Incretin-based therapy and the risk of diabetic foot ulcers and related events.

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.

Protective Effects of Home T2DM Treatment with Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Co-transporter-2 Inhibitors Against Intensive Care Unit Admission and Mortality in the Acute Phase of the COVID-19 Pandemic: A Retrospective Observational Study in Italy.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a relevant risk factor for severe forms of COVID-19 (SARS coronavrus 2 [SARS-CoV-2] disease 2019), and calls for caution because of the high prevalence of T2DM worldwide and the high mortality rates observed in patients with T2DM who are infected with SARS-CoV-2. People with T2DM often take dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1ras), or sodium-glucose co-transporter-2 inhibitors (SGLT-2is), all of which have clear anti-inflammatory effects. The study aimed to compare (i) the severity and duration of hospital stay between patients with T2DM categorized by pre-hospitalization drug class utilization and (ii) the COVID-19-related death rates of those three groups. METHODS: We designed an observational, retrospective, multi-center, population-based study and extracted the hospital admission data from the health care records of 1916 T2DM patients over 18 years old who were previously on GLP-1ra, SGLT-2i, or DPP-4i monotherapy and were hospitalized for COVID-19 (diagnosis based on ICD.9/10 codes) between January 2020 and December 2021 in 14 hospitals throughout Italy. We analyzed general data, pre-admission treatment schedules, date of admission or transfer to the intensive care unit (ICU) (i.e., the index date; taken as a marker of increased COVID-19 disease severity), and death (if it had occurred). Statistics analyzed the impact of drug classes on in-hospital mortality using propensity score logistic regressions for (i) those admitted to intensive care and (ii) those not admitted to intensive care, with a random match procedure used to generate a 1:1 comparison without diabetes cohort replacement for each drug therapy group by applying the nearest neighbor method. After propensity score matching, we checked the balance achieved across selected variables if a balance was ever achieved. We then used propensity score matching between the three drug classes to assemble a sample in which each patient receiving an SGLT-2i was matched to one on a GLP-1ra, and each patient on a DPP-4i was matched to one on a GLP-1ra, adjusting for covariates. We finally used GLP-1ras as references in the logistic regression. RESULTS: The overall mortality rate (MR) of the patients was 14.29%. The MR in patients with COVID was 53.62%, and it was as high as 42.42% in the case of associated T2DM, regardless of any glucose-lowering therapy. In those on DPP-4is, there was excess mortality; in those treated with GLP-1ras and SGLT-2is, the death rate was significantly lower, i.e., almost a quarter of the overall mortality observed in COVID-19 patients with T2DM. Indeed, the odds ratio (OR) in the logistic regression resulted in an extremely high risk of in-hospital death in individuals previously treated with DPP-4is [incidence rate (IR) 4.02, 95% confidence interval (CI) 2.2-5.7) and only a slight, nonsignificantly higher risk in those previously treated with SGLT-2is (IR 1.42, 95% CI 0.6-2.1) compared to those on GLP-1ras. Moreover, the longer the stay, the higher the death rate, which ranged from 22.3% for ≤ 3-day stays to 40.3% for 4- to 14-day stays (p < 0.01 vs. the former) and 77.4% for over-14-day stays (p < 0.001 vs. both the others). DISCUSSION: Our data do not support a protective role of DPP-4is; indeed, this role has already been questioned due to previous observations. However, the data do show a strong protective effect of SGLT-2is and GLP-1ras. Beyond lowering circulating glucose levels, those two drug classes were found to exert marked anti-phlogistic effects: SGLT-2is increased adiponectin and reduced urate, leptin, and insulin concentrations, thus positively affecting overall low-grade inflammation, and GLP-1ras may also greatly help at the lung tissue level, meaning that their extra-glycemic effects extend well beyond those acknowledged in the cardiovascular and renal fields. CONCLUSIONS: The aforedescribed observational clinical data relating to a population of Italian inpatients with T2DM suggest that GLP-1ras and SGLT-2is can be considered antidiabetic drugs of choice against COVID-19, and might even prove beneficial in the event of any upcoming pandemic that has life-threatening effects on the pulmonary and cardiovascular systems.

