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

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

Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors for the treatment of diabetes mellitus in liver transplant recipients.

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/m2, 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/m2, 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.

Saxagliptin/dapagliflozin is non-inferior to insulin glargine in terms of ß-cell function in subjects with latent autoimmune diabetes in adults: A 12-month, randomized, comparator-controlled pilot study.

AIM: To compare the efficacy and safety of saxagliptin/dapagliflozin and insulin glargine in people with latent autoimmune diabetes in adults (LADA). METHODS: In this phase 2b multicentre, open-label, comparator-controlled, parallel-group, non-inferiority study, we randomly assigned 33 people with LADA who had a fasting C-peptide concentration ≥0.2 nmol/L (0.6 ng/mL) to receive 1-year daily treatment with either the combination of saxagliptin (5 mg) plus dapagliflozin (10 mg) or insulin glargine (starting dose: 10 IU), both on top of metformin. The primary outcome was the 2-h mixed meal-stimulated C-peptide area under the curve (AUC), measured 12 months after randomization. Secondary outcomes were glycated haemoglobin (HbA1c) levels, change in body mass index (BMI), and hypoglycaemic events. RESULTS: In the modified intention-to-treat analysis, the primary outcome was similar in participants assigned to saxagliptin/dapagliflozin or to insulin glargine (median C-peptide AUC: 152.0 ng*min/mL [95% confidence interval {CI} 68.2; 357.4] vs. 122.2 ng*min/mL [95% CI 84.3; 255.8]; p for noninferiority = 0.0087). Participants randomized to saxagliptin/dapagliflozin lost more weight than those randomized to insulin glargine (median BMI change at the end of the study: -0.4 kg/m2 [95% CI -1.6; -0.3] vs. +0.4 kg/m2 [95% CI -0.3; +1.1]; p = 0.0076). No differences in HbA1c or in the number of participants experiencing hypoglycaemic events were found. CONCLUSIONS: Saxagliptin/dapagliflozin was non-inferior to glargine in terms of ß-cell function in this 12-month, small, phase 2b study, enrolling people with LADA with still viable endogenous insulin production. Weight loss was greater with saxagliptin/dapagliflozin, with no differences in glycaemic control or hypoglycaemic risk.

The potential for improved outcomes in the prevention and therapy of diabetic kidney disease through 'stacking' of drugs from different classes.

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.

Linagliptin ameliorates tacrolimus-induced renal injury: role of Nrf2/HO-1 and HIF-1α/CTGF/PAI-1.

BACKGROUND: Tacrolimus (TAC) is a frequently used immunosuppressive medication in organ transplantation. However, its nephrotoxic impact limits its long-term usage. This study aims to investigate the effect of linagliptin (Lina) on TAC-induced renal injury and its underlying mechanisms. METHODS AND RESULTS: Thirty-two Sprague Dawley rats were treated with TAC (1.5 mg/kg/day, subcutaneously) and/or Lina (5 mg/kg/day, orally) for 4 weeks. Histological examination was conducted, and serum and urinary biomarkers were measured to assess kidney function and integrity. Furthermore, ELISA, Western blot analysis and immunohistochemical assay were employed to determine signaling molecules of oxidative stress, profibrogenic, hypoxic, and apoptotic proteins. Tacrolimus caused renal dysfunction and histological deterioration evidenced by increased serum creatinine, blood urea nitrogen (BUN), urinary cystatin C, and decreased serum albumin as well as elevated tubular injury and interstitial fibrosis scores. Additionally, TAC significantly increased the expression of collagen type-1, alpha-smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), and transforming growth factor-beta1 (TGF-ß1) renal content. Moreover, TAC decreased the expression of nuclear factor erythroid-2-related factor2 (Nrf2), heme oxygenase 1 (HO-1), and mitochondrial superoxide dismutase (SOD2). In addition, TAC increased protein expression of hypoxia-inducible factor1-alpha (HIF-1α), connective tissue growth factor (CTGF), inducible nitric oxide synthase (iNOS), 8-hydroxy-2-deoxyguanosine (8-OHdG), as well as nitric oxide (NO), 4-hydroxynonenal, caspase-3 and Bax renal contents. Furthermore, TAC decreased Bcl-2 renal contents. The Lina administration markedly attenuated these alterations. CONCLUSION: Lina ameliorated TAC-induced kidney injury through modulation of oxidative stress, hypoxia, and apoptosis related proteins.

