Dipeptidyl Peptidase-4 Inhibitors In Patients Research Articles

Comparing ischemic cardiovascular effectiveness and safety between individual SGLT-2 inhibitors and DPP-4 inhibitors in patients with type 2 diabetes: a nationwide population-based cohort study.

This study compared the ischemic cardiovascular events (iCVEs) effectiveness and safety of initiating empagliflozin or dapagliflozin with those of dipeptidyl peptidase-4 inhibitors (DPP-4is), as well as the comparative effects between empagliflozin and dapagliflozin. Using data from the National Health Insurance Service in Korea, patients with type 2 diabetes mellitus (T2DM) who were newly prescribed empagliflozin, dapagliflozin, or DPP-4is from 2016 to 2019 and who did not have a recent CVE history were included. A Cox proportional hazards regression model was used to estimate the adjusted hazard ratio (aHR) with 95% confidence intervals (CIs) for iCVEs and safety events. Empagliflozin and dapagliflozin significantly reduced the risks of ischemic stroke (aHR 0.568, 95% CI 0.408-0.791; aHR 0.612, 95% CI 0.476-0.786, respectively) and all-cause mortality (aHR 0.590, 95% CI 0.442-0.788; aHR 0.730, 95% CI 0.603-0.884, respectively) compared with DPP-4is. Initiating dapagliflozin or empagliflozin was associated with significantly lower incidence of severe hypoglycemia, bone fracture, urinary tract infection, and acute kidney injury than that of DPP-4is. No significant differences were observed between empagliflozin and dapagliflozin in iCVEs and most safety outcomes. Empagliflozin and dapagliflozin showed significant preventive effects on ischemic stroke and all-cause mortality compared with DPP-4is in patients with T2DM, and their protective effects were similar. Both empagliflozin and dapagliflozin were not related to the harmful effects on most safety events. These results suggest that it may be beneficial to initiate empagliflozin or dapagliflozin for ischemic stroke prevention in patients with T2DM. However, further validation studies, such as randomized controlled trials, are needed to generalize these results.

GLP1-RA versus DPP4 inhibitors on cardiovascular outcomes: A three-year real-world analysis

Abstract Background Cardiovascular outcome trials of GLP1-RAs have massively impacted the clinical practice in the management of patients with type 2 diabetes. The cardiovascular protective properties of GLP1-RA compared to DPP4 have been demonstrated in an observational setting before, however recent methodological developments have enabled clinically relevant effect estimation. Aim This study aimed to evaluate the real-world cardiovascular outcomes of GLP1-RA versus DPP4 inhibitors in patients with type 2 diabetes and high cardiovascular risk. Methods In this study, we utilized the Danish nationwide registers to identify new users of GLP1-RA or DPP4 therapies from 2012 to 2022. Participants were required to be either at least 50 years of age and have one or more of the following conditions: hypertension, chronic obstructive pulmonary disease, cardiovascular disease, or chronic renal disease or be at least 60 years of age and have hypertension. Additionally, their glycated hemoglobin (HbA1c) levels needed to be 53 mmol/mol or higher within the year preceding their first prescription date for these therapies. The index date was defined as the initial prescription date, and comorbidities and medicine use were evaluated up to 10 years prior to this date. Individuals who had filled prescriptions for SGLT2 inhibitors within six months prior to their index date were excluded from the study. The outcome of interest was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE). Patients were followed for up to three years until MACE, all-cause mortality, emigration, or until the end of follow-up on December 31, 2022. To assess the three-year risk of MACE, the Aalen Johansson estimator was used. A casual inference framework was employed estimating the three-year average treatment effect using g-formula based on Cox regression with competing risk. Results A total of 26,190 individuals were included, with 19,494 initiating DPP4 inhibitor therapy and 6,696 initiating GLP1-RA therapy. The three-year risk of MACE was 8.56% (95% confidence interval [CI]: 8.11 to 9.00) for the DPP4 initiator group, compared to 4.76% (95% CI: 4.08 to 5.43) for the GLP1-RA initiator group. Emulating what would have happened had all included individuals initiated GLP1-RA treatment versus had all initiated treatment with DPP4, accounting for age, sex, income, education, degree of urbanization, diabetes duration, baseline hba1c level, co-medicine, and co-morbidities, we estimated an three-year average treatment effect of -2.05% (95% CI:-2.92;-1.18) , p-value<0.001) for GLP1-RA initiation versus DPP4 initiation for MACE. Conclusion Our findings suggest that GLP1-RA use is associated with a significantly lower risk of MACE compared to DPP4 inhibitors in a real-world population of patients with type 2 diabetes and high cardiovascular risk. This supports the cardiovascular protective role of GLP1-RA in clinical practice.