The Impact of GLP-1 RAs and DPP-4is on Hospitalisation and Mortality in the COVID-19 Era: A Two-Year Observational Study.

Novel antidiabetic drugs have the ability to produce anti-inflammatory effects regardless of their glucose-lowering action. For this reason, these molecules (including GLP-1 RAs and DPP-4is) were hypothesized to be effective against COVID-19, which is characterized by cytokines hyperactivity and multiorgan inflammation. The aim of our work is to explore the potential protective role of GLP-1 RAs and DPP-4is in COVID-19 (with the disease intended to be a model of an acute stressor) and non-COVID-19 patients over a two-year observation period. Retrospective and one-versus-one analyses were conducted to assess the impact of antidiabetic drugs on the need for hospitalization (in both COVID-19- and non-COVID-19-related cases), in-hospital mortality, and two-year mortality. Logistic regression analyses were conducted to identify the variables associated with these outcomes. Additionally, log-rank tests were used to plot survival curves for each group of subjects, based on their antidiabetic treatment. The performed analyses revealed that despite similar hospitalization rates, subjects undergoing home therapy with GLP-1 RAs exhibited significantly lower mortality rates, even over a two-year period. These individuals demonstrated improved survival estimates both within hospital and non-hospital settings, even during a longer observation period.

Identification of levomenthol derivatives as potential dipeptidyl peptidase-4 inhibitors: a comparative study with gliptins.

Dipeptidyl peptidase-4 (DPP4) inhibitors are a potent therapeutic treatment for type 2 diabetes mellitus (T2DM). There is a family of compounds used as DPP4 inhibitors (DPP4Is) called gliptins. They bind tightly to DPP4 to form an inactive protein-ligand complex. However, there remains a need to identify novel DPP4Is that are more efficacious and safer due to the increasing prevalence of T2DM and the undesirable side effects of gliptins. To identify potential DPP4Is, we screened over 1800 novel compounds in a comparative study with gliptins. We performed dual-factor molecular docking to assess the binding affinity of the compounds to DPP4 and found four compounds with a higher binding affinity to DPP4 than currently used gliptins. The newly identified compounds interacted with the dyad glutamate (GLU205 and GLU206) and tyrosine (TYR662 and TYR666) residues in DPP4's active site. We performed molecular dynamics simulations to determine the stability of the protein-ligand complexes formed by the compounds and DPP4. Furthermore, we examined the toxicity and pharmacological profile of the compounds. The compounds are drug-like, easy to synthesize, and relatively less toxic than gliptins. Collectively, our results suggest that the novel compounds are potential DPP4Is and should be considered for further studies to develop novel antidiabetics.Communicated by Ramaswamy H. Sarma.

Is the combination of linagliptin and allopurinol better prophylaxis against post-contrast acute kidney injury? A multicenter prospective randomized controlled study.

BACKGROUND: Patients with diabetic kidney disease (DKD) are at increased risk to develop post-contrast acute kidney injury (AKI). Diabetic patients under dipeptidyl peptidase 4 inhibitors (DPP4Is) experience a lower propensity to develop AKI. We speculated that linagliptin as a single agent or in combination with allopurinol may reduce the incidence of post-contrast AKI in stage 3-5 chronic kidney disease (CKD) patients with underlying DKD. METHODS: Out of 951 DKD patients eligible for this study, 800 accepted to sign informed consent. They were randomly allocated to 4 equal groups that received their prophylaxis for 2 days before and after radiocontrast. The first control group received N-acetyl cysteine and saline, the 2nd received allopurinol, the 3rd group received linagliptin, and the 4th received both allopurinol and linagliptin. Post-procedure follow-up for kidney functions was conducted for 2 weeks in all patients. RESULTS: 20, 19, 14, and 8 patients developed post-contrast AKI in groups 1 through 4, respectively. Neither linagliptin nor allopurinol was superior to N-acetyl cysteine and saline alone. However, the combination of the two agents provided statistically significant renal protection: post-contrast AKI in group 4 was significantly lower than in groups 1 and 2 (p < 0.02 and <0.03, respectively). None of the post-contrast AKI cases required dialysis. CONCLUSION: Linagliptin and allopurinol in combination may offer protection against post-contrast AKI in DKD exposed to radiocontrast. Further studies are needed to support this view. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT03470454.