Unveiling anti-diabetic potential of new thiazole-sulfonamide derivatives: Design, synthesis, in vitro bio-evaluation targeting DPP-4, α-glucosidase, and α-amylase with in-silico ADMET and docking simulation.

Diabetes mellitus type 2 (T2DM) can be managed by targeting dipeptidyl peptidase-4 (DPP-4), an enzyme that breaks down and deactivates peptides such as GIP and GLP-1. In this context, a new series of 2-(2-substituted hydrazineyl)thiazole derivatives 4, 5, 6, 8, 10, and 11 conjugated with the 2-hydroxy-5-(pyrrolidin-1-ylsulfonyl)benzylidene fragment were designed and synthesized. The virtual screening of the designed derivatives inside DPP-4 demonstrated good to moderate activity, with binding affinity ranging from -6.86 to -5.36 kcal/mol compared to Sitagliptin (S=-5.58 kcal/mol). These results encourage us to evaluate DPP-4 using in-vitro fluorescence-based assay. The in-vitro results exhibited inhibitory percentage (IP) values ranging from 40.66 to 75.62 % in comparison to Sitagliptin (IP=63.14 %) at 100 µM. Subsequently, the IC50 values were determined, and the 5-aryl thiazole derivatives 10 and 11 revealed strong potent IC50 values 2.75 ± 0.27 and 2.51 ± 0.27 µM, respectively, compared to Sitagliptin (3.32 ± 0.22 µM). The SAR study exhibited the importance of the substituents on the thiazole scaffold, especially with the hydrophobic fragment at C5 of the thiazole, which has a role in the activity. Compounds 10 and 11 were further assessed toward α-glucosidase and α-amylase enzymes and give promising results. Compound 10 showed good activity against α-glucosidase with IC50 value of 3.02 ± 0.23 µM compared to Acarbose 3.05 ± 0.22 µM and (11 = 3.34 ± 0.10 µM). On the other hand, for α-amylase, compound 11 was found to be most effective with IC50 value of 2.91 ± 0.23 µM compared to compound 10 = 3.30 ± 0.16 µM and Acarbose (2.99 ± 0.21 µM) indicating that these derivatives could reduce glucose by more than one target. The most active derivatives 10 and 11 attracted great interest as candidates for oral bioavailability and safe toxicity profiles compared to positive controls. The in-silico docking simulation was performed to understand the binding interactions inside the DPP-4, α-glucosidase, and α-amylase pockets, and it was found to be promising antidiabetic agents through a number of interactions.

Recent advances and structure-activity relationship studies of DPP-4 inhibitors as anti-diabetic agents.

Diabetes mellitus (DM) is one of the largest public health problems worldwide and in the last decades various therapeutic targets have been investigated. For the treatment of type-2 DM (T2DM), dipeptidyl peptidase-4 (DPP-4) is one of the well reported target and has established safety in terms of cardiovascular complexicity. Preclinical and clinical studies using DPP-4 inhibitors have demonstrated its safety and effectiveness and have lesser risk of associated hypoglycaemic effect making it suitable for elderly patients. FDA has approved a number of structurally diverse DPP-4 inhibitors for clinical use. The present manuscript aims to focus on the well reported hybrid and non-hybrid analogues and their structural activity relationship (SAR) studies. It aims to provide structural insights for this class of compounds pertaining to favourable applicability of selective DPP-4 inhibitors in the treatment of T2DM.

A comprehensive review on potential drug-drug interactions of proton pump inhibitors with antidiabetic drugs metformin and DPP-4 inhibitors.

