation vs nonusers (RR: 1.24, 95% CI: 1.04, 1.48, p< .02). There was a statistically significant decrease in hospitalization for SGLT-2i users vs nonusers (RR: 0.89, 95% CI: 0.84-0.95, p< .001). Glucagon-like peptide-1 receptor agonist (GLP-1RA) use was associated with a statistically significant decrease in mortality (RR: 0.56, 95% CI: 0.42, 073, p< 0.001), ICU admission, and/or mechanical ventilation (RR: 0.79, 95% CI: 0.69-0.89, p< .001), and hospitalization (RR: 0.73, 95% CI: 0.54, 0.98, p= .04). AGM use was not associated with increased mortality. However, metformin and GLP-1RA use reduced mortality risk statistically significantly. DPP-4i use was associated with a statistically significant increase in the risk of hospitalization and admission to the ICU.

Association of Sodium-Glucose Cotransporter 2 Inhibitor vs Dipeptidyl Peptidase-4 Inhibitor Use With Risk of Incident Obstructive Airway Disease and Exacerbation Events Among Patients With Type 2 Diabetes in Hong Kong

Patients with diabetes are at higher risk for obstructive airway disease (OAD). In recent meta-analyses of post hoc analyses of cardiorenal trials, sodium-glucose cotransporter 2 inhibitors (SGLT2Is) were suggested to reduce the risk of OAD adverse events. However, a clinical investigation of this association is warranted. This study aimed to investigate the association of SGLT2I use vs dipeptidyl peptidase-4 inhibitor (DPP4I) use with OAD incidence and exacerbation events in patients with type 2 diabetes. This retrospective population-based cohort study used electronic health data from a territory-wide electronic medical database in Hong Kong. Data were collected for patients with type 2 diabetes who were prescribed SGLT2Is or DPP4Is between January 1, 2015, and December 31, 2018. Patients were followed for a median of 2.2 years between January 1, 2015, and December 31, 2020. A prevalent new-user design was adopted to match patients based on previous exposure to the study drugs. Propensity score matching was used to balance baseline characteristics. Patients with type 2 diabetes using SGLT2Is (exposure of interest) or DPP4Is (active comparator). The main outcomes were the first incidence of OAD and the count of OAD exacerbations. The risk of incident OAD was estimated using a Cox proportional hazards regression model. The rate of exacerbations was estimated using zero-inflated Poisson regression. Statistical analysis was performed on November 13, 2022. This study included 30 385 patients. The propensity score-matched non-OAD cohort (incidence analysis) consisted of 5696 SGLT2I users and 22 784 DPP4I users, while the matched OAD cohort (exacerbations analysis) comprised 381 SGLT2I users and 1524 DPP4I users. At baseline, 56% of patients in the non-OAD cohort were men and the mean (SD) age was 61.2 (9.9) years; 51% of patients in the OAD cohort were men and the mean age was 62.2 (10.8) years. Compared with DPP4I use, SGLT2I use was associated with a lower risk of incident OAD (hazard ratio, 0.65 [95% CI, 0.54-0.79]; P < .001) and a lower rate of exacerbations (rate ratio, 0.54 [95% CI, 0.36-0.83]; P = .01). The associations were consistent in sex subgroup analysis. The findings of this retrospective cohort study of patients with type 2 diabetes in Hong Kong suggest that SGLT2I use was associated with a reduced risk of incident OAD and a lower rate of exacerbations in a clinical setting compared with DPP4I use. These findings further suggest that SGLT2Is may provide additional protective effects against OAD for patients with type 2 diabetes and that further investigation is warranted.

Inverse association between DPP-4 inhibitor use and fracture in older adults: A disproportionality analysis ofthe FAERS and JADER.

Fractures are significantly associated with increased morbidity and mortality in older individuals; additionally, patients with diabetes mellitus are highly prone to fractures. The aim of the present study was to examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitor use and the risk of fracture in older patients by analyzing data obtained from spontaneous adverse event reporting databases from the United States and Japan. Data on older patients registered in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) from the first quarter of 2013 to the end of 2019 and data registered in the Japanese Adverse Drug Event Report database (JADER) from April 2004 to December 2019 were used. Reporting odds ratio (ROR) and information component (IC) values were used for disproportionality analysis. Significant inverse associations between DPP-4 inhibitor use and fracture were found for DPP-4 inhibitors as a whole (ROR = 0.80; 95% CI = 0.73-0.88; IC = -0.31, 95% CI = -0.46 to -0.17); linagliptin (ROR = 0.74; 95% CI = 0.59-0.94; IC = -0.42, 95% CI = -0.75 to -0.08); and sitagliptin (ROR = 0.77; 95% CI = 0.68-0.88; IC = -0.36, 95% CI = -0.55 to -0.17) in the analyses of FAERS data. Similarly, significant inverse associations were also found for DPP-4 inhibitors as whole (ROR = 0.71; 95% CI = 0.59 to 0.86; IC = -0.46, 95% CI = -0.74 to -0.18); sitagliptin (ROR = 0.70; 95% CI = 0.52-0.95; IC = -0.49, 95% CI = -0.93 to -0.05); and vildagliptin (ROR = 0.54; 95% CI = 0.35-0.83; IC = -0.85, 95% CI = -1.49 to -0.22) in the analyses of JADER data. Our analysis of adverse event databases using different algorithms revealed that DPP-4 inhibitor use was inversely associated with fracture in older patients.

