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Aims: To assess the efficacy and safety of cofrogliptin for impaired glucose tolerance (IGT)., Methods: In this multicenter, double-blind, placebo-controlled phase 2 trial, IGT patients were randomized 1:1:1 to receive cofrogliptin 10 mg, cofrogliptin 25 mg or placebo once biweekly. The primary endpoint was the change from baseline in glucose total AUC 0-3 h during meal tolerance test (MTT) at week 12., Results: Among 261 subjects screened, 99 were enrolled. At week 12, significant mean reductions from baseline in glucose total AUC 0-3 h during MTT were observed in cofrogliptin groups (10 mg: -1.75 mmol h/L, p = 0.01; 25 mg: -1.54 mmol h/L, p = 0.02) versus placebo (0.36 mmol h/L). Significant benefits were also seen with cofrogliptin for secondary endpoints of the change from baseline in C max of glucose during MTT 0-3 h at week 12, and the change from baseline in glucose total AUC 0-3 h and C max of glucose during OGTT 0-3 h at week 10 versus placebo. Additionally, more cofrogliptin-treated patients achieved normoglycaemia versus placebo at week 10. The incidence of AEs was generally comparable in all groups, and all of AEs were mild or moderate. No serious AEs or severe hypoglycaemia were reported., Conclusion: A 12-week treatment with cofrogliptin provided significant glucose-lowering, and was safe, well tolerated., (© 2024 John Wiley & Sons Ltd.)

Background: This study compared the risks of atherothrombotic major adverse cardiovascular events in patients with type 2 diabetes taking SGLT2 (sodium-glucose cotransporter 2) inhibitors to those taking DPP-4 (dipeptidyl peptidase-4) inhibitors., Methods and Results: All adult patients (≥18 years of age) with type 2 diabetes and newly prescribed with SGLT2 inhibitors or DPP-4 inhibitors across all public hospitals in Hong Kong between January 2015 and December 2019 were included. Patients were propensity matched in a 1:1 ratio using a caliper distance of 0.2 without replacement. The primary outcome was atherothrombotic major adverse cardiovascular events as a composite outcome of cardiovascular mortality, nonfatal stroke, and nonfatal myocardial infarction. Time-to-first event analysis was conducted using a univariable Cox proportional hazards model. Primary and secondary analyses were repeated using stabilized inverse probability weighting and propensity score adjustment in the complete case cohort. A total of 20 642 patients (10 321 SGLT2 inhibitors versus 10 321 DPP-4 inhibitors) were included in the final analysis. The mean age was 59±11 years, and 13 142 (63.7%) were men. The median follow-up period was 2.9 years. The use of SGLT2 inhibitors was associated with a significant reduction in atherothrombotic major adverse cardiovascular events (453 [4.4%] versus 719 [7.0%]; hazard ratio, 0.64 [95% CI, 0.57-0.72]; P <0.001) compared with DPP-4 inhibitors. SGLT2 inhibitors were independently associated with reduced all-cause mortality, cardiovascular mortality, stroke, myocardial infarction, and incident dialysis (all P values <0.001)., Conclusions: SGLT2 inhibitors in patients with diabetes were independently associated with reduction in atherothrombotic major adverse cardiovascular events, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and incident dialysis, compared with DPP-4 inhibitors.

Aim: To compare cardiorenal outcomes of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose co-transporter-2 inhibitors (SGLT-2is) in a national diabetic kidney disease (DKD) population., Methods: A cohort study was conducted using Taiwan's National Health Insurance Research Database and Laboratory Databases. Propensity score-matched prevalent new users of SGLT-2is (n = 1524) and DPP-4is (n = 6005) during 2017-2018 were selected from adults with DKD and an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m 2 . Composite renal outcomes included sustained eGFR decrease, renal failure and renal mortality. Composite cardiovascular (CV) outcomes included acute myocardial infarction, stroke, hospitalization for heart failure and CV death. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: Compared with DPP-4i users, SGLT-2i users had a reduced risk of composite renal endpoint (HR: 0.16; CI: 0.12-0.24), consistently for a prolonged time to 50% or higher eGFR decrease (HR 0.17; CI: 0.11-0.27), renal failure (HR: 0.14; CI: 0.08-0.23) and decreased renal death (HR: 0.10; CI: 0.01-0.70). SGLT-2i users had a better composite CV outcome than DPP-4i users (HR: 0.74; CI: 0.64-0.85), and lower risks of stroke (HR: 0.76; CI: 0.62-0.92) and hospitalization for heart failure (HR: 0.68; CI: 0.55-0.84). Findings were consistent in analyses stratified by concomitant antidiabetic agents or intervals between DKD diagnosis and study drug initiation., Conclusions: This study shows the superior cardiorenal benefits of SGLT-2is compared with DPP-4is in the DKD population, regardless of concomitant antidiabetic agents or time from DKD onset to study drug initiation. SGLT-2is should be prioritized in adult patients with DKD., (© 2024 John Wiley & Sons Ltd.)

Aim: We conducted a multicentre, randomized phase 3 trial in China to evaluate the efficacy and safety of cofrogliptin (HSK7653), a novel long-acting dipeptidyl peptidase-4 inhibitor, in patients with drug-naïve type 2 diabetes (T2D)., Materials and Methods: Patients with inadequately controlled T2D were randomly assigned (1:1:1) to cofrogliptin 10 mg, cofrogliptin 25 mg or placebo, taken orally once every 2 weeks for a 24-week double-blind period. Eligible patients then received cofrogliptin 25 mg in a 28-week open-label extension. The primary endpoint was the change in glycated haemoglobin (HbA 1c ) from baseline to week 24., Results: In total, 475 patients (median age: 54.0 years) were randomized and received at least one dose of cofrogliptin 10 mg (n = 158), cofrogliptin 25 mg (n = 158) or placebo (n = 159); 401 patients entered the open-label extension. At week 24, the least-squares (LS) mean difference (95% confidence interval [CI]) in HbA 1c versus placebo was -0.63% (-0.81, -0.46) with cofrogliptin 10 mg and -0.59% (-0.77, -0.42) with cofrogliptin 25 mg (both p < 0.0001). The LS mean (standard error) change in HbA 1c from baseline was maintained at the end of the study in patients given open-label cofrogliptin 25 mg for an additional 28 weeks: cofrogliptin 10 mg: -0.86% (0.07); cofrogliptin 25 mg: -0.74% (0.07); placebo: -0.89% (0.07). Over the entire study, common adverse events were hyperuricaemia, hyperlipidaemia, hypertriglyceridaemia, increased lipase, upper respiratory tract infection and urinary tract infection. Hypoglycaemic events did not significantly differ between groups., Conclusions: Cofrogliptin provided glycaemic control over 52 weeks and was generally well tolerated in patients with T2D., Clinical Trial Registration: Registered on Clinicaltrials.gov with the registration number NCT04556851 (https://clinicaltrials.gov/study/NCT04556851)., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: The aim of this study was to examine contemporary trends in the use of, time to, and type of first add-on anti-hyperglycaemic therapy to metformin in Australia., Methods: We used the dispensing records of a 10% random sample of Pharmaceutical Benefits Scheme (PBS) eligible people. We included people aged 40 years and older initiating metformin from 1 January 2018 to 31 December 2020. Our primary outcome was first add-on anti-hyperglycaemic medicine within 2 years of metformin initiation. We analysed time to dispensing of first add-on therapy. All analyses were stratified by metformin initiation year., Results: Overall, 38 747 people aged 40 years and older initiated metformin between 2018 and 2020. Approximately one-third (n = 12 946) of people received add-on therapy with the proportion increasing slightly by year of metformin initiation (32.3% in 2018 to 34.8% in 2020). Amongst people with add-on therapy following metformin initiation, sodium-glucose cotransporter 2 inhibitor (SGLT2i) use increased from 28.8% (2018) to 35.0% (2020), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) increased from 3.0% to 9.6%, respectively. Dipeptidyl peptidase-4 inhibitors and sulfonylureas as first add-on therapy decreased and insulin remained stable. One-third of people with add-on therapy initiated the therapy on the same day metformin was initiated, i.e. initial combination therapy., Conclusions: Amongst people initiating metformin from 2018 to 2020, there was an increasing proportion of SGLT2i and GLP-1 RA being used as first add-on therapy. However, the overall prevalence of add-on therapy was low. Advocacy to promote add-on therapy with cardiorenal beneficial medicines is critical to reduce type 2 diabetes morbidity and mortality., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aim: Many patients with type 1 diabetes mellitus (T1DM) met the histological criteria for non-alcoholic steatohepatitis (NASH), which leads to cardiovascular disease morbidity and mortality. Matrix metalloproteinase-14 (MMP-14) is involved in cardiovascular disease and atherosclerosis., Objectives: To assess the impact of oral dipeptidyl peptidase-4 inhibitor, vildagliptin, as adjunctive therapy on NASH in adolescents with T1DM and its effect on glycaemic control, MMP-14 levels and carotid intima media thickness (CIMT)., Methods: Sixty adolescents with T1DM and NASH were randomly assigned to receive oral vildagliptin (50 mg once daily) for 6 months or not. Glycated haemoglobin, lipid profile, hepatic steatosis index, triglyceride glucose (TyG) index and MMP-14 levels were assessed. Transient elastography with controlled attenuation parameter (CAP) was performed together with measuring CIMT., Results: By transient elastography, 12 (20%) patients with T1DM with NASH had elevated liver stiffness ≥7 kPa (F2 stage or higher). Baseline MMP-14 was positively correlated to insulin dose (p = 0.016), triglycerides and TyG index, CIMT, liver stiffness and CAP levels among the studied patients (p < 0.001 for all). After 6 months, patients with T1DM on vildagliptin therapy had significantly lower glycated haemoglobin, lipid profile, hepatic steatosis index and TyG index, as well as MMP-14 (p < 0.001). CIMT, liver stiffness and CAP were significantly decreased post-therapy compared with baseline levels and compared with the control group (p < 0.001). Vildagliptin was safe and well-tolerated., Conclusions: Administration of vildagliptin for adolescents with T1DM and NASH improved glycaemic control, dyslipidaemia and MMP-14 levels and decreased liver stiffness and CIMT; hence, reducing subclinical atherosclerosis and disease progression., (© 2024 John Wiley & Sons Ltd.)