Comparison of the Risk of Diabetic Retinopathy Between Sodium-Glucose Cotransporter-2 Inhibitors and Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes Mellitus in Japan: A Retrospective Analysis of Real-World Data.

Diabetic retinopathy (DR), a microvascular complication of type 2 diabetes mellitus (T2DM), is a leading cause of blindness and has detrimental effects on patients' quality of life. We compared the risk of DR diagnosis with sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP-4i) in patients with T2DM in Japan. This Japanese retrospective cohort study used the JMDC Claims Database (data collected from January 2015 to September 2022). Patients with T2DM and no record of microvascular or macrovascular diseases who were newly treated with an SGLT2i (23,061 patients) or a DPP-4i (53,986 patients) were matched 1:1 using propensity score (10,166 per matched group). Incidence rates (IRs) and cumulative IRs of DR diagnosis were calculated for each treatment group; hazard ratio (HR) and its 95% confidence interval (CI) were calculated using Cox proportional hazard models to compare the risk between the groups. The IR of DR diagnosis was 46.23 and 57.12 per 1000 person-years in the SGLT2i and DPP-4i groups, respectively, with a significantly lower risk in the SGLT2i group than in the DPP-4i group (HR 0.83, 95% CI 0.75-0.92, P = 0.0003). In this study, the risk of DR diagnosis was lower with SGLT2i compared with DPP-4i in patients with T2DM without microvascular and macrovascular diseases in Japan. Findings suggest that early SGLT2i treatment may be beneficial in preventing DR development in early-stage T2DM. Graphical abstract available for this article.

Financial Benefits of Renal Dose-Adjusted Dipeptidyl Peptidase-4 Inhibitors for Patients with Type 2 Diabetes and Chronic Kidney Disease.

Dipeptidyl peptidase-4 (DPP4) inhibitors are frequently prescribed for patients with type 2 diabetes; however, their cost can pose a significant barrier for those with impaired kidney function. This study aimed to estimate the economic benefits of substituting non-renal dose-adjusted (NRDA) DPP4 inhibitors with renal dose-adjusted (RDA) DPP4 inhibitors in patients with both impaired kidney function and type 2 diabetes. This retrospective cohort study was conducted from January 1, 2012 to December 31, 2018, using data obtained from common data models of five medical centers in Korea. Model 1 applied the prescription pattern of participants with preserved kidney function to those with impaired kidney function. In contrast, model 2 replaced all NRDA DPP4 inhibitors with RDA DPP4 inhibitors, adjusting the doses of RDA DPP4 inhibitors based on individual kidney function. The primary outcome was the cost difference between the two models. In total, 67,964,996 prescription records were analyzed. NRDA DPP4 inhibitors were more frequently prescribed to patients with impaired kidney function than in those with preserved kidney function (25.7%, 51.3%, 64.3%, and 71.6% in patients with estimated glomerular filtration rates [eGFRs] of ≥60, <60, <45, and <30 mL/min/1.73 m2, respectively). When model 1 was applied, the cost savings per year were 7.6% for eGFR <60 mL/min/1.73 m2 and 30.4% for eGFR <30 mL/min/1.73 m2. According to model 2, 15.4% to 51.2% per year could be saved depending on kidney impairment severity. Adjusting the doses of RDA DPP4 inhibitors based on individual kidney function could alleviate the economic burden associated with medical expenses.