Pemphigoid Nodularis Induced by Long-Term Use of Dipeptidyl Peptidase-4 Inhibitors.

Pemphigoid Nodularis Induced by Long-Term Use of Dipeptidyl Peptidase-4 Inhibitors.

Restricted Mean Survival Time Analysis to Estimate SGLT2i–Associated Heterogeneous Treatment Effects on Primary and Secondary Prevention of Cardiorenal Outcomes in Patients With Type 2 Diabetes in Taiwan

Increasing numbers of post hoc analyses have applied restricted mean survival time (RMST) analysis on the aggregated-level data from clinical trials to report treatment effects, but studies that use individual-level claims data are needed to determine the feasibility of RMST analysis for quantifying treatment effects among patients with type 2 diabetes in routine clinical settings. To apply RMST analysis for assessing sodium-glucose cotransporter-2 inhibitor (SGLT2i)-associated cardiovascular (CV) events and estimating heterogenous treatment effects (HTEs) on CV and kidney outcomes in routine clinical settings. This comparative effectiveness study of Taiwan's National Health Insurance Research Database examined 21 144 propensity score (PS)-matched pairs of patients with type 2 diabetes with SGLT2i and dipeptidyl peptidase-4 inhibitor (DPP4i) treatment for assessing CV outcomes, and 19 951 PS-matched pairs of patients with type 2 diabetes with SGLT2i and DPP4i treatment for assessing kidney outcomes. Patients were followed until December 31, 2018. Statistical analysis was performed from August 2021 to April 2022. Newly stable SGLT2i or DPP4i use in 2017. Study outcomes were CV events including hospitalization for heart failure (HHF), 3-point major adverse CV events (3P-MACE: nonfatal myocardial infarction [MI], nonfatal stroke, and CV death), 4-point MACE (4P-MACE: HHF and 3P-MACE), and all-cause death, and chronic kidney disease (CKD). RMST and Cox modeling analyses were applied to estimate treatment effects on study outcomes. After PS matching, the baseline patient characteristics were comparable between 21 144 patients with stable SGLT2i use (eg, mean [SD] age: 58.3 [10.7] years; 11 990 [56.7%] male) and 21 144 patients with stable DPP4i use (eg, mean [SD] age: 58.1 [11.6] years; 12 163 [57.5%] male) for assessing CV outcomes, and those were also comparable between 19 951 patients with stable SGLT2i use (eg, mean [SD] age: 58.1 [10.7] years; 11 231 [56.2%] male) and 19 951 patients with stable DPP4i use (eg, mean [SD] age: 57.9 [11.5] years; 11 340 [56.8%] male) for assessing kidney outcome. The 2-year difference in RMST between patients with SGLT2i use and patients with DPP4i use was 4.99 (95% CI, 3.56-6.42) days for HHF, 4.12 (95% CI, 2.72-5.52) days for 3P-MACE, 7.72 (95% CI, 5.83-9.61) days for 4P-MACE, 1.26 (95% CI, 0.47-2.04) days for MI, 2.70 (95% CI, 1.57-3.82) days for stroke, 0.69 (95% CI, 0.28-1.11) days for CV death, 6.05 (95% CI, 4.89-7.20) days for all-cause death, and 14.75 (95% CI, 12.99-16.52) days for CKD. Directions of hazard ratios from Cox modeling analyses were consistent with RMST estimates. No association was found between study treatment and the negative control outcome (dental visits for tooth care). Consistent results across sensitivity analyses using high-dimensional PS-matched and PS-weighting approaches supported the validity of primary analysis results. Largest difference in RMST of SGLT2i vs DPP4i use for HHF and CKD was found among patients with established heart failure (30.80 [95% CI, 5.08-56.51] days) and retinopathy (40.43 [95% CI, 31.74-49.13] days), respectively. In this comparative effectiveness study, RMST analysis was feasible for translating treatment effects into more clinical intuitive estimates and valuable for quantifying HTEs among diverse patients in routine clinical settings.