Dipeptidyl peptidase-4 inhibitor use is not associated with elevated risk of severe joint pain in patients with type 2 diabetes: a population-based cohort study.

The aim of this study was to investigate the putative link between dipeptidyl peptidase-4 inhibitor (DPP-4i) use and the risk of fracture in patients with type 2 diabetes. This propensity-score-matched population-based cohort study was performed between 2009 and 2013 on patients with type 2 diabetes who were stable metformin users. A total of 3996 patients with type 2 diabetes used DPP-4i as a second-line antidiabetic drug. The same number of matched non-DPP-4i users were followed up until fracture occurrence, health insurance policy termination, or the end of 2013. The incidence rates of overall and cause-specific fractures were estimated based on the Poisson assumption. A multiple Cox proportional hazard model was used to estimate the covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) to determine the association between DPP-4i use and overall and cause-specific fractures stratified by age and sex. Over a maximum follow-up period of 5 years, 340 DPP-4i users and 419 non-DPP-4i users were newly diagnosed with fractures, yielding incidence rates of 28.03 and 32.04 per 1000 people per year, respectively. The Cox proportional hazard model revealed that DPP-4i use significantly reduced the risk of all-cause fractures and upper extremity fractures, with adjusted HRs of 0.86 (95% CI: 0.74-0.99) and 0.75 (95% CI: 0.59-0.95), respectively. The aforementioned associations of DDP-4i use with fracture were sustained across sex and age stratifications. The results of this study supported the premise that DPP-4i usage is associated with a reduced risk of all-cause fractures and upper extremity fractures in patients with type 2 diabetes.

COPD is a comorbid condition often associated with type 2 diabetes (T2D) and cardiovascular diseases, but few studies have observed the impact of various antidiabetic drugs in patients with COPD and T2D. We conducted this study to investigate the long-term outcomes of dipeptidyl peptidase-4 (DPP-4) inhibitor use in patients with COPD and T2D. We recruited 55 924 pairs of propensity score-matched DPP-4 inhibitor users and nonusers from Taiwan's National Health Insurance Research Database between 1 January 2008 and 31 December 2020. We used the Cox proportional hazards models with robust sandwich se estimates to compare the risks of all-cause mortality, major adverse cardiovascular events (MACEs) and respiratory outcomes in participants with COPD and T2D. Compared with no use of DPP-4 inhibitors, the adjusted hazard ratios (aHRs) (95% confidence interval (CI)) for DPP-4 inhibitor use for all-cause mortality, MACEs, hospitalisation for COPD, invasive mechanical ventilation, bacterial pneumonia and lung cancer were 0.47 (0.45-0.49), 0.92 (0.88-0.95), 0.73 (0.62-0.85), 0.76 (0.71-0.82), 0.73 (0.70-0.76) and 0.74 (0.71-0.78), respectively. DPP-4 inhibitor users also exhibited a significantly lower cumulative incidence of hospitalisation for COPD (log-rank test, p=0.004), mechanical ventilation (log-rank test, p<0.001), lung cancer (log-rank test, p<0.001), bacterial pneumonia (log-rank test, p<0.001) and mortality (log-rank test, p<0.001) than nonusers. This nationwide cohort study showed that DPP-4 inhibitor use was associated with a significantly lower risk of mortality, cardiovascular events, respiratory complications and lung cancer in patients with COPD and T2D. Patients with COPD may benefit from DPP-4 inhibitors.

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.

To investigate the association between long-term dipeptidyl peptidase-4 (DPP-4) inhibitor use and risk of fracture among people with type 2 diabetes mellitus (T2DM). A retrospective population-based cohort study, using data from the Clinical Practice Research Datalink database (2007-2015), was conducted. All those (N = 328 254) with at least one prescription for a non-insulin antidiabetic drug (NIAD), aged ≥18 years at the time of data collection, were included. Cox proportional hazards models were used to estimate the hazard ratios of any fracture, osteoporotic fracture and hip fracture in DPP-4 inhibitor users compared with those using other NIADs. Analyses were stratified by continuous duration of DPP-4 inhibitor use. Time-dependent adjustments were made for age, sex, lifestyle, comorbidity and concomitant drug use. Current use of DPP-4 inhibitors was not associated with risk of any fracture (adjusted hazard ratio [HR] 0.99 [95% confidence interval {CI} 0.93-1.06]) as compared with current other NIAD use. Current use of DPP-4 inhibitors was also not associated with risk of osteoporotic or hip fracture. After stratification by continuous duration of DPP-4 inhibitor use the highest category was not associated with any (>4.0-8.5 years of use, adjusted HR 0.99 [95% CI 0.70-1.41]), osteoporotic (>3.0-8.5 years of use, adjusted HR 0.75 [95% CI 0.52-1.09]) or hip (>2.0-8.5 years of use; adjusted HR 1.24 [95% CI 0.85-1.79]) fracture. Continuous long-term DPP-4 inhibitor use (defined as >4.0-8.5 years of DPP-4 inhibitor use for any fracture, >3.0-8.5 years for osteoporotic fracture and >2.0-8.5 years for hip fracture was not associated with risk of any, osteoporotic or hip fracture. These findings may be of value for clinical decisions regarding treatment of patients with T2DM, especially those at high risk of fracture.