Compliance with the DPP-4 inhibitors dose adjustment recommendations based on renal function in a population database.

OBJECTIVE: To examine the prescription pattern of the different dipeptidyl peptidase-4 inhibitors (DPP4is), depending on the estimated glomerular filtration rate (eGFR) under real-world clinical practice conditions. METHOD: This was a descriptive, observational study using a population database (SIDIAP Catalonia). Subjects diagnosed with T2DM with kidney function assessed and on active treatment with DPP4is were enrolled. Patients were included at the time of the measurement of eGFR (CKD-epi) and were monitored for 6 months after enrolment. For each subject, the prescribed daily dose (PDD) of DPP4i, the theoretical dose according to the degree of renal failure established by the recommendations in the summary of product characteristics (DDD-adj), and the PDR ratio (PDD/DDD-adj) were estimated. A subject was considered overtreated if his/her RDR was greater than 1.2 (>20%). RESULTS: The study sample consisted of 72,135 subjects with a mean age of 69.7 (±11.6) years and 55.9% males. The proportion of patients overtreated varied depending on the type of DPP4i and the renal function stage. Overall, overdosage was recorded in 7.15% of all DPP4i treatments. In advanced stages (IIIb, IV, and V), overdosage was much higher (36.8% for all DPP4is, and 58.7% if linagliptin is excluded). DISCUSSION: Under real-world clinical practice conditions, more than one third of T2DM patients with advanced renal failure were overdosed with DPP4is because the doses were not adequately adjusted to the glomerular filtration rate of each patient.

Three new categories of hypoglycaemic agents and various cardiovascular diseases: A meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: New hypoglycaemic agents consist of dipeptidyl peptidase four inhibitors (DPP4is), glucagon-like peptide one receptor agonists (GLP1RAs) and sodium-glucose cotransporter two inhibitors (SGLT2is). We aimed to define the association between each category of these new hypoglycaemic drugs and various cardiovascular diseases. METHODS: Large randomized trials comparing DPP4is, GLP1RAs or SGLT2is with placebo were included. Outcomes of interest were 95 kinds of cardiovascular diseases. Meta-analysis was conducted to generate pooled risk ratio (RR) and 95% confidence interval (CI). RESULTS AND DISCUSSION: Twenty-one large randomized trials were included in this meta-analysis. Compared with placebo, SGLT2is were associated with the lower risks of hypertension (RR 0.67, 95% CI 0.49-0.93), atrial fibrillation (RR 0.78, 95% CI 0.67-0.91), bradycardia (RR 0.60, 95% CI 0.40-0.89) and heart failure (RR 0.74, 95% CI 0.68-0.80); GLP1RAs were associated with the lower risk of peripheral arterial occlusive disease (RR 0.73, 95% CI 0.56-0.97) and with the higher risk of deep vein thrombosis (RR 2.12, 95% CI 1.32-3.4), while DPP4is were associated with the lower risk of peripheral ischaemia (RR 0.57, 95% CI 0.37-0.89). WHAT IS NEW AND CONCLUSIONS: Our meta-analysis revealed that SGLT2is were associated with the lower risks of hypertension, atrial fibrillation, bradycardia and heart failure; GLP1RAs were associated with the lower risk of peripheral arterial occlusive disease and with the higher risk of deep vein thrombosis, while DPP4is were associated with the lower risk of peripheral ischaemia. These findings propose that each category of these new hypoglycaemic agents should be avoided or preferred in patients at high risks of specific cardiovascular diseases.

Compliance with the DPP-4 inhibitors dose adjustment recommendations based on renal function in a population database. / Cumplimiento de las recomendaciones de ajuste de la dosis de inhibidores DPP4 según la función renal en una base de datos poblacional.