Autonomic modulation by SGLT2i or DPP4i in patients with diabetes favors cardiovascular outcomes as revealed by skin sympathetic nerve activity.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i) are important second-line treatments for patients with type 2 diabetes mellitus (T2DM). Patients taking SGLT2i have favorable cardiovascular outcomes via various mechanisms, including autonomic nervous system (ANS) modulation. This study aimed to use neuro-electrocardiography (neuECG) to test the effects of SGLT2i or DPP4i on the ANS. Patients with T2DM, who did not reach target hemoglobin (Hb)A1C levels despite metformin treatment, were enrolled. SGLT2i or DPP4i were prescribed randomly unless a compelling indication was present. NeuECG and heart rate were recorded for 10min before and after a 3-month treatment. The patients were treated according to standard practice and the obtained data for skin sympathetic nerve activity (SKNA) and ANS entropy were analyzed offline. We enrolled 96 patients, of which 49 received SGLT2i and 47 received DPP4i. The baseline parameters were similar between the groups. No adverse event was seen during the study period. In the burst analysis of SKNA at baseline, all parameters were similar. After the 3-month treatment, the firing frequency was higher in SGLT2i group (0.104 ± 0.045 vs 0.083 ± 0.033 burst/min, p < 0.05), with increased long firing duration (7.34 ± 3.66 vs 5.906 ± 2.921, p < 0.05) in 3-s aSKNA scale; the other parameters did not show any significant change. By symbolic entropy, the most complex patterns (Rank 3) were found to be significantly higher in SGLT2i-treated patients than in DDP4i-treated group (0.084 ± 0.028 vs 0.07 ± 0.024, p = 0.01) and the direction of change in Rank 3, after SGLT2i treatment, was opposite to that observed in the DDP4i group (0.012 ± 0.036 vs. -0.005 ± 0.037, p = 0.024). Our findings demonstrated the favorable autonomic modulation by SGLTi and the detrimental effects of DPP4i on ANS. We demonstrated the autonomic modulation by SGLTi and DPP4i using SKNA in patients with DM, which might provide insights into the favorable outcomes of SGLT2i. Furthermore, we refined the analytical methods of neuECG, which uses SKNA to evaluate autonomic function.

A review of the latest real-world evidence studies in diabetic kidney disease: What have we learned about clinical practice and the clinical effectiveness of interventions?

Diabetic nephropathy, also known as diabetic kidney disease (DKD), remains a challenge in clinical practice as this is the major cause of kidney failure worldwide. Clinical trials do not answer all the questions raised in clinical practice and real-world evidence provides complementary insights from randomized controlled trials. Real-life longitudinal data highlight the need for improved screening and management of diabetic nephropathy in primary care. Adherence to the recommended guidelines for comprehensive care appears to be suboptimal in clinical practice in patients with DKD. Barriers to the initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors for patients with DKD persist in clinical practice, in particular for the elderly. Attainment of blood pressure targets often remains an issue. Initiation of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in routine clinical practice is associated with a reduced risk of albuminuria progression and a possible beneficial effect on kidney function. Real-world evidence confirms a beneficial effect of SGLT2 inhibitors on the decline of glomerular filtration, even in the absence of albuminuria, with a lower risk of acute kidney injury events compared to GLP-1RA use. In addition, SGLT2 inhibitors confer a lower risk of hyperkalaemia after initiation compared with dipeptidyl peptidase-4 inhibitors in patients with DKD. Data from a large population indicate that diuretic treatment increases the risk of a significant decline in glomerular filtration rate in the first few weeks of treatment after SGLT2 inhibitor initiation. The perspective for a global approach targeting multifaceted criteria for diabetic individuals with DKD is emerging based on real-world evidence but there is still a long way to go to achieve this goal.

#762 Hyperkalemia and discontinuation of RAS blockade after initiating SGLT-2i vs. DPP-4i in patients with type 2 diabetes; a population-based cohort study