Importance: Diabetes increases the risk of Parkinson disease (PD). Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new glucose-lowering therapeutic class, have shown neuroprotective effects in mechanistic studies. However, the association between SGLT2 inhibitors and PD risk in real-world populations with type 2 diabetes (T2D) remains unclear., Objective: The aim was to assess the association between SGLT2 inhibitors and the risk of PD in older populations with T2D., Design, Setting and Participants: This retrospective cohort analysis used Medicare claims data from 2016 to 2020 to identify fee-for-service beneficiaries ≥65 years diagnosed with T2D and without pre-existing PD., Exposures: The initiation of an SGLT2 inhibitor was compared with that of a dipeptidyl peptidase-4 (DPP4) inhibitor., Main Outcomes and Measures: The outcome was the first incident PD ever since the date initiating either an SGLT2 inhibitor or a DPP4 inhibitor. We employed a 1:1 propensity score matching to balance the baseline covariates between treatment groups, including sociodemographics, comorbidities and co-medications. We applied Cox regression models to assess the effect of SGLT2 inhibitors versus DPP4 inhibitors on incident PD., Results: Of 89 330 eligible Medicare beneficiaries (mean age: 75 ± 7 years, 52% women), 0.6% (n = 537) had incident PD over the follow-up. After 1:1 propensity matching, the PD incidence was 2.5 and 3.5 events per 1000 person-years in the SGLT2 inhibitor group and DPP4 inhibitor group, respectively. The SGLT2 inhibitor group was associated with a significantly lower risk of incident PD than the DPP4 inhibitor group (hazard ratio: 0.70 [95% confidence interval: 0.55-0.89]). There is a potential trend that the risk reduction in incident PD was profound in non-Hispanic Black individuals and insulin users., Conclusion and Relevance: Compared to DPP4 inhibitors, SGLT2 inhibitors were associated with a significantly lower risk of incident PD in older populations with T2D., (© 2024 John Wiley & Sons Ltd.)

Aim: To comprehensively evaluate the benefits and risks of glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), and sodium-glucose cotransporter 2 inhibitors (SGLT2i)., Materials and Methods: A systematic search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to November 2023 to identify randomized cardiovascular and kidney outcome trials that enrolled adults with type 2 diabetes, heart failure, or chronic kidney disease and compared DPP4i, GLP-1RAs, or SGLT2i to placebo. Twenty-one outcomes (e.g., major adverse cardiovascular events [MACE], stroke, and hospitalization for heart failure [HHF]) were assessed. Data were pooled using population-averaged odds ratios (ORs) with 95% CIs., Results: Twenty-six trials enrolling 198 177 participants were included. GLP-1RAs were most effective in lowering the risks of MACE (OR, 0.85, [95% CI, 0.79 to 0.92]) and stroke (0.84 [0.77, 0.91]), but increased the risk of thyroid cancer (1.58 [1.36, 2.50]). SGLT2i showed the greatest benefits in reducing the risk of HHF (0.68 [0.64, 0.73]) and improving composite renal outcomes (0.67 [0.58, 0.77]), but increased the risk of genital infections (3.11 [2.15, 4.50]). DPP4i were associated with a lower risk of certain psychiatric disorders, Parkinson's disease (0.54 [0.32, 0.92]), and amputation (0.70 [0.86, 0.93]), but an increased risk of neuropathy (1.10 [1.02, 1.18]) and pancreatitis (1.63 [1.40, 1.91]). The weighted origami plot suggested that GLP-1RAs were more suitable for reducing macrovascular and microvascular outcomes, while DPP4i might be better for neurodegenerative diseases and cancer concerns., Conclusions: Given the distinct benefit-risk profiles, the selection of glucose-lowering drugs should be individualized based on patient characteristics and risk factors., (© 2024 John Wiley & Sons Ltd.)

Aims: To compare the efficacy of adding imeglimin versus that of metformin dose escalation on glycemic control in subjects with type 2 diabetes treated with a dipeptidyl peptidase-4 inhibitor plus low-dose metformin (500-1000 mg/day)., Materials and Methods: In this multicentre, open-labelled, prospective, randomized, parallel-group comparison study, the addition of imeglimin (2000 mg/day) or metformin escalation was applied for 24 weeks in eligible subjects. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) over 24 weeks. As the secondary endpoints, the occurrence of adverse events, changes in metabolic parameters, biomarkers and factors associated with HbA1c improvement were analysed., Results: Seventy-three eligible subjects were enrolled. Of them, 65 participants comprised the full analysis set. At 24 weeks, the addition of imeglimin (n = 33) resulted in greater improvement in HbA1c compared with metformin dose escalation (n = 32) (from 7.61 ± 0.48% to 6.93 ± 0.49% in imeglimin and from 7.56 ± 0.61% to 7.09 ± 0.56% in metformin escalation; change difference: -0.21% [95% confidence interval: -0.41%, -0.01%] [p = 0.038]); however, seven subjects in the imeglimin group discontinued imeglimin because of serious adverse events on gastrointestinal tract. In intra-group pre/post comparisons, imeglimin treatment significantly reduced body weight and improved liver enzyme elevation. There was a significant correlation between improvement levels of HbA1c and indicators of fatty liver disease in the imeglimin group., Conclusions: Imeglimin in combination with a dipeptidyl peptidase-4 inhibitor and low-dose metformin improved HbA1c compared with metformin dose escalation., (© 2024 John Wiley & Sons Ltd.)

Aims: To assess outcomes of oral anti-hyperglycaemic therapies in people with diabetes secondary to a pancreatic condition (type 3c), where specific treatment guidance is limited., Materials and Methods: Using hospital-linked UK primary care records (Clinical Practice Research Datalink; 2004-2020), we identified 7084 people with a pancreatic condition (acute pancreatitis, chronic pancreatitis, pancreatic cancer and haemochromatosis) preceding diabetes diagnosis (type 3c cohort), initiating oral glucose-lowering therapy (metformin, sulphonylureas, SGLT2-inhibitors, DPP4-inhibitors or thiazolidinediones), and without concurrent insulin treatment. We stratified by pancreatic exocrine insufficiency [PEI] (n = 5917 without PEI, 1167 with PEI) and matched to 97 227 type 2 diabetes (T2D) controls. 12-month HbA1c response and weight change and 6-month treatment discontinuation were compared in type 3c versus T2D., Results: People with type 3c diabetes had substantial mean HbA1c reduction with oral therapies in those without PEI (12.2 [95%CI 12.0-12.4] mmol/mol) and with PEI (9.4 [8.9-10.0] mmol/mol). Compared to T2D controls, people with type 3c without PEI had similar mean HbA1c reduction (0.7 [0.4-1.0] mmol/mol difference) and odds of discontinuation (Odds ratio [OR] 1.08 [0.98-1.19]). In contrast, people with type 3c and PEI had lower mean HbA1c response (3.5 [2.9-4.1] mmol/mol lesser reduction) and greater discontinuation (OR 2.03 [1.73-2.36]) versus T2D controls. Weight change in type 3c was similar to T2D. Results were largely consistent across underlying pancreatic conditions and drug classes., Conclusions: Oral anti-hyperglycaemic therapies are effective in people with type 3c diabetes and could provide an important component of glycaemic management. PEI could identify people with type 3c requiring closer monitoring of treatment response., (© 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: We have compiled updated evidence on the benefits and drawbacks of dipeptidyl peptidase-4 (DPP-4) inhibitors in treating type 2 diabetes mellitus., Materials and Methods: We systematically searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov (as of 20 May 2024). Effect estimates were calculated using network meta-analysis under the frequentist framework. The P-score established the ranking of competing treatments., Results: The authors incorporated 58 studies containing data from a substantial sample size of 21 332 patients. Based on evidence of high and moderate certainty, respectively, teneligliptin and vildagliptin were found to be superior to all other DPP-4 inhibitors in lowering haemoglobin A1c (mean difference [MD] -0.81%, 95% CI -1.03, -0.60) and fasting blood glucose (MD -1.18 mmol/L, 95% CI -1.56, -0.81) compared to placebo. The absence of conclusive differences between interventions for serious adverse events was supported by evidence, which was interpreted with low to very low certainty., Conclusions: In adults with type 2 diabetes, teneligliptin was most effective for HbA1c control, and vildagliptin for fasting blood glucose. No significant differences in serious adverse events were noted among DPP-4 inhibitors compared to placebo. Given the therapeutic significance of these findings, more studies are needed to explore this issue more thoroughly., (© 2024 John Wiley & Sons Ltd.)