A drug interaction is a condition in which two or more drugs are taken at the same time. Type 2 diabetes mellitus is a significant contributor to polypharmacy. Proton pump inhibitors (PPIs) are often prescribed in combination with metformin or DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin) or a combined dose of metformin and DPP-4 inhibitor to treat gastritis in diabetic patients. This review article mainly focused on evaluating the potential drug-drug interactions (DDIs) between PPIs (i.e. esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole) with metformin and PPIs with DPP-4 inhibitors. The findings demonstrated the existence of pharmacokinetic and pharmacodynamic DDIs between the aforementioned PPIs with metformin and DPP-4 inhibitors, which could impact the biological activities (i.e., hypoglycemia) of these drugs. Moreover, this review suggested that esomeprazole could be the best drug in the PPI group to be prescribed simultaneously with metformin and DPP-4 inhibitors, as most of the antidiabetic drugs of this study did not show any interaction with esomeprazole. The findings of this study also revealed that both antidiabetic drugs and PPIs could have positive interactions as PPIs have the potential to lessen the gastrointestinal side effects of metformin and DPP-4 inhibitors. To achieve the greatest therapeutic impact with the fewest side effects, careful dose control of these drugs is required. So, more extensive research on both human and animal subjects are needed to ascertain the veracity of this hypothesis.

Meta-Analysis on the Association Between DPP-4 Inhibitors and Bone Mineral Density and Osteoporosis.

Background Type 2 Diabetes Mellitus (T2DM) frequently coexists with osteoporosis and reduced bone mineral density (BMD). Dipeptidyl peptidase-4 inhibitors (DPP-4i), a class of antihyperglycemic agents, are commonly employed in T2DM treatment. However, the influence of DPP-4i on bone health remains unclear and debated. This meta-analysis is conducted to explore the relationship between the use of DPP-4i and changes in BMD, as well as the prevalence of osteoporosis among T2DM patients. Methods We conducted a comprehensive search in PubMed, Embase, and Cochrane Library and Web of Science databases for relevant studies published up until June 2023. Studies included in the meta-analysis were those investigating T2DM patients under DPP-4i treatment, and examining the effects on BMD and osteoporosis. Random-effects models and fixed-effect models were utilized to compute the pooled effects. Heterogeneity among the included studies was evaluated using I² statistics. Results This meta-analysis incorporated a total of 10 studies, encompassing a combined population of 214,541 individuals. The results from this meta-analysis indicated an increase in BMD following DPP-4i usage (SMD 0.15, 95 % confidence interval 0.03-0.26). Additionally, the risk of osteoporosis was significantly reduced (OR 0.90, 95 % confidence interval 0.86-0.94) with very low heterogeneity, recorded at 0 % and 53.0 % respectively. No publication bias was detected in the funnel plot, and sensitivity analyses affirmed the stability of the study's conclusions. Conclusion Our results offer valuable insights into the positive impact of DPP-4i on bone health in T2DM patients, contributing to informed clinical decision-making. These findings may inform the development of more comprehensive T2DM management strategies that account for bone health.

Discovery of Nine Dipeptidyl Peptidase-4 Inhibitors from Coptis chinensis Using Virtual Screening, Bioactivity Evaluation, and Binding Studies.

The objective of this study was to identify multiple alkaloids in Coptis chinensis that demonstrate inhibitory activity against DPP-4 and systematically evaluate their activity and binding characteristics. A combined strategy that included molecular docking, a DPP-4 inhibition assay, surface plasmon resonance (SPR), and a molecular dynamics simulation technique was employed. The results showed that nine alkaloids in Coptis chinensis directly inhibited DPP-4, with IC50 values of 3.44-53.73 µM. SPR-based binding studies revealed that these alkaloids display rapid binding and dissociation characteristics when interacting with DPP-4, with KD values ranging from 8.11 to 29.97 µM. A molecular dynamics analysis revealed that equilibrium was rapidly reached by nine DPP-4-ligand systems with minimal fluctuations, while binding free energy calculations showed that the ∆Gbind values for the nine test compounds ranged from -31.84 to -16.06 kcal/mol. The most important forces for the binding of these alkaloids with DPP-4 are electrostatic interactions and van der Waals forces. Various important amino acid residues, such as Arg125, His126, Phe357, Arg358, and Tyr547, were involved in the inhibition of DPP-4 by the compounds, revealing a mechanistic basis for the further optimization of these alkaloids as DPP-4 inhibitors. This study confirmed nine alkaloids as direct inhibitors of DPP-4 and characterized their binding features, thereby providing a basis for further research and development on novel DPP-4 inhibitors.