Abstract Rate of hyperkalemia and discontinuation of renin-angiotensin system blockade after initiating SGLT-2 inhibitors vs. DPP-4 inhibitors in patients with type 2 diabetes; a population-based cohort study Background and Aims Post-hoc analyses of clinical trials have suggested that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) lower the rate of hyperkalemia and facilitate the use of renin-angiotensin system inhibitors (RASi) in people with type 2 diabetes and CKD. Whether these effects are generalizable to patients treated in routine clinical practice is unclear. Here, we evaluated the comparative effects of SGLT-2i and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the rate of hyperkalemia and RASi discontinuation. Method We conducted a population-based active-comparator, new-user cohort study using data from the Stockholm CREAtinine Measurements (SCREAM) project of people with type 2 diabetes who newly initiated SGLT-2i or DPP-4i between January 2014 and December 2021. The primary outcomes were time to first outpatient hyperkalemia (plasma potassium &amp;gt;5.0 mmol/L) occurrence and recurrent hyperkalemia. The secondary outcomes were mild (potassium &amp;gt;5-≤5.5 mmol/L) and moderate-severe (potassium &amp;gt;5.5 mmol/L) hyperkalemias. Among RASi users, we also studied time to RASi discontinuation through evaluation of pharmacy fills. Cox regression with inverse probability of treatment weighting was used to estimate hazard ratios (HRs) and rate differences for time to first hyperkalemia. Weighted Poisson regression was used to estimate incidence rate ratios (IRRs) for hyperkalemia recurrence. Results We included 24 417 individuals (of which 14 470 initiated SGLT-2i and 9, 947 DPP-4i therapy), followed for median 2.0 (Q1-Q3 0.8-3.7) years. Mean age was 67 years and 37% were women. Compared with DPP-4i, initiation of SGLT-2i was associated with a lower rate of first hyperkalemia (adjusted hazard ratio [HR] 0.83; 95% CI 0.72-0.96) and recurrent hyperkalemia (incidence rate ratio [IRR] 0.75; 0.64-0.85). Similar findings were observed among people with eGFR ≥60 (HR 0.73; 95% CI 0.63-0.86) and &amp;lt;60 (HR 0.87; 95% CI 0.63-1.16) ml/min/1.73 m2, as well as for mild (HR 0.82; 95% CI 0.71-0.95) and moderate-severe (HR 0.67; 95% CI 0.52-0.84) hyperkalemias. Out of 15 746 participants that were prevalent RASi users, 17% discontinued RASi therapy during 2.0 (IQR 0.8-3.7) years of follow-up. Initiation of SGLT-2i vs. DPP-4i was not associated with the rate of RASi discontinuation (HR: 1.00; 0.91-1.11). Conclusion In patients with type 2 diabetes managed in routine clinical care, the use of SGLT-2i was associated with a lower rate of first and recurrent hyperkalemia compared with DPP-4i. However, this was not accompanied by higher persistence on RASi therapy.

Kidney and Cardiovascular Effectiveness of Empagliflozin Compared With Dipeptidyl Peptidase-4 Inhibitors in Patients With Type 2 Diabetes

Placebo-controlled trials of sodium-glucose cotransporter-2 inhibitors (SGLT2i) demonstrate kidney and cardiovascular benefits for people with type 2 diabetes (T2D) and chronic kidney disease (CKD). We used real-world data to compare the kidney and cardiovascular effectiveness of empagliflozin to dipeptidyl peptidase-4 inhibitors (DPP4i), a commonly prescribed antiglycemic medication, in a diverse population with and without CKD. Using electronic health record data from 20 large US health systems, we leveraged propensity overlap weighting to compare outcomes for empagliflozin and DPP4i initiators with T2D between 2016 and 2020. The primary composite kidney outcome included 40% estimated glomerular filtration rate (eGFR) decline, incident end-stage kidney disease (ESKD), or all-cause mortality through 2 years or censoring. We also assessed cardiovascular and safety outcomes. Among 62,197 new users, 20,279 initiated empagliflozin, and 41,918 initiated DPP4i. Over a median follow-up of 1.1 years, empagliflozin prescription was associated with a lower risk of the primary outcome (HR 0.75, 95% CI 0.65-0.87) compared with DPP4i. Risks for mortality (HR 0.76, 95% CI 0.62-0.92) and a cardiovascular composite of stroke, myocardial infarction, or all-cause mortality (HR 0.81, 95% CI 0.70-0.95) were also lower for empagliflozin initiators. No difference in heart failure hospitalization risk between groups was observed. Genital mycotic infections were more common in patients prescribed empagliflozin (HR 1.72, 95% CI 1.58 - 1.88). Empagliflozin was associated with a lower risk of the primary outcome in patients with CKD (HR 0.68, 95% CI 0.53-0.88) and those without CKD (HR 0.79, 95% CI 0.67 - 0.94). In conclusion, initiation of empagliflozin was associated with a significantly lower risk of kidney and cardiovascular outcomes compared with DPP4i over a median of just over 1 year. The association with a lower risk for clinical outcomes was apparent even for people without known CKD at baseline.