Aim: To compare the effectiveness of sodium-glucose co-transporter-2 inhibitors (SGLT2is) with dipeptidyl peptidase-4 inhibitors (DPP4is) on major liver outcomes (MLO) in patients with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD)., Materials and Methods: We included adult patients with T2D and MASLD, using metformin without specific liver conditions or surgeries, from the Merative MarketScan database. Patients initiating SGLT2is or DPP4is from 1 January 2014 to 31 December 2022 were identified. The primary outcome was time to MLO diagnosis. Overlap weighting balanced covariates, integrated with a Cox proportional hazards model for survival analysis., Results: Among 44 651 patients, 22 100 initiated SGLT2is, and 22 551 began DPP4is. After weighting, the incidence rate of MLO in the SGLT2i group was 3.8 per 1000 person-years, and it was 3.9 per 1000 person-years in the DPP4i group, resulting in an adjusted hazard ratio (aHR) of 0.82 (95% CI, 0.60-1.10). SGLT2i initiation was not associated with cirrhosis (aHR: 0.77; 95% CI, 0.55-1.06) or hepatocellular carcinoma (aHR: 0.99; 95% CI, 0.47-1.83) separately. Subgroup and sensitivity analyses did not yield significant results., Conclusions: In patients with T2D and MASLD, SGLT2is did not show a lower risk of MLO compared with DPP4is. Clinicians should consider the overall patient conditions and the additional benefits of SGLT2is to support the decision to switch from DPP4is., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Limited evidence exists to support any specific medication over others to prevent dementia in older patients with type 2 diabetes (T2D). We investigated whether treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors is associated with a lower risk of incident dementia and all-cause mortality, relative to dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA)., Methods: In this retrospective, active-comparator cohort study, we used data from the TriNetX electronic health records network. Our primary cohort comprised patients with T2D aged ≥50 years, registered between January 2012 and December 2022. Patients with a history of dementia were excluded. We used Kaplan-Meier survival analysis to estimate the incidence of dementia and all-cause mortality in our cohort after they had used glucose-lowering drugs for at least 12 months. Propensity score matching was performed to balance the SGLT-2 inhibitor, DPP-4 inhibitor and GLP-1 RA cohorts. Subgroup analyses for sex and age were also conducted., Results: Our first cohort comprised 193 948 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and DPP-4 inhibitors. In this cohort, the risk of dementia and all-cause mortality was lower in patients treated with SGLT-2 inhibitors than in those treated with DPP-4 inhibitors (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.59-0.65, for dementia; HR: 0.54, 95% CI: 0.52-0.56, for all-cause mortality). Our second cohort comprised 165 566 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and GLP-1 RAs. In this cohort, the risk of dementia and all-cause mortality was lower in those treated with SGLT-2 inhibitors than in those treated with GLP-1 RAs (HR: 0.92, 95% CI: 0.87-0.98, for dementia; HR: 0.88, 95% CI: 0.85-0.91, for all-cause mortality)., Conclusions: The use of SGLT-2 inhibitor was associated with a lower risk of incident dementia and all-cause mortality in older adults with T2D compared to DPP-4 inhibitor and GLP-1 RA., (© 2024 John Wiley & Sons Ltd.)

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., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: We evaluated the efficacy and safety of cofrogliptin, a novel dipeptidyl peptidase-4 inhibitor taken once every 2 weeks (Q2W), compared with linagliptin (taken daily) in patients with type 2 diabetes inadequately controlled on metformin in China., Materials and Methods: In this phase 3 randomized, double-blind, active-controlled, multicentre study, patients were randomly assigned 1:1:1 to receive cofrogliptin 10 mg Q2W, cofrogliptin 25 mg Q2W, or linagliptin 5 mg daily, all as an add-on treatment to metformin, for 24 weeks. Eligible patients could enter an open-label extension period and receive cofrogliptin 25 mg Q2W for an additional 28 weeks. The primary endpoint was change in glycated haemoglobin from baseline to 24 weeks, with a non-inferiority margin of 0.4% for cofrogliptin versus linagliptin treatment., Results: Overall, 465 patients entered the 24-week treatment period (median age: 57.0 years). The least-squares mean (standard error) change in glycated haemoglobin from baseline to week 24 was -0.96 (0.063), -0.99 (0.064) and -1.07 (0.065) for the cofrogliptin 10 mg, cofrogliptin 25 mg and linagliptin 5 mg groups, respectively. The between-group difference met the predefined margin for non-inferiority of cofrogliptin (10 and 25 mg) versus linagliptin treatment. The incidence of common adverse events (≥5% patients) during the 24-week treatment period was similar between treatment groups. There were no serious hypoglycaemic events., Conclusion: In Chinese patients with type 2 diabetes inadequately controlled on metformin, the glucose-lowering effect of cofrogliptin (Q2W) was non-inferior to linagliptin (daily), with a similar safety profile maintained over 52 weeks of treatment., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objectives: To investigate the utilization and costs of non-insulin glucose-lowering drugs (GLDs) in Australia from 2013 to 2023., Materials and Methods: We conducted a retrospective analysis of the Australian Pharmaceutical Benefits Scheme (PBS) administrative dataset of 118 727 494 GLD prescriptions. The main outcome measures were the annual number of GLD prescriptions dispensed, accounting for type 2 diabetes mellitus (T2DM) prevalence and healthcare system costs, adjusted for inflation., Results: Utilization of GLDs doubled from 6.4 million prescriptions in 2013 to 15.6 million in 2023. The average annual percent increase in utilization was 8.1%, compared to the average annual increase in prevalence of T2DM of 1.8%. The biggest change was in sodium-glucose cotransporter-2 (SGLT2) inhibitors, for which there was an average annual increase in utilization of 59.4% (95% confidence interval [CI] 51.7%, 68.2%; p < 0.05) from 2014 (first full year of PBS listing), followed by glucagon-like peptide-1 receptor agonists (GLP-1RAs), which showed an increase of 31.4% (95% CI 28.5%, 33.8%; p < 0.05) annually (2013 to 2023). Dipeptidyl peptidase-4 inhibitor utilization tripled, with an average annual increase of 10.9% (95% CI 8.1%, 13.8%; p < 0.05), but this plateaued from 2020. Metformin utilization increased by 4.7% (95% CI 2.0%, 6.9%; p < 0.05) annually. In contrast, sulphonylurea, glitazone and acarbose utilization declined. Total GLD costs increased threefold over the same period. Despite only accounting for 11.7% of utilization, GLP-1RAs contributed to 35% of the costs., Conclusion: Utilization of GLDs doubled, and associated costs tripled over the past 11 years, with no sign of either utilization or costs plateauing, predominantly due to increased GLP-1RA and SGLT2 inhibitor prescribing., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objectives: To present the Real-World Progression In Diabetes (RAPIDS) 2.0 Risk Engine, the only simulation model to study the long-term trajectories of outcomes arising from dynamic sequences of glucose-lowering treatments in type 2 diabetes (T2DM)., Research Design and Methods: The RAPIDS model's risk equations were re-estimated using a Least Absolute Shrinkage and Selection Operator (LASSO)-based regularization of features that spanned baseline data from the last two quarters of current time and interactions with age. These equations were supplemented with estimates for the impact of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitor classes of drugs as monotherapies and their combinations with metformin based on newer trial data and comprehensive meta-analyses. The probabilistic RAPIDS 2.0 model was calibrated (N = 25 000) and validated (N = 263 816) using electronic medical records (EMR) data between 2008 and 2021 from a national network of US healthcare organizations., Results: The EMR-based cohort had a mean age of 61 years at baseline, with 50% women, 70% non-Hispanic White individuals and 20% non-Hispanic Black individuals, and was followed for 17.5 quarters (range: 3-50). The final RAPIDS 2.0 risk engine accurately predicted the long-term trajectories of all nine biomarkers and nine outcomes in the hold-out validation sample. Similar accuracies in predictions were observed in each of the 14 subgroups studied., Conclusion: The RAPIDS 2.0 model demonstrated valid long-term predictions of outcomes in individuals with T2DM in the United States as a function of dynamic sequences of treatment use patterns. This highlights its potential to project long-term comparative effectiveness between alternative sequences of glucose-lowering treatment uses in the United States., (© 2024 John Wiley & Sons Ltd.)

Aim: To analyse patterns of glucose-lowering therapies among people with type 2 diabetes (T2D) in Denmark from 2016 to 2023., Materials and Methods: We examined time trends in the clinical profiles of people with T2D who initiated different glucose-lowering therapy classes for the first time. We furthermore investigated individual-level treatment trajectories following first-ever glucose-lowering therapy in people with or without cardiorenal disease. The study utilized data from the nationwide Danish health registries and included all individuals who filled a first-ever prescription for metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium-glucose co-transporter-2 inhibitors (SGLT-2is) or insulin, excluding those without HbA1c-confirmed T2D or probable type 1 diabetes., Results: We included 260 393 individuals initiating a new glucose-lowering therapy class from 2016 to 2023, during which there were 6- and 3-fold increases in initiators of GLP-1RAs and SGLT-2is, respectively. The median HbA1c level at treatment initiation with GLP-1RAs or SGLT-2is decreased, from 67-68 mmol/mol in 2016-2017 to 57-58 mmol/mol in 2022-2023. Among individuals who initiated metformin as first-line therapy, the proportion who started additional glucose-lowering therapy within 2 years increased from 25% in 2016 to 40% in 2021. Among the 38% of individuals who had established cardiorenal disease when they initiated first-ever glucose-lowering therapy in 2020, 22% used SGLT-2is and 18% GLP-1RAs after 2.5 years, compared with 17% and 21% among initiators without cardiorenal disease, respectively., Conclusions: Our study documents a trend towards earlier T2D treatment intensification and an increase in the use of GLP-1RAs and SGLT-2is in Denmark. However, optimal T2D treatment is still not received by most individuals with early T2D and established cardiorenal disease., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: Recently, the development of the oral glucagon-like peptide-1 receptor agonist semaglutide has drawn a great deal of attention. This study aimed to compare the effectiveness of oral glucagon-like peptide-1 receptor agonist semaglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors on glycaemic control and several metabolic parameters in patients with type 2 diabetes mellitus over a 6-month period., Methods: Fifty-nine participants were included, and we compared various clinical parameters between before and after switching from DPP-4 inhibitors to oral semaglutide in 'study 1' (pre-post comparison) and set the control group using the propensity score matching method in 'study 2'., Results: In 'study 1', 6 months after the switching, the glycated haemoglobin value was significantly reduced from 7.5% to 7.0%, and the body mass index was also decreased from 29.7 kg/m 2 to 28.8 kg/m 2 . Such effects were more clearly observed in participants whose glycaemic control was poor. In 'study 2', after 1:1 propensity score matching, 51 participants from each group were matched, and glycaemic control as well as body weight management were improved in the switching group compared with the DPP-4 inhibitor continuation group over the 6-month observation period., Conclusion: In this study, including obese participants with poor glycaemic control, switching DPP-4 inhibitors to oral semaglutide showed more beneficial effects on both glycaemic and weight control, irrespective of age, body weight and diabetes duration. Therefore, we should bear in mind that it would be better to start using an oral semaglutide in clinical practice, particularly in obese participants with poor glycaemic control with DPP-4 inhibitors., (© 2024 John Wiley & Sons Ltd.)