Background/Objectives: Patients with diabetes mellitus face increased risk of severe outcomes and mortality from COVID-19. Dipeptidyl peptidase-4 (DPP-4) inhibitors, widely used antidiabetic agents, are hypothesized to affect COVID-19 outcomes via anti-inflammatory and immune-modulating mechanisms. However, real-world evidence, especially in Korean populations, remains limited. Methods: We conducted a retrospective cohort study using Korea’s nationwide Health Insurance Review and Assessment (HIRA) database. Adults with diabetes hospitalized for confirmed COVID-19 between 1 March 2021, and 28 February 2022, were included and stratified by DPP-4 inhibitor use. The primary outcome was 30-day all-cause mortality. Cox proportional hazards models adjusted for age, sex, and comorbidities estimated hazard ratios (HRs). Subgroup analyses examined angiotensin receptor blocker (ARB) and insulin use. Results: Among 16,134 eligible patients, 7082 received DPP-4 inhibitors. The 30-day mortality rate was lower in DPP-4 inhibitor users than non-users (4.3% vs. 10.3%, p < 0.0001). Adjusted analyses showed DPP-4 inhibitor use was associated with reduced mortality risk (adjusted HR: 0.455; 95% CI: 0.414–0.499). Subgroup analyses yielded consistent results across ARB and insulin users. Kaplan-Meier curves demonstrated higher survival probability in the DPP-4 inhibitor group. Conclusions: In this nationwide Korean cohort, DPP-4 inhibitor use was associated with lower mortality among hospitalized diabetic patients with COVID-19. While these findings suggest a potential benefit, causality cannot be confirmed due to the observational design. Prospective studies are needed to verify these associations and explore underlying mechanisms.

After a safety warning was issued for a risk of muscular injury associated with dipeptidyl peptidase-4 (DPP-4) inhibitor use, especially when co-prescribed with statins, spontaneous reporting analyses provided conflicting results. The aim of this study was to investigate the association between DPP-4 inhibitor use and the risk of muscular injury in individuals with type 2 diabetes mellitus using statins or fibrates. We conducted a nested case-control study amongst a cohort of individuals with type 2 diabetes using statins or fibrates, identified from a nationwide French health insurance database (2009-2014). Cases of serious muscular injury were defined as subjects hospitalized for rhabdomyolysis or myopathy, or for whom testing for myoglobin or creatine phosphokinase followed by a change in statin or fibrate prescription (dose decrease, treatment switch, or stop) was identified. Up to ten controls were matched to each case according to sex, age, and type of lipid-lowering agent. Associations between DPP-4 inhibitor use and serious muscular injury were estimated using a multivariate conditional logistic regression model, providing odds ratios (ORs) adjusted for alcoholism, chronic renal failure, hypothyroidism, and number of concomitant drugs. Within the 35,117 individuals with type 2 diabetes mellitus constituting the source cohort, 437 statin-user cases were identified who were matched to 4358 statin-user controls. Similarly, 54 fibrate-user cases were identified who were matched to 540 fibrate-user controls. The adjusted OR for DPP-4 inhibitor use and serious muscular injury was estimated at 1.0 (95% confidence interval [CI] 0.7-1.2) in statin users and 0.8 (95% CI 0.4-1.9) in fibrate users. In this study, DPP-4 inhibitor use was not associated with an increased risk of serious muscular injury among patients with type 2 diabetes mellitus using statins or fibrates.

BackgroundAlthough recent clinical trials raised concerns about the risk for heart failure (HF) in dipeptidyl peptidase-4 (DPP-4) inhibitor use, data on the cardiovascular risks in the patients with pre-existing HF...

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.

To evaluate impact of baseline systemic dipeptidyl peptidase-4 (DPP-4) inhibitor use in diabetic macular edema (DME). This was a post hoc exploratory analysis of previously completed randomized, controlled clinical trials (VISTA and VIVID) in patients with DME evaluating intravitreal aflibercept injection (IAI) every 4 weeks (2q4) or every 8 weeks (2q8) or macular laser photocoagulation. Overall, a small number of patients (12.2% [n = 35], 9.7% [n = 28], and 15.4% [n = 44]) in the laser control, 2q4, and 2q8 groups reported baseline DPP-4 inhibitor use. There were no differences in changes from baseline in best-corrected visual acuity, central subfield thickness, or rates of 2-or-greater-step improvement in Diabetic Retinopathy Severity Scale score based on DPP-4 inhibitor use within each treatment group. DPP-4 inhibitor use at baseline did not influence the magnitude of visual and anatomic benefit in patients with DME being treated with IAI or laser. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:226-234.].