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.

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. 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. 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. 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.

Empagliflozin Use Is Associated With Lower Risk of All-Cause Mortality, Hospitalization for Heart Failure, and End-Stage Renal Disease Compared to DPP-4i in Nordic Type 2 Diabetes Patients: Results From the EMPRISE (Empagliflozin Comparative Effectiveness and Safety) Study.

Objective: To evaluate the effectiveness of empagliflozin in reducing all-cause mortality (ACM), hospitalization for heart failure (HHF), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), and end-stage renal disease (ESRD) in routine clinical practice in the Nordic countries of the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) study. Methods: This noninterventional, multicountry cohort study used secondary data from four Nordic countries (Denmark, Sweden, Finland, and Norway). Propensity score (PS) matched (1:1) adults with type 2 diabetes (T2D) initiating empagliflozin (a sodium-glucose cotransporter-2 inhibitor) during 2014-2018 who were compared to those initiating a dipeptidyl peptidase-4 inhibitor (DPP-4i). Cox proportional hazards regression modelling was used to assess the risk for ACM, HHF, MI, stroke, CVM, and ESRD. Meta-analyses were conducted and hazard ratios (HRs) with 95% confidence intervals (CIs) from random-effects models were calculated. Results: A total of 43,695 pairs of PS-matched patients were identified. Patients initiating empagliflozin exhibited a 49% significantly lower risk of ACM (HR: 0.51, 95% CI 0.40-0.64) compared to DPP-4i. Additionally, empagliflozin was associated with a 36% significantly lower risk of HHF (HR: 0.64, 95% CI 0.46-0.89), a 52% significantly lower risk of CVM (HR: 0.48, 95% CI 0.37-0.63), and a 66% significantly lower risk of ESRD (HR: 0.34, 95% CI 0.15-0.77) compared to DPP-4i. No significant differences were observed in the risk of stroke and MI between patients initiating empagliflozin compared with those initiating a DPP-4i. Results were generally consistent for subgroups (with/without pre-existing CV disease or congestive heart failure) and in sensitivity analyses. Conclusion: Empagliflozin initiation was associated with a significantly reduced risk of ACM, HHF, CVM, and ESRD compared with initiation of DPP-4i in patients with T2D when examining routine clinical practice data from Nordic countries.

Prevalence and Predictors of Adverse Events Associated With Dipeptidyl Peptidase-4 (DPP-4) Inhibitors in Type 2 Diabetic Patients: A Cross-sectional Study.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral hypoglycemic agents widely prescribed in India despite safety concerns. However, studies focused on their safety profile are scarce, especially in South India. To evaluate the prevalence and predictors of adverse events (AEs) with DPP-4 inhibitors in patients with type 2 diabetes mellitus (T2DM). This retrospective cross-sectional study analyzed data from medical records of T2DM patients prescribed DPP-4 inhibitors admitted to the medicine department from 2019 to 2021 at a South Indian tertiary care hospital. The causality of AEs was assessed using the WHO-Uppsala Monitoring Centre (WHO-UMC) criteria and the Naranjo scale, and severity using the Modified Hartwig and Seigel scale. We applied a Generalized model with a binary response and logit-link function to understand the factors that best explain the AE. The best-fit models were chosen based on least Akaike's information criterion and highest PseudoR 2 and presented the odds ratio (OR) with a 95% confidence interval. The analyses were performed in R software version 4.2.1. Among the 796 patients included in the study, 26% experienced AEs. A total of 212 AEs were observed, and Saxagliptin-associated AEs were the most prevalent (66.6%). Hepatic AEs were predominant (37.7%), followed by gastrointestinal events (16.5%) and electrolyte imbalances (12.3%). Most AEs were possible based on WHO-UMC criteria (78.7%) and the Naranjo scale (86.7%), with 58% being of moderate severity and 42% mild. In the multivariate analysis, aspartate transaminase [OR: 1.013 (0.006-1.020)], alkaline phosphatase [OR: 1.004 (1.001-1.007)] and patients already on DPP-4 inhibitors [OR 1.191(1.012-1.366)] were significant predictors for AEs with DPP-4 inhibitors. The study highlighted a high prevalence of AEs with DPP-4 inhibitors and identified significant predictors of these AEs. These findings underscore the necessity of vigilant monitoring and risk assessment while prescribing DPP-4 inhibitors to the Indian population.