Aim: To evaluate the renal prognosis of dipeptidyl peptidase-4 inhibitor (DPP-4i) users and non-users using real-world Asian data., Methods: Using databases from DeSC Healthcare, Inc., patients aged 30 years or older who used antidiabetic drugs from 2014 to 2021 were identified. Propensity score matching analyses were used to compare renal prognosis between DPP-4i users and non-users. The primary outcomes were estimated glomerular filtration rate (eGFR) decline and end-stage kidney disease (ESKD) development in the eGFR of 45 mL/min/1.73m 2 or higher and eGFR of less than 45 mL/min/1.73m 2 groups, respectively., Results: In total, 65 375 and 9866 patients were identified in the eGFR of 45 mL/min/1.73m 2 or higher and eGFR of less than 45 mL/min/1.73m 2 groups, respectively. In the eGFR of 45 mL/min/1.73m 2 or higher group, propensity score matching created 16 002 pairs. A significant difference was observed in the primary outcome of eGFR decline between DPP-4i users and non-users at 2 years (-2.31 vs. -2.56 mL/min/1.73m 2 : difference, 0.25 mL/min/1.73m 2 ; 95% confidence interval [CI], 0.06-0.44) and 3 years (-2.75 vs. -3.41 mL/min/1.73m 2 : difference, 0.66 mL/min/1.73m 2 ; 95% CI, 0.39-0.93). In the eGFR less than 45 mL/min/1.73m 2 group, propensity score matching created 2086 pairs. After a mean of 2.2 years of observation, ESKD development was 1.15% and 2.30% in users and non-users, respectively, and Kaplan-Meier analysis revealed a significant difference (log rank P = .005)., Conclusions: This retrospective real-world study revealed that patients using DPP-4is had a better renal prognosis than those not using DPP-4is., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To investigate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors in liver transplant (LT) recipients with diabetes., Methods: A single-centre, retrospective analysis of prospectively collected data from an LT recipient database (1990-2023) was conducted. We included adults with pre-existing diabetes and post-transplant diabetes, newly started on GLP-1RAs and/or SGLT2 inhibitors after LT. Metabolic and biochemical parameters and outcomes were collected for up to 12 months after starting medications and were compared to those in patients receiving dipeptidyl peptidase-4 (DPP-4) inhibitors. Statistical analysis included descriptive statistics and linear mixed models., Results: We included participants on GLP-1RAs (n = 46), SGLT2 inhibitors (n = 87), combination therapy (n = 12), and a DPP-4 inhibitor comparator (n = 217). Both GLP-1RAs and combination therapy decreased mean glycated haemoglobin (HbA1c) levels, and combination therapy remained significant when adjusted for DPP-4 inhibitor treatment (-3.5%, 95% CI [-6.1, -0.95]; p = 0.0089) at 12 months. All three groups had significant decreases in mean weight and body mass index, but these remained significant in the GLP-1RA (-5.2 kg, 95% CI [-8.7, -1.7], p = 0.0039 and 1.99 kg/m 2 , 95% CI [-3.4, -0.6], p = 0.0048) and combination therapy groups (-5.4 kg, 95% CI [-10.5, -0.36], p = 0.04 and -3.4 kg/m 2 , 95% CI [-5.5, -1.3], p = 0.0015) when adjusted for DPP-4 inhibitor treatment at 12 months. Alanine aminotransferase levels decreased with GLP-1RA and combination therapy. There were two (1.4%) cases of graft rejection., Conclusion: We found that GLP-1RAs, SGLT2 inhibitors, and their combination, led to significant weight loss in LT recipients with diabetes. Combination therapy, in particular, lowered HbA1c and alanine aminotransferase levels compared to DPP-4 inhibitors. Further studies are needed to assess long-term safety and efficacy., (© 2024 John Wiley & Sons Ltd.)

Aim: To investigate the effect of dipeptidyl peptidase-4 inhibitors (DPP4-Is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) on diabetic foot ulcer (DFU) and DFU-related outcomes (lower limb amputation [LLA], DFU-related hospitalization and mortality)., Methods: We performed a cohort study with data from the Clinical Practice Research Datalink Aurum database with linkage to hospital data. We included people with type 2 diabetes starting treatment with metformin. Then we propensity score matched new users of DPP4-Is and sulphonylureas (N = 98 770), and new users of GLP1-RAs and insulin (N = 25 422). Cox proportional hazards models estimated the hazard ratios (HRs) for the outcomes., Results: We observed a lower risk of DFU with both DPP4-I use versus sulphonylurea use (HR 0.88, 95% confidence interval [CI]: 0.79-0.97) and GLP1-RA use versus insulin use (HR 0.44, 95% CI: 0.32-0.60) for short-term exposure (≤ 400 days) and HR 0.74 (95% CI: 0.60-0.92) for long-term exposure (>400 days). Furthermore, the risks of hospitalization and mortality were lower with both DPP4-I use and GLP1-RA use. The risk of LLA was lower with GLP1-RA use. The results remained consistent across several sensitivity analyses., Conclusions: Incretin-based therapy was associated with a lower risk of DFU and DFU-related outcomes. This suggests benefits for the use of this treatment in people at risk of DFU., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To date, there are limited clinical studies and real-world evidence investigating whether sodium-glucose cotransporter-2 inhibitors (SGLT2i) are associated with improved hepatic steatosis. This study aimed to evaluate the effectiveness of SGLT2i compared with that of dipeptidyl peptidase-4 inhibitors (DPP4i) in improving the fatty liver index (FLI) in patients with type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD)., Materials and Methods: This retrospective cohort study included new users of SGLT2i or DPP4i with T2DM and MASLD from a large claims database (JMDC Claims Database). The primary outcome was the incidence of improvement of the FLI. Cox proportional hazard models, weighted using propensity scores for predicting the initiation of treatment, were fitted to estimate hazard ratios with 95% confidence intervals (CIs). Time-course changes in the FLI values were also assessed., Results: This study included 9127 SGLT2i and 12 286 DPP4i initiators. SGLT2i showed a higher incidence of improvement in the FLI (≥30%, ≥40% and ≥50% reduction from baseline FLI) compared with DPP4i, and the weighted hazard ratios were 1.27 (95% CI 1.18-1.38), 1.24 (95% CI 1.13-1.37) and 1.19 (95% CI 1.05-1.33), respectively. SGLT2i indicated a greater decreased in FLI values compared with DPP4i at up to 3 years of the follow-up period., Conclusion: SGLT2is use appeared to be associated with a greater improvement of the FLI than DPP4i use in patients with T2DM and MASLD. In the absence of direct head-to-head comparisons from clinical studies, our study, using real-world data, may support physicians' decision-making in clinical practice., (© 2024 John Wiley & Sons Ltd.)

Aim: Therapeutic inertia, hypoglycaemia and poor treatment persistence can lead to glycaemic fluctuation and poor outcomes in type 2 diabetes (T2D). We compared glycated haemoglobin (HbA1c) variability, insulin initiation, severe hypoglycaemia and clinical events in patients with T2D initiated dipeptidyl peptidase-4 inhibitors (DPP4is) at low versus high HbA1c thresholds., Methods: Using territory-wide electronic medical records in Hong Kong, we curated a propensity score-matched cohort of patients initiated DPP4i at HbA1c <7.5% versus ≥7.5% in 2007-2019. We expressed the HbA1c variability score (HVS) as a proportion of HbA1c varied by ≥0.5% compared with preceding values. We used the Cox model to compare the risks of insulin initiation and clinical outcomes, adjusted for time-varying variables between the two groups. Mediation analysis estimated the effects of HbA1c variability on outcomes., Results: Among 6874 insulin-naïve patients who initiated DPP4i, 88.7% were treated with metformin and 79.6% with sulphonylureas at baseline (54.9% men; mean age 65.2 ± 11.4 years). After a median follow-up of 4.6 years, compared with the high-threshold plus high-HVS group (≥50%), the low-threshold plus low-HVS (<50%) group had reduced hazard ratios (95% confidence interval) of insulin initiation (0.35, 0.31-0.40), severe hypoglycaemia (0.38, 0.34-0.44), major adverse cardiovascular endpoints (0.76, 0.66-0.88), heart failure (0.42, 0.36-0.49), end-stage kidney disease (0.65, 0.36-0.49) and mortality (0.45, 0.35-0.57). Reduced HbA1c variability explained 31.1%-81.2% of the effect size of DPP4i initiation at HbA1c <7.5% versus ≥7.5% on outcomes., Conclusions: In Chinese patients with T2D, avoiding therapeutic inertia with intensified glycaemic control at HbA1c <7.5% using drugs with low risk of hypoglycaemia and good tolerability, such as DPP4i, delayed insulin treatment, reduced HbA1c variability and improved clinical events., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To evaluate the effects of initiating sodium-glucose cotransporter-2 (SGLT2) inhibitors on cardiorenal outcomes and mortality compared to dipeptidyl peptidase-4 (DPP-4) inhibitors as active comparators in patients diagnosed with type 2 diabetes with a history of percutaneous coronary intervention (PCI)., Materials and Methods: We used an active-comparator, new-user design and nationwide data from the National Health Insurance Service in South Korea from 2014 to 2019. Of the 56 392 patients who underwent PCI, 4610 new SGLT2 inhibitor users were paired 1:1 with DPP-4 inhibitor users for analysis using propensity-score matching., Results: During 13 708.59 person-years of follow-up, the initiation of SGLT2 inhibitors, compared with the initiation of DPP-4 inhibitors, was associated with a significantly lower risk of composite repeat revascularization, myocardial infarction, stroke, heart failure (HF), all-cause death and end-stage renal disease (ESRD). The beneficial effects of SGLT2 inhibitor use were consistent with the components of stroke, HF, all-cause death and ESRD. In the cohort that included health examination data, including anthropometric and metabolic factors, new use of SGLT2 inhibitors was associated with a significantly lower risk of HF (hazard ratio [HR] 0.574, 95% confidence interval [CI] 0.36-0.915), all-cause death (HR 0.731, 95% CI 0.567-0.942), and ESRD (HR 0.076, 95% CI 0.018-0.319). The effects of SGLT2 inhibitor use were consistent regardless of the timing of the previous PCI., Conclusions: The initiation of SGLT2 inhibitors in patients with type 2 diabetes and a history of PCI was significantly associated with a reduced risk of cardiorenal consequences and mortality, irrespective of time since the last PCI., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To evaluate the efficacy and safety of retagliptin in Chinese patients with type 2 diabetes (T2D) inadequately controlled with metformin., Materials and Methods: This multicentre, phase 3 trial consisted of a 16-week, randomized, double-blind, placebo-controlled period, where patients with HbA1c levels between 7.5% and 11.0% were randomized to receive either once-daily (QD) retagliptin 100 mg (n = 87) or placebo (n = 87), both as an add-on to metformin. The primary endpoint was the change in HbA1c from baseline to week 16., Results: At week 16, the least squares mean change in HbA1c from baseline, compared with placebo, was -0.82% (95% CI, -1.05% to -0.58%) for the retagliptin 100 mg QD group (P < .0001) per treatment policy estimand. Significantly higher proportions of patients in the retagliptin 100 mg QD group achieved HbA1c levels of less than 6.5% (11.5%) and less than 7.0% (26.4%) compared with those receiving placebo (0% and 4.6%; P = .0016 and P < .0001, respectively) at week 16. Retagliptin 100 mg QD also lowered fasting plasma glucose and 2-hour postprandial plasma glucose levels. The incidence of adverse events (AEs) during the treatment period was similar between the two groups. However, slightly higher proportions of increased lipase and increased amylase in the retagliptin 100 mg QD group were observed. No patients discontinued treatment permanently because of AEs, and no episodes of severe hypoglycaemia were reported., Conclusions: Retagliptin 100 mg QD as an add-on therapy to metformin offers a new therapeutic option for treating Chinese patients with T2D inadequately controlled by metformin alone, and is generally well tolerated., (© 2024 John Wiley & Sons Ltd.)