OBJECTIVE: To examine the prescription pattern of the different dipeptidyl peptidase-4 inhibitors (DPP4is), depending on the estimated glomerular filtration rate (eGFR) under real-world clinical practice conditions. METHOD: This was a descriptive, observational study using a population database (SIDIAP Catalonia). Subjects diagnosed with T2DM with kidney function assessed and on active treatment with DPP4is were enrolled. Patients were included at the time of the measurement of eGFR (CKD-EPI) and were monitored for 6 months after enrolment. For each subject, the prescribed daily dose (PDD) of DPP4i, the theoretical dose according to the degree of renal failure established by the recommendations in the summary of product characteristics (DDD-adj), and the PDR ratio (PDD/DDD-adj) were estimated. A subject was considered overtreated if his/her RDR was greater than 1.2 (>20%). RESULTS: The study sample consisted of 72,135 subjects with a mean age of 69.7 (±11.6) years and 55.9% males. The proportion of patients overtreated varied depending on the type of DPP4i and the renal function stage. Overall, overdosage was recorded in 7.15% of all DPP4i treatments. In advanced stages (IIIb, IV and V), overdosage was much higher (36.8% for all DPP4is, and 58.7% if linagliptin is excluded). DISCUSSION: Under real-world clinical practice conditions, more than one third of T2DM patients with advanced renal failure were overdosed with DPP4is because the doses were not adequately adjusted to the glomerular filtration rate of each patient.

Dynamics of switching, adherence, and persistence of dipeptidyl peptidase-4 inhibitors use: A nationwide cohort study.

AIMS: To characterise the patterns of switching, adherence, and persistence among adults aged ≥18 years with diabetes prescribed dipeptidyl peptidase-4 inhibitors (DPP-4is) in Australia. METHODS: The analysis included 15,915 adults newly prescribed DPP-4is (sitagliptin = 9576; vildagliptin = 1130; saxagliptin = 1126; linagliptin = 3560; and alogliptin = 523). Multivariable logistic regression model was used to compare the non-adherence (proportion of days covered [PDC] <0.80) rates whereas Cox proportional hazards regression models were used to compare switching and non-persistence (≥90-day gap) among different DPP4-is over 12-months. RESULTS: Overall, 36.0% (5722/15,915) of DPP-4i users were non-adherent and 30.0% (4775/15,915) were non-persistent at 12-months. Compared to sitagliptin, vildagliptin, linagliptin, and alogliptin were not associated with higher non-adherence and non-persistence. However, saxagliptin was associated with a higher likelihood of being non-adherent (odds ratio 1.41, 95% confidence interval [CI] 1.23-1.60) or non-persistent (hazard ratio 1.27, 95% CI 1.15-1.42) compared to sitagliptin. Just 3.2% of people switched between different DPP-4is. Compared to sitagliptin, people initiated on vildagliptin, saxagliptin, alogliptin, and linagliptin were more likely to switch. CONCLUSIONS: We found no significant differences in the adherence and persistence rates between alogliptin, vildagliptin or linagliptin and sitagliptin. However, saxagliptin was associated with higher non-adherence and non-persistence compared to sitagliptin. Switching was lowest amongst users of sitagliptin.

Future perspectives of the pharmacological management of diabetic dyslipidemia.

INTRODUCTION: Diabetic dyslipidemia is frequent among patients with type 2 diabetes mellitus (T2DM) and is characterized by an increase in triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and small-dense (atherogenic) particles, and by a decrease in low high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo) A1 that are strongly related to insulin resistance. The increased flux of free fatty acids from adipose tissue to the liver aggravates hepatic insulin resistance and promotes all of aspects of the dyslipidemic state. Areas covered: Statins are the first-line agents for treatment while other lipid-lowering drugs (ezetimibe, fibrate and proprotein convertase subtilisin/kexin type 9) or novel anti-diabetic agents (dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon like peptide-1 receptor agonist (GLP-1RA), sodium/glucose cotransporter 2 inhibitors (SGLT2is)) or nutraceuticals (berberine, omega 3 fatty acid, red yeast rice) can be used alone or in combination. Expert commentary: In patients with T2DM, lipid abnormalities should be identified and treated as part of the overall diabetic treatment, in order to prevent cardiovascular disease. The choice of drugs to be used is mainly based on the lipid profile and on the characteristic lipoprotein abnormalities; the use of new drugs for the treatment of hyperglycemia and lipids alteration in these patients can improve diabetic dyslipidemia.