Comparison of SGLT2 inhibitors vs. DPP4 inhibitors for patients with metabolic dysfunction associated fatty liver disease and diabetes mellitus

PurposeThis study aimed to examine the potential benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and diabetes mellitus (DM) using a real-world database.MethodsWe analyzed individuals with MAFLD and DM newly initiated on SGLT2 or dipeptidyl peptidase 4 (DPP4) inhibitors from a large-scale administrative claims database. The primary outcome was the change in the fatty liver index (FLI) assessed using a linear mixed-effects model from the initiation of SGLT2 or DPP4 inhibitors. A propensity score-matching algorithm was used to compare the change in FLI among SGLT2 and DPP4 inhibitors.ResultsAfter propensity score matching, 6547 well-balanced pairs of SGLT2 and 6547 DPP4 inhibitor users were created. SGLT2 inhibitor use was associated with a greater decline in FLI than DPP4 inhibitor use (difference at 1-year measurement, − 3.8 [95% CI − 4.7 to − 3.0]). The advantage of SGLT2 inhibitor use over DPP4 inhibitor use for improvement in FLI was consistent across subgroups. The relationship between SGLT2 inhibitors and amelioration of FLI was comparable between individual SGLT2 inhibitors.ConclusionsOur analysis using large-scale real-world data demonstrated the potential advantage of SGLT2 inhibitors over DPP4 inhibitors in patients with MAFLD and DM.

A population-based cohort defined risk of hyperkalemia after initiating SGLT-2 inhibitors, GLP1 receptor agonists or DPP-4 inhibitors to patients with chronic kidney disease and type 2 diabetes

Hyperkalemia is a common adverse event in patients with chronic kidney disease (CKD) and type 2 diabetes and limits the use of guideline-recommended therapies such as renin-angiotensin system inhibitors. Here, we evaluated the comparative effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of hyperkalemia. We conducted a population-based active-comparator, new-user cohort study using claims data from Medicare and two large United States commercial insurance databases (April 2013-April 2022). People with CKD stages 3-4 and type 2 diabetes who newly initiated SGLT-2i vs. DPP-4i (141671 patients), GLP-1RA vs. DPP-4i (159545 patients) and SGLT-2i vs. GLP-1RA (93033 patients) were included. The primary outcome was hyperkalemia diagnosed in inpatient or outpatient settings. Secondary outcomes included hyperkalemia diagnosed in inpatient or emergency department setting, and serum potassium levels of 5.5 mmol/L or more. Pooled hazard ratios and rate differences were estimated after propensity score matching to adjust for over 140 potential confounders. Initiation of SGLT-2i was associated with a lower risk of hyperkalemia compared with DPP-4i (hazard ratio 0.74; 95% confidence interval 0.68-0.80) and contrasted to GLP-1RA (0.92; 0.86-0.99). Compared with DPP-4i, GLP-1RA were also associated with a lower risk of hyperkalemia (0.80; 0.75-0.86). Corresponding absolute rate differences/1000 person-years were -24.8 (95% confidence interval -31.8 to -17.7), -5.0 (-10.9 to 0.8), and -17.7 (-23.4 to -12.1), respectively. Similar findings were observed for the secondary outcomes, among subgroups, and across single agents within the SGLT-2i and GLP-1RA classes. Thus, SGLT-2i and GLP-1RA are associated with a lower risk of hyperkalemia than DPP-4i in patients with CKD and type 2 diabetes, further supporting the use of these drugs in this population.