Senescent cells increase in many tissues with age and induce age-related pathologies, including osteoarthritis (OA). Senescent chondrocytes (SnCs) are found in OA cartilage, and the clearance of those chondrocytes prevents OA progression. However, targeting SnCs is challenging due to the absence of a senescent chondrocyte-specific marker. Therefore, we used flow cytometry to screen and select senescent chondrocyte surface markers and cross-validated with published transcriptomic data. Chondrocytes expressing dipeptidyl peptidase-4 (DPP-4), the selected senescent chondrocyte-specific marker, had multiple senescence phenotypes, such as increased senescence-associated-galactosidase, p16, p21, and senescence-associated secretory phenotype expression, and showed OA chondrocyte phenotypes. To examine the effects of DPP-4 inhibition on DPP-4+ SnCs, sitagliptin, a DPP-4 inhibitor, was treated in vitro. As a result, DPP-4 inhibition selectively eliminates DPP-4+ SnCs without affecting DPP-4- chondrocytes. To assess in vivo therapeutic efficacy of targeting DPP-4+ SnCs, three known senolytics (ABT263, 17DMAG, and metformin) and sitagliptin were comparatively verified in a DMM-induced rat OA model. Sitagliptin treatment specifically and effectively eliminated DPP-4+ SnCs, compared to the other three senolytics. Furthermore, Intra-articular sitagliptin injection to the rat OA model increased collagen type II and proteoglycan expression and physical functions and decreased cartilage destruction, subchondral bone plate thickness and MMP13 expression, leading to the amelioration of OA phenotypes. Collectively, OARSI score was lowest in the sitagliptin treatment group. Taken together, we verified DPP-4 as a surface marker for SnCs and suggested that the selective targeting of DPP-4+ chondrocytes could be a promising strategy to prevent OA progression., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Aim: To assess the use of non-insulin antidiabetic medicines in China., Materials and Methods: We analysed the national procurement data for 29 non-insulin antidiabetic medicines from nine subgroups in China from 2015 to 2022. We estimated the number of defined daily doses (DDDs) procured per year in seven regions of China for nine subgroups and adjusted the data by the number of patients with diabetes. For each subgroup, the regional ratio was calculated by comparing the procurement per patient in each region with the procurement nationwide. The regional disparity was the difference between the highest and lowest regional ratios. We compared the medication patterns across regions., Results: Nationally, between 2015 and 2022, the number of DDDs per patient increased from 14.45 to 47.37. The two most commonly used categories were sulphonylurea and biguanides, which increased from 7.04 to 15.39 (119%) and 3.28 to 11.11 (239%) DDDs per patient, respectively. The procurement of new drugs (dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter type 2 inhibitors and glucagon-like peptide-1 receptor agonists) increased quickly and had >5000% relative changes. Particularly for sodium-glucose cotransporter type 2 inhibitors, it increased from 0.08 to 5.03 DDDs (6662%). The southwest region had the highest relative change (319%), while the southern region had the lowest (118%). Biguanide and thiazolidinediones had the lowest (1.19) and highest level (2.21) of regional disparity in 2022, respectively., Conclusion: The procurement of non-insulin antidiabetic medicines in China has increased a lot from 2015 to 2022. In terms of DDDs per patient, sulphonylurea ranked first, followed by metformin. The procurement of new drugs increased greatly. A large regional disparity existed in medicine usage and patterns., (© 2024 John Wiley & Sons Ltd.)

Aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors suppress the inactivation of incretin hormones and lower blood glucose levels by inhibiting DPP-4 function. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels in an insulin-independent manner by inhibiting renal reabsorption of glucose. DPP-4 and SGLT2 inhibitors each have the potential to improve hepatic steatosis; however, their combined effects remain unclear. In this study, we examined the effects of the combination of these drugs on hepatic steatosis using high-fat diet-fed mice., Method: C57BL/6J male mice were fed a 60% high-fat diet for 2 months to induce hepatic steatosis. Mice were divided into four groups (control; DPP-4 inhibitor anagliptin; SGLT2 inhibitor luseogliflozin; anagliptin and luseogliflozin combination), and the effects of each drug and their combination on hepatic steatosis after a 4-week intervention were evaluated., Results: There were no differences in blood glucose levels among the four groups. Anagliptin suppresses inflammation- and chemokine-related gene expression. It also improved macrophage fractionation in the liver. Luseogliflozin reduced body weight, hepatic gluconeogenesis and blood glucose levels in the oral glucose tolerance test. The combination treatment improved hepatic steatosis without interfering with the effects of anagliptin and luseogliflozin, respectively, and fat content and inflammatory gene expression in the liver were significantly improved in the combination group compared with the other groups., Conclusion: The combination therapy with the DPP-4 inhibitor anagliptin and the SGLT2 inhibitor luseogliflozin inhibits fat deposition in the liver via anti-inflammatory effects during the early phase of diet-induced liver steatosis., (© 2024 John Wiley & Sons Ltd.)

Aggressive therapy of diabetic kidney disease (DKD) can not only slow the progression of DKD to renal failure but, if utilized at an early enough stage of DKD, can also stabilize and/or reverse the decline in renal function. The currently recognized standard of therapy for DKD is blockade of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). However, unless utilized at a very early stage, monotherapy with these drugs in DKD will only prevent or slow the progression of DKD and will neither stabilize nor reverse the progression of DKD to renal decompensation. Recently, the addition of a sodium-glucose cotransporter-2 inhibitor and/or a mineralocorticoid receptor blocker to ACE inhibitors or ARBs has been clearly shown to further decelerate the decline in renal function. The use of glucagon-like peptide-1 (GLP-1) agonists shown promise in decelerating the progression of DKD. Other drugs that may aid in the deceleration the progression of DKD are dipeptidyl peptidase-4 inhibitors, pentoxifylline, statins, and vasodilating beta blockers. Therefore, aggressive therapy with combinations of these drugs (stacking) should improve the preservation of renal function in DKD., (© 2024 John Wiley & Sons Ltd.)