Cardiovascular Actions and Clinical Outcomes With Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors.

Potentiation of glucagon-like peptide-1 (GLP-1) action through selective GLP-1 receptor (GLP-1R) agonism or by prevention of enzymatic degradation by inhibition of dipeptidyl peptidase-4 (DPP-4) promotes glycemic reduction for the treatment of type 2 diabetes mellitus by glucose-dependent control of insulin and glucagon secretion. GLP-1R agonists also decelerate gastric emptying, reduce body weight by reduction of food intake and lower circulating lipoproteins, inflammation, and systolic blood pressure. Preclinical studies demonstrate that both GLP-1R agonists and DPP-4 inhibitors exhibit cardioprotective actions in animal models of myocardial ischemia and ventricular dysfunction through incompletely characterized mechanisms. The results of cardiovascular outcome trials in human subjects with type 2 diabetes mellitus and increased cardiovascular risk have demonstrated a cardiovascular benefit (significant reduction in time to first major adverse cardiovascular event) with the GLP-1R agonists liraglutide (LEADER trial [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Ourcome Results], -13%) and semaglutide (SUSTAIN-6 trial [Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide], -24%). In contrast, cardiovascular outcome trials examining the safety of the shorter-acting GLP-1R agonist lixisenatide (ELIXA trial [Evaluation of Lixisenatide in Acute Coronary Syndrom]) and the DPP-4 inhibitors saxagliptin (SAVOR-TIMI 53 trial [Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53]), alogliptin (EXAMINE trial [Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome]), and sitagliptin (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin]) found that these agents neither increased nor decreased cardiovascular events. Here we review the cardiovascular actions of GLP-1R agonists and DPP-4 inhibitors, with a focus on the translation of mechanisms derived from preclinical studies to complementary findings in clinical studies. We highlight areas of uncertainty requiring more careful scrutiny in ongoing basic science and clinical studies. As newer more potent GLP-1R agonists and coagonists are being developed for the treatment of type 2 diabetes mellitus, obesity, and nonalcoholic steatohepatitis, the delineation of the potential mechanisms that underlie the cardiovascular benefit and safety of these agents have immediate relevance for the prevention and treatment of cardiovascular disease.

Changes of the glycemic control and therapeutic regimen for diabetes mellitus in the Japanese patients on hemodialysis.

OBJECTIVES/METHODS: Diabetes mellitus (DM) has become important with regard to mortality in hemodialysis (HD) patients, so it is necessary to optimize the treatment of these patients. We examined the changes in glycemic control and therapeutic regimen, including insulin and oral hypoglycemic agent (OHA) and the diet/exercise in the HD patients. RESULTS: Although DM was observed in 42 (32.6%) of the 129 (male/female 89/40) patients, there was a male predominance, with 35 DM patients being male (83.3%). The therapeutic regimens of DM patients were as follows: insulin was used in 13, OHA in 20, and diet/exercise in nine patients. The DM patients, who had not used insulin, included five patients receiving OHA (25.0%) and diet/exercise in five patients (55.6%). Nineteen of 20 OHA patients used a dipeptidyl peptidase-IV inhibitor. Although the postprandial blood glucose (PBG) in insulin was 191 ± 89 (the mean ± standard deviation [SD]) mg/dL, that in OHA group was 140 ± 36 mg/dL. The mean and the SD of the PBG were larger in insulin than in OHA group. The body mass index (BMI) and hemoglobin A1c were higher in patients treated with insulin (24.1 ± 4.2 kg/m(2), 7.1 ± 1.2%) than in patients treated with the OHA (21.2 ± 2.8 kg/m(2), 5.8 ± 0.5%; P<0.05) or diet/exercise (19.2 ± 3.6 kg/m(2), 5.3 ± 0.6%; P<0.05). The BMI and hemoglobin A1c were higher in diet/exercise compared to OHA and insulin groups. CONCLUSION: The patients undergoing HD develop DM, especially males. The BMI and hemoglobin A1c were useful to determine whether there should be a change from insulin to OHA or to diet/exercise therapy. A dipeptidyl peptidase-IV inhibitor might be a preferable treatment for the DM patients with HD in terms of the mean and SD of PBG.