Comparative Kidney and Cardiovascular Effectiveness of Empagliflozin Compared to Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes Mellitus

Comparative Kidney and Cardiovascular Effectiveness of Empagliflozin Compared to Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes Mellitus

FRI633 Financial Benefits Of Renal Dose-adjusted Dipeptidyl Peptidase-4 Inhibitors For Patients With Type 2 Diabetes And Chronic Kidney Disease: A Multicenter Study Utilizing Common Data Model

Abstract Disclosure: H. Choe: None. Y. Ko: None. S. Moon: None. C.H. Ahn: None. K. Ha: None. H. Lee: None. J. Bae: None. H. Joo: None. H. Lee: None. J. Sohn: None. D. Kim: None. S. Kim: None. K. Kim: None. Y. Cho: None. Objective: To estimate the economic benefit of replacing non-renal dose adjusted (NRDA) dipeptidyl peptidase-4 (DPP4) inhibitors with renal dose adjusted (RDA) DPP4 inhibitors in patients with impaired kidney function and type 2 diabetes. Patients and Methods: This multicenter study analyzed a total of 67,964,996 prescription records of five teaching hospitals in Korea from January 1, 2012 to December 31, 2018 using a common data model. Prescription patterns of NRDA and RDA DPP4 inhibitors were subgrouped based on estimated glomerular filtration rate (eGFR) determined by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Results: NRDA DPP4 inhibitors were more frequently prescribed to patients with impaired kidney function than those with preserved kidney function (25.7%, 51.3%, 64.3%, and 71.6% in patients with eGFR of ≥60, &amp;lt;60, &amp;lt;45, and &amp;lt;30 mL/min/1.73m2, respectively). When applying the prescription pattern of DPP4 inhibitors for patients with preserved kidney function to those with impaired kidney function, cost savings per year were 7.6% for eGFR &amp;lt;60 mL/min/1.73m2 and 30.4% for eGFR &amp;lt;30 mL/min/1.73m2. Assuming patients with impaired kidney function are solely prescribed with RDA DPP4 inhibitors with appropriate dose reduction, 15.4% to 51.2% per year could be saved depending on kidney impairment severity. Conclusion: NRDA DPP4 inhibitors are frequently prescribed in patients with type 2 diabetes and CKD. Prescribing RDA DPP4 inhibitors with doses adjusted to individual kidney function could alleviate the economic burden associated with medical expenditure. Presentation: Friday, June 16, 2023

Risk of thyroid cancer associated with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: A population-based cohort study.

To determine the potential association between the use of either glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 (DPP-4) inhibitors, and the risk of thyroid cancer in individuals with type 2 diabetes. This population-based cohort study used claims data from the Korean National Health Insurance Database, 2014-2020. Two distinct cohorts were established to compare each incretin-based drug with sodium-glucose cotransporter-2 (SGLT2) inhibitors, chosen as active comparators because of their previous non-association with thyroid cancer, and their common usage as add-on therapy to metformin along with GLP-1RAs and DPP-4 inhibitors. The first cohort included 21 722 new users of GLP-1RAs and 326 993 new users of SGLT2 inhibitors, whereas the second cohort included 904 300 DPP-4 inhibitor new users and 112 017 SGLT2 inhibitor new users. The outcome was the time to incident thyroid cancer. Weighted Cox proportional models were used to estimate hazard ratios of thyroid cancer incidence associated with incretin-based drugs of interest. The use of GLP-1RAs was not associated with an increased risk of thyroid cancer (weighted hazard ratio 0.98, 95% confidence interval 0.62-1.53) compared with that of SGLT2 inhibitors. Using DPP-4 inhibitors was also not associated with an increased risk of thyroid cancer (0.95, 0.79-1.14) compared with that of SGLT2 inhibitors. No significant effect modifications were observed across subgroup analyses. Sensitivity analyses, including alternative outcome definition analysis of medullary thyroid cancer, were consistent with the primary analysis results. GLP-1RAs and DPP-4 inhibitors were not associated with an increased risk of thyroid cancer in individuals with type 2 diabetes.

Post-authorization safety study (PASS) assessing the risk of liver, renal, genitourinary, and diabetic ketoacidosis outcomes among users of empagliflozin versus DPP-4 inhibitors in patients with type 2 diabetes mellitus (T2D)

Post-authorization safety study (PASS) assessing the risk of liver, renal, genitourinary, and diabetic ketoacidosis outcomes among users of empagliflozin versus DPP-4 inhibitors in patients with type 2 diabetes mellitus (T2D)

Dipeptidyl-peptidase-4 inhibitors have anti-inflammatory effects in patients with type 2 diabetes.