Aim: Using a systematic review and meta-analysis of placebo-controlled cardiovascular outcome trials (CVOTs) of newer glucose-lowering agents [sodium-glucose cotransporter-2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4is)] in type 2 diabetes (T2D), we aimed to determine the macrovascular and microvascular outcomes of these agents and clarify the relationships between glycated haemoglobin (HbA1c) reduction and risk of these outcomes., Materials and Methods: Randomized controlled trials were identified from MEDLINE, Embase and the Cochrane Library until September 2023. Study-specific hazard ratios with 95% confidence intervals (CIs) were pooled, and meta-regression was used to assess the relationships between outcomes and between trial arm HbA1c reductions., Results: Twenty unique CVOTs (six SGLT-2is, nine GLP-1RAs, five DPP-4is), based on 169 513 participants with T2D, were eligible. Comparing SGLT-2is, GLP-1RAs and DPP-4is with placebo, the hazard ratios (95% CIs) for 3-point major adverse cardiovascular events were 0.88 (0.82-0.94), 0.85 (0.79-0.92) and 1.00 (0.94-1.06), respectively. SGLT-2is and GLP-1RAs consistently reduced the risk of several macrovascular and microvascular complications, particularly kidney events. DPP-4is showed no macrovascular benefits. There was potential evidence of an inverse linear relationship between HbA1c reduction and 3-point major adverse cardiovascular event risk (estimated risk per 1% reduction in HbA1c: 0.84, 95% CI 0.67-1.06; p = .14; R 2  = 14.2%), which was driven by the component of non-fatal stroke (R 2  = 100.0%; p = .094). There were non-significant inverse linear relationships between HbA1c reduction and the risk of several vascular outcomes., Conclusions: SGLT-2is and GLP-1RAs showed consistent risk reductions in macrovascular and microvascular outcomes. The vascular benefits of SGLT-2is and GLP-1RAs in patients with T2D extend beyond mere glycaemic control., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: The effectiveness of sodium-glucose co-transporter-2 inhibitors (SGLT2i) on incident dementia in patients with diabetes and atrial fibrillation (AF) remains unknown. This study aimed to investigate the association between SGLT2i and the risk of incident dementia in diabetic patients with AF, and to explore the interactions with oral anticoagulants or dipeptidyl peptidase-4 inhibitors (DPP4i)., Materials and Methods: We conducted a cohort study using Taiwan's National Health Insurance Research Database. Patients with diabetes and AFwithout a prior history of established cardiovascular diseases, were identified. Using propensity score matching, 810 patients receiving SGLT2i were matched with 1620 patients not receiving SGLT2i. The primary outcome was incident dementia, and secondary outcomes included composite cardiovascular events and mortality., Results: After up to 5 years of follow-up, SGLT2i use was associated with a significantly lower risk of incident dementia (hazard: 0.71, 95% confidence interval: 0.51-0.98), particularly vascular dementia (HR: 0.44, 95% CI: 0.24-0.82). SGLT2i was related to reduced risks of AF-related hospitalisation (HR: 0.72, 95% CI: 0.56-0.93), stroke (HR: 0.75, 95% CI: 0.60-0.94), and all-cause death (HR: 0.33, 95% CI: 0.24-0.44). The protective effects were consistent irrespective of the concurrent use of non-vitamin K antagonist oral anticoagulants (NOACs) or DPP4i., Conclusions: In diabetic patients with AF, SGLT2i was associated with reduced risks of incident dementia, AF-related hospitalisation, stroke, and all-cause death. The protective effects were independent of either concurrent use of NOACs or DPP4i., (© 2024 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Aims: To examine whether early treatment intensification using dipeptidyl-peptidase 4 inhibitors (DPP4i) delays insulin initiation in Chinese patients diagnosed with type 2 diabetes for less than 5 years., Materials and Methods: In a territory-wide prospective cohort study, patients with type 2 diabetes initiating DPP4i at diabetes duration <2 years (early intensification) and 3-5 years (late intensification) were matched using 1:1 propensity-score matching (n = 908 in each arm). We used Cox regression to compare the risk of insulin initiation between the two groups. We explored the interactive and mediation effects of glycated haemoglobin (HbA1c) variability score (HVS), defined as the percentage of HbA1c varying by ≥0.5% compared with preceding values., Results: Of 1816 patients (60.7% men, mean age 54.4 ± 11.9 years), 92.4% and 71.9% were treated with metformin and sulphonylureas respectively at DPP4i initiation. Early DPP4i intensification [hazard ratio (HR) 0.71, (95% CI 0.58-0.68)] and low HVS (<50%) (HR = 0.40, 0.33-0.50) were associated with delayed insulin initiation during a median 4.08 years of follow-up. Early intensification with low HVS had the lowest risk versus late intensification with high HVS (HR = 0.30, 0.22-0.40) (p interaction  = 0.013). HVS mediated 19.5% of the total effect of early DPP4i intensification on delaying insulin initiation. The late and early intensification groups had similar HbA1c at month 0 (8.4 ± 1.3% vs. 8.4 ± 1.5%) and month 3 (7.6 ± 1.2% vs. 7.6 ± 1.3%) after DPP4i initiation. By month 12, HbA1c in the late intensification group deteriorated (7.9 ± 1.4%) but remained stable in the early intensification group (7.6 ± 1.4%, p = 0.001) with persistent between-group difference over 72 months (8.2 ± 1.7% vs. 7.7 ± 1.6%, p = 0.001)., Conclusions: In type 2 diabetes, early DPP4i intensification delayed insulin initiation, partially explained by reduced glycaemic variability., (© 2023 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Aims: To assess post-initiation predictors of discontinuation of sodium-glucose cotransporter-2 (SGLT2) inhibitors compared to dipeptidyl-peptidase-4 (DPP-4) inhibitors in the United Kingdom., Materials and Methods: We conducted a comparative population-based retrospective cohort study using primary care data from the UK Clinical Practice Research Datalink (CPRD) with linked data to hospital and death records. We included new metformin users who initiated either SGLT2 inhibitors or DPP-4 inhibitors between January 2013 and October 2019. The main outcome was treatment discontinuation, defined as the first 90-day gap after the estimated treatment end date. We used a series of extended Cox models to assess which time-dependent predictors were associated with treatment discontinuation. To test if the hazard ratio of discontinuation for each predictor was statistically different between SGLT2 and DPP-4 inhibitors, an exposure-predictor interaction term was added to each model., Results: There were 2550 new users of SGLT2 inhibitors and 8195 new users of DPP-4 inhibitors. Approximately 69% of SGLT2 inhibitor and 74% of DPP-4 inhibitor users had discontinued treatment by the end of follow-up. Occurrence of fractures after treatment initiation was a significant predictor of discontinuation of SGLT2 inhibitors (hazard ratio [HR] 4.13, 95% confidence interval [CI] 2.12-8.06) but not DPP-4 inhibitors (HR 0.93, 95% CI 0.79-1.11). The rate of treatment discontinuation was significantly higher for those with low estimated glomerular filtration rate and minimal contact with the healthcare system. Efficacy endpoints, such as heart failure and glycated haemoglobin level, were not associated with treatment discontinuation., Conclusions: Our findings reflect some discrepancy between the available evidence and prescribing behaviour for SGLT2 inhibitors., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To examine disparities in glucose-lowering drug (GLD) usage between migrants and native Danes with type 2 diabetes (T2D)., Materials and Methods: In a nationwide, register-based cross-sectional study of 253 364 individuals with prevalent T2D on December 31, 2018, we examined user prevalence during 2019 of (i) GLD combination therapies and (ii) individual GLD types. Migrants were grouped by origin (Middle East, Europe, Turkey, Former Yugoslavia, Pakistan, Sri Lanka, Somalia, Vietnam), and relative risk (RR) versus native Danes was computed using robust Poisson regression to adjust for clinical and socioeconomic characteristics., Results: In 2019, 34.7% of native Danes received combination therapy, and prevalence was lower in most migrant groups (RR from 0.78, 95% confidence interval CI 0.71-0.85 [Somalia group] to 1.00, 95% CI 0.97-1.04 [former Yugoslavia group]). Among native Danes, the most widely used oral GLD was metformin (used by 62.1%), followed by dipeptidyl peptidase-4 inhibitors (13.3%), sodium-glucose cotransporter-2 inhibitors (11.9%) and sulphonylureas (5.2%), and user prevalence was higher in most migrant groups (RR for use of any oral GLD: 0.99, 95% CI 0.97-1.01 [Europe group] to 1.09, 95% CI 1.06-1.11 [Sri Lanka group]). Furthermore, 18.7% of native Danes used insulins and 13.3% used glucagon-like peptide-1 receptor agonists (GLP-1RAs), but use was less prevalent in migrants (RR for insulins: 0.66, 95% CI 0.62-0.71 [Sri Lanka group] to 0.94, 95% CI 0.89-0.99 [Europe group]; RR for GLP-1RAs: 0.29, 95% CI 0.22-0.39 [Somalia group] to 0.95, 95% CI 0.89-1.01 [Europe group])., Conclusions: Disparities in GLD types and combination therapy were evident between migrants and native Danes. Migrants were more likely to use oral GLDs and less likely to use injection-based GLDs, particularly GLP-1RAs, which may contribute to complication risk and mortality among this group., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The aim of this study is to reveal the effects of the use of linagliptin, a DPP-4 inhibitor due to its beneficial cardiovascular effects, on endoplasmic reticulum stress (ERS) signaling, which is involved in the pathogenesis of cardiovascular complications related to type 1 diabetes. BALB/c female mice (n = 72) were divided into six groups: control, diabetes+insulin, diabetes+linagliptin, diabetes+linagliptin+insulin, diabetes+TUDCA, and diabetes+TUDCA+insulin. Immunohistochemistry and western blot method, qRT-PCR, ELISA method, and malondialdehyde (MDA) measurements were performed. Linagliptin administered to the type 1 diabetic mouse heart significantly reduced the expression levels of the total and cleaved forms of ATF6, ATF4, and p-JNK, caspase 3. Immunohistochemical and western blot analyses revealed that cleaved caspase 3 protein expression was significantly increased in the diabetes+insulin group compared to the other groups. According to ELISA findings, TUDCA was more effective in reducing NOX 1 and MDA levels than linagliptin. While linagliptin decreased the Chop mRNA level, no change was observed in the Grp78 mRNA level. Our findings showed that there was not much difference between the administration of linagliptin alone or in combination with insulin. Our study reveals that linagliptin is an effective therapeutic agent on ERS and apoptotic UPR in type 1 diabetic hearts., (© 2023 John Wiley & Sons Ltd.)

We aimed to summarise current evidence on different antidiabetic drugs to delay cognitive impairment, including mild cognitive impairment, dementia, Alzheimer's disease (AD) and vascular dementia, among subjects with type 2 diabetes mellitus (T2DM). Medline, Cochrane and Embase databases were searched from inception to 31 July 2022. Two investigators independently reviewed and screened trials comparing antidiabetic drugs with no antidiabetic drugs, placebo, or other active antidiabetic drugs on cognitive outcomes in T2DM. Data were analysed using meta-analysis and network meta-analysis. Twenty-seven studies met the inclusion criteria, including 3 randomised controlled trials, 19 cohort studies and 5 case-control studies. Compared with non-user, SGLT-2i (OR 0.41 [95% CI 0.22-0.76]), GLP-1RA (OR 0.34 [95% CI 0.14-0.85]), thiazolidinedione (OR 0.60 [95% CI 0.51-0.69]), and DPP-4i (OR 0.78 [95% CI 0.61-0.99]) users had a decreased risk of dementia, whereas sulfonylurea (OR 1.43 [95% CI 1.11-1.82]) increased dementia risk. Network meta-analysis showed that SGLT-2i was most likely to rank best (SUCRA = 94.4%), GLP-1 RA second best (SUCRA = 92.7%), thiazolidinedione third best (SUCRA = 74.7%) and DPP-4i fourth best (SUCRA = 54.9%), while sulfonylurea second worst (SUCRA = 20.0%) for decreasing dementia outcomes, by synthesising evidence from direct and indirect comparisons of multiple intervention. Evidence suggests the effects of SGLT-2i ≈ GLP-1 RAs > thiazolidinedione > DPP-4i for delaying cognitive impairment, dementia and AD outcomes, whereas sulfonylurea was associated with the highest risk. These findings provide evidence for evaluating the optional treatment for clinical practice. PROSPERO REGISTRATION: Registration no. CRD42022347280., (© 2023 John Wiley & Sons Ltd.)