BackgroundIncretin-based therapies including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon like peptide-1 (GLP-1) receptor agonists are novel medications for type 2 diabetes management. Several studies have found cardioprotective effects of incretin-based therapies; however, it remains unclear whether there is any difference in heart failure (HF) risk between the two incretin-based therapies (DPP-4 inhibitors and GLP-1 receptor agonists). We aimed to assess the risk of hospitalization due to HF with the use of DPP-4 inhibitors compared to GLP-1 receptor agonists.MethodsUsing Truven Health Marketscan data, we conducted a retrospective cohort study of patients with type 2 diabetes, who were newly initiated on DPP-4 inhibitors or GLP-1 agonists. Follow-up continued from drug initiation until the first occurrence of: HF hospitalization (primary outcome), discontinuation of therapy (i.e. no fill for 7 days), switch to the comparator, end of enrollment, or end of study (December 2013). Cox proportional hazards models with propensity-score-matching were used to compare the risk of HF hospitalization between DPP-4 inhibitors and GLP-1 agonists.ResultsA total of 321,606 propensity score-matched patients were included in the analysis (n = 160,803 for DPP-4 inhibitors; n = 160,803 for GLP-1 agonists). After adjusting for baseline characteristics and disease risk factors, the use of DPP-4 inhibitors was associated with a 14% decreased risk of HF hospitalization compared to GLP-1 agonists use [hazard ratio (HR), 0.86; 95% confidence interval (CI) 0.83, 0.90]. The results were consistent in patients without baseline HF (HR, 0.85; 95% CI 0.82, 0.89), but the association was not statistically significant for patients with baseline HF (HR, 0.90; 95% CI 0.74, 1.07).ConclusionIn this retrospective matched cohort of patients with type 2 diabetes, the use of DPP-4 inhibitors was associated with a reduced risk of HF hospitalization compared to GLP-1 agonists. However, the association was not statistically significant in patients who had HF prior to the use of DPP-4 inhibitors.

BackgroundThe purpose of this review was to examine if dipeptidyl peptidase-4 inhibitor (DPP4i) use affects the risk of diabetic retinopathy (DR).MethodsCohort studies published up to 20th July 2023 in the databases of PubMed, CENTRAL, Embase, Scopus, and Web of Science were searched. The adjusted effect size was pooled to calculate the odds ratio (OR).ResultsSeven studies were included. Meta-analysis showed that the use of DPP4i was not associated with any significant change in the risk of DR (OR: 0.86 95% CI: 0.70, 1.06 I2 = 78%). The pooled analysis also found that DPP4i use was not associated with any significant risk of progression of DR (OR: 0.87 95% CI: 0.47, 1.59 I2 = 86%). The results did not change during sensitivity analysis.ConclusionPresent evidence from a limited number of real-world studies shows that DPP4i may not affect the incidence and progression of DR. There is a need for further studies from different countries using accurate definitions of DR and its progression to validate the current results.

Objective: Although the use of dipeptidyl peptidase-4 (DPP-4) inhibitors has been increasing after their first approval in 2006, little is known about their prescribing pattern. Therefore, the objective of this study is to evaluate the prescribing pattern of the DPP-4 inhibitors for the treatment of type 2 diabetes mellitus (T2DM) and examine sociological factors associated with physician prescribing behavior in the U.S. outpatient setting.Methods: This cross-sectional study was conducted utilizing data from the 2006-2010 National Ambulatory Medical Care Survey (NAMCS) and employed the Eisenberg model that explains physician decision making in the context of sociologic influences. For independent variables, the following characteristics were determined based on the Eisenberg model: patient characteristics, physician characteristics, the physician-health care system interaction, and the physician-patient relationship. The dependent variable was the use of DPP-4 inhibitors. Multivariate logistic regressions were used for analyses.Results: The estimated population size was 535,158,796 patients during five years, and 3.85% of them were prescribed DPP-4 inhibitors. Among the patient characteristic-related factors, the odds of the use of DPP-4 inhibitors was 73% lower in patients with Medicaid compared to patients with private insurance (OR = 0.27; 95% CI, 0.08-0.88; p = .030). For the physician characteristic-related factor, the odds of prescribing DPP-4 inhibitors for primary care physicians are about 86% higher than the odds for non-primary care physicians (OR = 1.86; 95% CI, 1.17-2.95; p = .008). In addition, physicians in private offices were 3.01 times more likely to prescribe DPP-4 inhibitors than physicians in the health maintenance organizations (HMO) (OR = 3.01; 95% CI, 1.03-8.78; p = .043).Conclusions: Patient characteristics, physician characteristics, and the physician’s relationship with the health care system were associated with an increased use of DPP-4 inhibitors. However, the physician’s relationship with the patient was not associated with an increased use of DPP-4 inhibitors.