Systematic low-grade inflammation is considered to be an important factor leading to the development of T2DM and the progression of its complications. Dipeptidyl-peptidase-4 (DPP-4) inhibitors show potential anti-inflammatory effects in patients with T2DM. This meta-analysis aimed to evaluate the anti-inflammatory effects of DPP-4 inhibitors in patients with T2DM. A comprehensive search was performed in PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials to identify randomized controlled trials that assess the anti-inflammatory effects of DPP-4 inhibitors. Quantitative data analysis was conducted by a random-effects model. Sensitivityanalyses were conducted todeterminethe robustness ofthe pooled results. Twenty-two studies with 1595 patients with T2DM were included. Pooled results showed that DPP-4 inhibitor therapy was significantly associated with the reduction of C-reactive protein (CRP) (SMD, - 0.56, p < 0.01), TNF-α (SMD, - 1.69, p < 0.01), IL-6 (SMD, - 0.67, p < 0.01), and IL-1β (WMD, - 8.21pg/ml, p < 0.01). Leave-one-out meta-analysis showed no significant change in the pooled results of CRP and TNF-α. This meta-analysis demonstrated that DPP-4 inhibitors can significantly attenuate low-grade inflammatory state in patients with T2DM. In addition to improving glycemic control, DDP-4 inhibitors might offer extra therapeutic value by controlling inflammation.

Re-evaluation of dipeptidyl peptidase-4 inhibitors in patients with heart failure and diabetes mellitus

ObjectivesThe question of whether dipeptidyl peptidase-4 inhibitors (DPP-4i) should be preferred as new glucose-lowering agents in heart failure is controversial. This studyaimed to evaluate the effects of DPP-4i treatment on all-cause mortality and cardiovascular outcomes in patients with heart failure. MethodsWe searched for available studies of DPP-4i therapy in heart failure and performed a pooled analysis. Outcomes included all-cause mortality, cardiovascular death, hospitalization for heart failure, left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), acute coronary syndrome, and acute myocardial infarction. ResultsTreatment with DPP-4i did not reduce the risk of all-cause death, cardiovascular death, or hospitalization for heart failure. Subgroup analyses showed that DPP-4i significantly reduced all-cause mortality in trials with > 40% female patients (OR 0.30, 95% CI [0.16, 0.58], P = 0.0003) and in trials with > 20% patients with heart failure with preserved ejection fraction (HFpEF) (OR 0.34, 95% CI [0.19, 0.60], P = 0.0003). Changes in LVEF and LVEDV showed no statistical differences between the 2 groups. Accordingly, DPP-4i did not alter the risk of acute coronary syndrome and acute myocardial infarction. ConclusionsDPP-4i may reduce all-cause mortality in heart failure patients in subgroups of women and HFpEF and has a high coronary safety profile.

Can DPP-4 Enhibitors and SGLT-2 Inhibitors Pleotropic Effects be Extended to Treat Diabetic Nephropathy?

Impaired insulin secretion and resistance remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. Diabetic nephropathy is one of the most common microvascular complications and a major cause of end-stage renal disease. Despite many treatment options available, diabetic kidney disease continues to affect a large population with diabetes. The kidneys have the highest DPP-4 expression level in mammalians. DPP- 4 is expressed in several segments of the nephron and the tubule interstitium, placing it at the nexus of inflammation, immune system activation, glomerular and proximal tubular function, salt regulation, and kidney fibrosis. Moreover, DPP-4 expression and urinary activity are up-regulated in diabetic nephropathy, highlighting its role as a potential target to manage diabetic nephropathy. DPP-4 inhibition is associated with mitigation of diabetic and hypertensive renal injury and protection of renal function. Renal glucose reabsorption by SGLT proteins is a critical component of glycemic regulation. SGLT2 protein expression is increased in human diabetic nephropathy even with advanced kidney disease indicating that SGLT2 can be an effective target in treatment of diabetic nephropathy. This review article discusses roles played by DPP-4 inhibitors and SGLT-2 inhibitors alone and in combination in diabetic nephropathy supported by clinical evidences. MEDLINE and EMBASE were searched through September 2022. Randomized controlled trials published in English that evaluated SGLT2 inhibitors and/or DPP4 inhibitors in patients with T2DM were selected. J MEDICINE 2023; 24: 43-49