Aim: To examine trends of second-line glucose-lowering therapies among patients with type 2 diabetes (T2D) initiating first-line metformin in the United States and the United Kingdom, overall and by subgroups of cardiovascular disease (CVD) and calendar time., Methods: Using the US Optum Clinformatics and the UK Clinical Practice Research Datalink, we identified adults with T2D who initiated first-line metformin or sulphonylurea monotherapy, separately, from 2013 to 2019. Within both cohorts, we identified patterns of second-line medications through June 2021. We stratified patterns by CVD and calendar time to investigate the impact of rapidly evolving treatment guidelines., Results: We identified 148 511 and 169 316 patients initiating treatment with metformin monotherapy in the United States and the United Kingdom, respectively. Throughout the study period, sulphonylureas and dipeptidyl peptidase-4 inhibitors were the most frequently initiated second-line medications in the United States (43.4% and 18.2%, respectively) and the United Kingdom (42.5% and 35.8%, respectively). After 2018, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists were more commonly used as second-line agents in the United States and the United Kingdom, although these agents were not preferentially prescribed among patients with CVD. Initiation of first-line sulphonylureas was much less common, and most sulphonylurea initiators had metformin added as the second-line agent., Conclusions: This international cohort study shows that sulphonylureas remain the most common second-line medications prescribed following metformin in both the United States and the United Kingdom. Despite recommendations, the use of newer glucose-lowering therapies with cardiovascular benefits remains low., (© 2023 John Wiley & Sons Ltd.)

Aims: To examine whether simple clinical features can predict the 1-year glycaemic response to glucose-lowering drugs (GLDs) among Chinese with type 2 diabetes., Materials and Methods: We used data from a diabetes risk assessment and complication screening programme and electronic medical records. We used linear regression models to examine the association between clinical features and 1-year glycaemic response to GLDs., Results: Use of metformin (n = 15,433), sulphonylureas (SU) (n = 15,190), dipeptidyl peptidase-4 inhibitor (DPP-4i) (n = 7947), thiazolidinedione (TZD) (n = 4107), and sodium-glucose cotransporter 2 inhibitors (SGLT-2i) (n = 1883) were associated with a mean reduction of HbA1c ranging from 0.7% to 1.3% at one year. Men had a greater response to SU but a poorer response to metformin and TZD. Older age predicted a better response to all GLDs but not SGLT-2i, whereas increasing diabetes duration was associated with a poorer response to all GLDs except for DPP-4i. Obese patients responded greater to TZD and SGLT-2i but poorer to SU than those with normal weight. Patients with a higher level of triglycerides to high-density lipoprotein cholesterol ratio had a greater glycaemic response to TZD but a smaller response to SU and DPP-4i., Conclusions: Glycaemic response to GLDs differed considerably by clinical features among Chinese patients with type 2 diabetes., (© 2023 John Wiley & Sons Ltd.)

Aim: To investigate changes in the pattern of drugs used to treat type 2 diabetes in Denmark from 2005 to 2021., Materials and Methods: A nationwide, population-based drug utilization study based on medical databases covering the Danish population was conducted. We assessed incident and prevalent use patterns among all 441 205 individuals initiating at least one non-insulin, glucose-lowering drug., Results: The rate of new users of non-insulin, glucose-lowering drugs increased from 2005, peaked in 2011, decreased to stable levels during 2013 to 2019, then increased dramatically during 2020-2021. The prevalence of use increased from 2.1% (in 2005) to 5.0% (in 2021) of the entire adult population. In 2021, metformin comprised 39% of all glucose-lowering drug consumption, followed by insulin (17%), sodium-glucose co-transporter-2 inhibitors (SGLT-2is) (17%), glucagon-like peptide-1 receptor agonists (GLP-1RAs) (16%) and dipeptidyl peptidase-4 inhibitors (7.5%). Overall, 56% of users were on monotherapy, 28% used dual therapy, while 13% and 2.8% used three and four drug classes, respectively. Both the intensity and diversity of therapies increased substantially over time, with 15 different treatment regimens each covering more than 1% of users in 2021. General practitioners prescribed 88% of all glucose-lowering drugs. Marked shifts towards GLP-1RA initiation by general practitioners and SGLT-2i initiation by specialists were observed, and changing user profiles suggested increasing use for non-diabetes indications., Conclusions: The rate of new users of non-insulin, glucose-lowering drugs has increased in recent years and the prevalence of glucose-lowering drug use increases steadily. Glucose-lowering drugs are mainly prescribed by general practitioners, and the intensity, diversity and indications of glucose-lowering treatment are increasing., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: Disproportionality analysis is a common pharmacovigilance tool to detect safety signals of type 2 diabetes medications from spontaneous drug reporting databases. The aim was to demonstrate the impact of using active-comparator restricted disproportionality analysis (ACR-DA), wherein the reference group is restricted to reports with a clinically appropriate active comparator., Methods: Using reports from the Food and Drug Administration Adverse Event Reporting System, we assessed if sodium/glucose cotransporter 2 (SGLT2) inhibitors are associated with higher reporting of 5 potential adverse events: acute kidney injury, genitourinary tract infections, diabetic ketoacidosis, fractures, and amputations. For each adverse event, we calculated the proportional reporting ratio (PRR) and adjusted reporting odds ratio (aROR [95% confidence interval, CI]) using 3 types of reference groups: no SGLT2 inhibitor (background risk reference), other diabetes drugs (therapeutic class reference), and dipeptidyl peptidase 4 inhibitors (active comparator reference)., Results: Based on ACR-DA, we did not detect a safety signal for acute kidney injury (PRR 0.92 [0.81-1.04]; aROR 0.78 [95% CI 0.72-0.85]) or fractures (PRR 0.44[95% CI 0.17-1.15]; aROR 0.74 [95% CI 0.61-0.91]) associated with SGLT2 inhibitors compared to dipeptidyl peptidase 4 inhibitors. However, we detected safety signals for genitourinary tract infections (PRR 2.75[2.02-3.76]; aROR 2.54[2.26-2.86], diabetic ketoacidosis (PRR 63.85[39.37-103.53; aROR 91.49[70.66-118.48]), and amputations (PRR 52.60 [19.66-140.75]; aROR 22.64 [15.32-33.42]., Conclusion: The use of the proposed ACR-DA to detect safety signals of type 2 diabetes medications may reduce false positive safety signals through careful selection of the comparator which is expected to reduce channelling bias., (© 2021 British Pharmacological Society.)

Aim: To assess the efficacy and safety of a dipeptidyl peptidase-4 (DPP-4) inhibitor combined respectively with three oral antihyperglycaemic agents in Chinese patients with newly diagnosed type 2 diabetes mellitus (T2DM) with high levels of glycated haemoglobin (HbA1c)., Materials and Methods: Between 30 December 2014 and 1 November 2017, a 24-week, multicentre, parallel-controlled study was performed on drug-naive T2DM patients. In total, 648 patients with 8.0% ≤ HbA1c ≤ 11.0%, aged 18-80 years and body mass index (BMI) 19-40 kg/m 2 were randomly assigned 1:1:1 to receive saxagliptin (Saxa) combined with metformin (Met), acarbose (Aca) or gliclazide (Gli) modified release (MR) tablets (Saxa + Met, Saxa + Aca and Saxa + Gli). The primary outcome was the absolute change in HbA1c from baseline; secondary outcome was the percentage of patients achieving HbA1c <7.0% and ≤6.5%., Results: Each treatment arm contained 216 patients; overall, 583 completed the 24-week trial. At 24 weeks, the mean (95% confidence interval) change in HbA1c from baseline in Saxa + Met, Saxa + Aca and Saxa + Gli were, respectively: -2.9% [-3.1, -2.8]; -2.6% [-2.8, -2.5]; and -2.8% [-2.9, -2.6] (overall p = .04, Saxa + Aca vs. Saxa + Met, p = .010, Saxa + Gli vs. Saxa + Met, p = 0.18). At 24 weeks, 84.9%, 74.7% and 80.3% of participants were at HbA1c <7.0% (overall p = .05); and 72.6%, 59.8% and 63.3% were HbA1c ≤6.5% (overall p = 0.10). The rates of minor or symptomatic hypoglycaemia were very low., Conclusions: Initial treatment with a DPP-4 inhibitor combined with Metform, alpha-glycosidase inhibitor or sulphonylurea was safe and effective for patients with newly diagnosed T2DM and high HbA1c. DPP-4 inhibitor combined with Met showed the best efficacy for this population., (© 2022 John Wiley & Sons Ltd.)