Dipeptidyl Peptidase-4 Inhibitors, Peripheral Arterial Disease, and Lower Extremity Amputation Risk in Diabetic Patients

The goal of this study was to analyze the impact of dipeptidyl peptidase-4 inhibitor (DPP4i) use on the risk of bone fracture in patients diagnosed with type 2 diabetes mellitus (T2DM) in Germany. Patients with an initial prescription of metformin between 2008 and 2014 from 1262 German general practitioner practices were selected. We matched 4160 DPP4i ever users to never users (1:1) based on age, sex, diabetes duration, body mass index, index year, and physician type. The primary outcome measure was the rate of bone fractures within five years of the start of metformin or DPP-4i therapy. Time-dependent Cox regression models were used to estimate hazard ratios (HRs) for fractures as a function of the DPP4i therapy. The mean age among the patients was 61.6years (SD=11.1years), 59.6% were men, and 3.1% were followed in diabetologist practices. The mean diabetes duration was 1.5years (SD=2.4years), HbA1c levels were 7.1% in DPP4i users and 6.6% in non-users, and body mass index was 31.5kg/m2 (SD=5.0kg/m2). Within five years of the index date, 6.4% of users and 8.3% of non-users developed bone fractures (log-rank p-value<0.001). Within five years of the index date, 7.4% of female and 4.7% of male users and 13.3% of female and 8.8% of male non-users were diagnosed with bone fractures (both log-rank p-values<0.001). The use of DPP4i was associated with a significant decrease in the risk of developing bone fractures (all patients HR=0.67, 95% CI 0.54-0.84; women HR=0.72, 95% CI 0.54-0.97; men HR=0.62, 95% CI 0.44-0.88). DPP4i use was associated with a decrease in the risk of bone fracture.

Disclosure: S. Saad-Omer: None. M. Kinaan: None. N. Sami: None. I. Mansi: None. Introduction: Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are Autoimmune Blistering Disorders (AIBDs). GLP-1 Receptor Agonists (GLP1-RA) and Dipeptidyl peptidase 4 inhibitors (DPP4i) have been noted in various case reports and case control studies to be linked with certain AIBDs; however, their overall role in these diseases is not completely understood, despite the exponential increase in use of these medications. This study aims to be the first study to investigate the association of DPP-4 inhibitors and GLP-1 agonists with incidence of AIBD, PV, and BP in a large cohort of American veterans. Methods: This retrospective cohort study of veterans enrolled in the Veterans Health Administration (VHA) used Corporate Data Warehouse (CDW). We extracted data of patients from fiscal years (FY) 2006 to end of FY 2021 who filled either GLP1-RA or DPP4i prescriptions. CDW is a comprehensive data source that encompasses vital status, demographic data, inpatient and outpatient diagnoses and procedure codes, vital signs, laboratory data, and pharmacy fill data. The study groups included: 1) GLP1-RA group: patients who initiated GLP1-RA; and 2) DPP4i group: patients who initiated DPP4i. Our primary outcome was the incidence of AIBDs. We compared baseline characteristics of patients who experienced the outcome and those who did not among GLP1-RA or DDP4i users. We, thereafter, examined factors associated with incidence of AIBD, PV, and BP among GLP1-RA users and DPP4i users. Results: The initial cohort of GLP1-RA or DPP4i users comprised a total of 415,895 patients, from which we excluded 397 (0.095%) patients with prior bullous skin diseases before starting GLP1-RA or DPP4i medications. Overall, a total of 154 patients developed PV/BP disease after initiation of either DPP4i or GLP1-RA. Of these 154 patients, 123 of these patients were on DPP4i and 31 of these patients were on GLP1-RA. The mean age (SD) of PV/BP patients was 72 (11) years compared to an average age of 66 (10) years in patients who did not develop PV/BP. Patients were also found to be predominately white (77.9%). Factors associated with increased risk of BP were use of DPP4i (Odds Ratio [OR] 1.90, 95% confidence interval [95% CI: 1.14-3.47, p=&amp;lt;0.01), and older age (OR: 1.07, 95%CI: 1.04-1.09, p&amp;lt;0.01). Use of GLP1-RA or DPP4i was not associated with PV incidence. (OR: 1.31, 95% CI: 0.65-2.62, p=&amp;lt;0.45). Conclusion: In conclusion, our study supports existing literature that DPP4i use is associated with an increased risk of developing BP. Our data does not find association with GLP-1 agonists nor DPP4 inhibitors in increasing the risk of PV. Presentation: 6/3/2024