Aims: To evaluate effectiveness and healthcare resource utilization (HCRU) of empagliflozin versus dipeptidyl peptidase-4 inhibitors (DPP-4i) in Swedish clinical practice, as part of the EMPRISE EU study (EUPAS27606, NCT03817463)., Materials and Methods: A non-interventional, cohort study using retrospectively collected data from Swedish national registries. Adults with type 2 diabetes newly initiated on empagliflozin or DPP-4i from May 2014 to December 2018 were matched 1:1 using propensity scores based on >180 covariates. Cardiovascular outcomes included hospitalization for heart failure (HHF), all-cause mortality (ACM), myocardial infarction (MI), stroke and cardiovascular mortality (CVM), as well as their composite outcomes. Renal outcomes included end-stage renal disease (ESRD), estimated glomerular filtration rate (eGFR) decline to <60 ml/min/1.73 m 2 and progression to micro/macroalbuminuria. HCRU outcomes were also assessed. Comparisons were done using Cox proportional hazards and Poisson regression models., Results: Overall, 15,785 matched-pairs were identified, with a mean follow-up of 6.4 and 9.7 months for patients initiating empagliflozin versus DPP-4i, respectively. Empagliflozin was associated with significant reduction in rates of HHF (hazard ratio [HR] = 0.67; 95% confidence interval: 0.49-0.91), ACM (HR = 0.53; 0.41-0.68), HHF + ACM (HR = 0.59; 0.48-0.73), MI + stroke + ACM (HR = 0.68; 0.57-0.81), CVM (HR = 0.46; 0.29-0.73), HHF + CVM (HR = 0.61; 0.47-0.79) and MI + stroke + CVM (HR = 0.79; 0.63-0.98) versus DPP-4i. Empagliflozin also reduced the rates of ESRD (HR = 0.13; 0.03-0.57) and eGFR decline (HR = 0.83; 0.70-0.99). Regarding HCRU, empagliflozin was associated with lower risk of first inpatient stay (HR = 0.87; 0.81-0.93), and lower rate of inpatient and outpatient visits (rate ratio [RR] = 0.85; 0.80-0.89 and RR = 0.96; 0.94-0.98) than DPP-4i., Conclusions: Empagliflozin treatment compared to DPP-4i reduced cardiorenal events and overall mortality, which may explain lower HCRU among empagliflozin users in Sweden., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To confirm the reno-protective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors compared with dipeptidyl peptidase-4 (DPP-4) inhibitors on the onset and progression of chronic kidney disease (CKD) in routine clinical practice., Materials and Methods: We conducted a retrospective cohort study using the Clinical Practice Research Datalink Aurum database linked to Hospital Episode Statistics. The primary outcome was risk of the composite CKD endpoint based on the recent consensus guidelines for kidney disease: >40% decline in estimated glomerular filtration rate (eGFR), kidney death or end-stage kidney disease (ESKD; a composite of kidney transplantation, maintenance of dialysis, sustained low eGFR <15 ml/min/1.73m² or diagnosis of ESKD). Secondary outcomes were components of the composite CKD endpoint, analysed separately. Patients were propensity-score-matched 1:1 for SGLT2 inhibitor versus DPP-4 inhibitor use., Results: A total of 131 824 people with type 2 diabetes (T2D) were identified; 79.0% had no known history of CKD. During a median follow-up of 2.1 years, SGLT2 inhibitor initiation was associated with lower risk of progression to composite kidney endpoints than DPP-4 inhibitor initiation (7.48 vs. 11.77 events per 1000 patient-years, respectively). Compared with DPP-4 inhibitor initiation, SGLT2 inhibitor initiation was associated with reductions in the primary composite CKD endpoint (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.56-0.74), all-cause mortality (HR 0.74, 95% CI 0.64-0.86) and ESKD (HR 0.37, 95% CI 0.25-0.55), reduced the rate of sustained low eGFR (HR 0.33, 95% CI 0.19-0.57), and reduced diagnoses of ESKD in primary care (HR 0.04, 95% CI 0.01-0.18). Results were consistent across subgroup and sensitivity analyses., Conclusions: In adults with T2D, initiation of an SGLT2 inhibitor was associated with a significantly reduced risk of CKD progression and death compared with initiation of a DPP-4 inhibitor., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Bullous pemphigoid (BP), the by far most frequent autoimmune blistering skin disease (AIBD), is immunopathologically characterized by autoantibodies against the two hemidesmosomal proteins BP180 (collagen type XVII) and BP230 (BPAG1 or dystonin). Several comorbidities and potentially disease-inducing medication have been described in BP, yet a systematic analysis of these clinically relevant findings and autoantibody reactivities has not been performed., Objective: To determine associations of autoantibody reactivities with comorbidities and concomitant medication., Methods: In this prospective multicenter study, 499 patients diagnosed with BP in 16 European referral centers were included. The relation between anti-BP180 NC16A and anti-BP230 IgG ELISA values at the time of diagnosis as well as comorbidities and concomitant medication collected by a standardized form were analysed., Results: An association between higher serum anti-BP180 reactivity and neuropsychiatric but not atopic and metabolic disorders was observed as well as with the use of insulin or antipsychotics but not with dipeptidyl peptidase-4 (DPP4) inhibitors, inhibitors of platelet aggregation and L-thyroxine. The use of DPP4 inhibitors was associated with less anti-BP180 and anti-BP230 reactivity compared with BP patients without these drugs. This finding was even more pronounced when compared with diabetic BP patients without DPP4 inhibitors. Associations between anti-BP180 and anti-BP230 reactivities were also found in patients using insulin and antipsychotics, respectively, compared with patients without this medication, but not for the use of inhibitors of platelet aggregation, and L-thyroxine., Conclusion: Taken together, these data imply a relation between autoantibody reactivities at the time of diagnosis and both neuropsychiatric comorbidities as well as distinct concomitant medication suggesting a link between the pathological immune mechanisms and clinical conditions that precede the clinically overt AIBD., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Aims: Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post-hoc analysis of a 3-year randomized controlled trial showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase-4 inhibitor increases active glucagon-like peptide-1 (GLP-1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase-4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP-1., Methods: We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured., Results: Postprandial plasma glucose increased by 57% (incremental area under the curve 0-240 min) (p = .0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6-2.9) (p = .003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP-1 and C-peptide concentrations increased after sacubitril/valsartan, but insulin and glucose-dependent insulinotropic polypeptide did not change., Conclusions: The glucose-lowering effects of long-term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero-pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study., Clinicaltrials: gov (NCT03893526)., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To conduct a systematic review and network meta-analysis to determine the comparative effectiveness of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with diabetic kidney disease (DKD)., Methods: Phase III or IV randomized, placebo-controlled trials evaluating SGLT2 inhibitors, GLP-1RAs or DPP-4 inhibitors in patients with DKD were identified from the MEDLINE database. The outcomes of interest were a kidney-specific composite outcome, kidney disease progression, major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF) and cardiovascular death. A network meta-analysis was conducted to calculate hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: Sixteen trials representing a total of 46 292 patients were included. SGLT2 inhibitors significantly reduced the risk of the kidney-specific composite outcome by 26% compared to GLP-1RAs (HR 0.74, 95% CI 0.62-0.88) and by 36% compared to DPP-4 inhibitors (HR 0.64, 95% CI 0.52-0.79). The risk of MACE was significantly reduced with SGLT2 inhibitors (by 18%; HR 0.82, 95% CI 0.72-0.93), and with GLP-1RAs (by 18%; HR 0.82, 95% CI 0.69-0.96), compared to DPP-4 inhibitors. SGLT2 inhibitors significantly reduced the risk of HHF by 28% compared to GLP-1RAs (HR 0.72, 95% CI 0.56-0.92) and by 41% compared to DPP-4 inhibitors (HR 0.59, 95% CI 0.49-0.71)., Conclusions: A clear advantage was demonstrated by SGLT2 inhibitors in reducing the risks of CV and renal events in patients with DKD, compared to GLP-1RAs and DPP-4 inhibitors. We recommend that SGLT2 inhibitors be considered the treatment of choice in patients with DKD., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: We conducted a model-based economic analysis of sodium-glucose cotransporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) in patients with type 2 diabetes (T2D), with and without established cardiovascular diseases (CVDs), using 10-year real-world data., Materials and Methods: A Markov model was utilized to estimate healthcare costs and quality-adjusted life-years (QALYs) over a 10-year simulation time horizon from a healthcare sector perspective, with both costs and QALYs discounted at 3% annually. Model inputs were derived from analyses of Taiwan's National Health Insurance Research Database or published studies of Taiwanese populations. The primary outcome measure was the incremental cost-effectiveness ratios (ICERs). Incorporated with our study findings, a targeted literature review was conducted to synthesize updated evidence on the cost-effectiveness of SGLT2is versus DPP4is., Results: Over 10 years, use of SGLT2is versus DPP4is yielded ICERs of $3244 and $4186 per QALY gained for patients with T2D, with and without established CVDs, respectively. Results were robust across a series of sensitivity and scenario analyses, showing ICERs between $-1074 (cost-saving) and $8467 per QALY gained for patients with T2D with established CVDs and between $369 and $37 122 per QALY gained for patients with T2D without established CVDs., Conclusions: Use of SGLT2is versus DPP4is was highly cost-effective for patients with T2D regardless of their CVD history in real-world clinical practice. Our results extend current evidence by showing SGLT2is as an economically rational alternative over DPP4is for T2D treatment in routine care. Future research is warranted to explore the heterogeneous economic benefits of SGLT2is given diverse patient characteristics in clinical settings., (© 2022 John Wiley & Sons Ltd.)

Aim: To assess selected cardiorenal outcomes with ertugliflozin according to use of baseline glucose-lowering agent., Materials and Methods: VERTIS CV was a cardiovascular (CV) outcome trial for ertugliflozin versus placebo, conducted in patients with type 2 diabetes and established atherosclerotic CV disease. The primary outcome was time to the first event of CV death, myocardial infarction or stroke (major adverse CV events [MACE]), with other CV outcomes also assessed. Outcomes were analysed using Cox proportional hazards models stratified by baseline use of metformin, insulin, sulphonylureas (SUs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, with interaction testing to assess for treatment effect modification. Changes from baseline in glycaemic, metabolic and haemodynamic variables were also assessed., Results: Of 8246 randomized patients, at baseline 6286 (76%) were on metformin, 3898 (47%) were on insulin, 3383 (41%) were on SUs and 911 (11%) were on DPP-4 inhibitors, alone or in combination therapy (67% used >1 glucose-lowering agent at baseline). For each glucose-lowering agent evaluated, no evidence for effect modification was observed for MACE by baseline use of metformin (with: hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.790, 1.073; without: 1.13, 95% CI 0.867, 1.480), insulin (with: HR 0.91, 95% CI 0.765, 1.092; without: 1.06, 95% CI 0.867, 1.293), SUs (with: HR 1.11, 95% CI 0.890, 1.388; without: 0.90, 95% CI 0.761, 1.060) or DPP-4 inhibitors (with: HR 0.77, 95% CI 0.502, 1.173; without: 1.00, 95% CI 0.867, 1.147) (all P interaction  > 0.05). Similar results were observed for all secondary outcomes analysed., Conclusion: In VERTIS CV, the effects of ertugliflozin on cardiorenal outcomes were consistent across subgroups of patients stratified by baseline glucose-lowering agent., Clinicaltrials: gov identifier: NCT01986881., (© 2022 Pfizer Inc. and Merch Sharp & Dohme Corp. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)