Socioeconomic aspects of incretin-based therapy.

Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have demonstrated cardiovascular benefits in people with type 2 diabetes. However, socioeconomic disparities in their uptake may constrain the collective advantages offered by these medications to the broader population. In this review we examine the socioeconomic disparities in the utilisation of incretin-based therapies and discuss strategies to address these inequalities. Based on real-world evidence, the uptake of GLP-1 RAs is reduced in people who live in socioeconomically disadvantaged areas, have low income and education level, or belong to racial/ethnic minorities, even though these individuals have a greater burden of type 2 diabetes and cardiovascular disease. Contributing factors include suboptimal health insurance coverage, limited accessibility to incretin-based therapies, financial constraints, low health literacy and physician-patient barriers such as provider bias. Advocating for a reduction in the price of GLP-1 RAs is a pivotal initial step to enhance their affordability among lower socioeconomic groups and improve their value-for-money from a societal perspective. By implementing cost-effective strategies, healthcare systems can amplify the societal benefits of incretin-based therapies, alongside measures that include maximising treatment benefits in specific subpopulations while minimising harms in vulnerable individuals, increasing accessibility, enhancing health literacy and overcoming physician-patient barriers. A collaborative approach between governments, pharmaceutical companies, healthcare providers and people with diabetes is necessary for the effective implementation of these strategies to enhance the overall societal benefits of incretin-based therapies.

Incretins and microvascular complications of diabetes: neuropathy, nephropathy, retinopathy and microangiopathy.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs, incretin mimetics) and dipeptidyl peptidase-4 inhibitors (DPP-4is, incretin enhancers) are glucose-lowering therapies with proven cardiovascular safety, but their effect on microvascular disease is not fully understood. Both therapies increase GLP-1 receptor agonism, which is associated with attenuation of numerous pathological processes that may lead to microvascular benefits, including decreased reactive oxygen species (ROS) production, decreased inflammation and improved vascular function. DPP-4is also increase stromal cell-derived factor-1 (SDF-1), which is associated with neovascularisation and tissue repair. Rodent studies demonstrate several benefits of these agents in the prevention or reversal of nephropathy, retinopathy and neuropathy, but evidence from human populations is less clear. For nephropathy risk in human clinical trials, meta-analyses demonstrate that GLP-1RAs reduce the risk of a composite renal outcome (doubling of serum creatinine, eGFR reduction of 30%, end-stage renal disease or renal death), whereas the benefits of DPP-4is appear to be limited to reductions in the risk of albuminuria. The relationship between GLP-1RAs and retinopathy is less clear. Many large trials and meta-analyses show no effect, but an observed increase in the risk of retinopathy complications with semaglutide therapy (a GLP-1RA) in the SUSTAIN-6 trial warrants caution, particularly in individuals with baseline retinopathy. Similarly, DPP-4is are associated with increased retinopathy risk in both trials and meta-analysis. The association between GLP-1RAs and peripheral neuropathy is unclear due to little trial evidence. For DPP-4is, one trial and several observational studies show a reduced risk of peripheral neuropathy, with others reporting no effect. Evidence in other less-established microvascular outcomes, such as microvascular angina, cerebral small vessel disease, skeletal muscle microvascular disease and autonomic neuropathies (e.g. cardiac autonomic neuropathy, gastroparesis, erectile dysfunction), is sparse. In conclusion, GLP-1RAs are protective against nephropathy, whereas DPP-4is are protective against albuminuria and potentially peripheral neuropathy. Caution is advised with DPP-4is and semaglutide, particularly for patients with background retinopathy, due to increased risk of retinopathy. Well-designed trials powered for microvascular outcomes are needed to clarify associations of incretin therapies and microvascular diseases.

Evaluation of selected antidiabetics in cardiovascular complications associated with cancer cachexia.

So far, the cardio-protective potential of antidiabetics is proved, but their effect on cardiovascular complications associated with cancer cachexia is not explored until now. Insulin resistance and glucose intolerance along with systemic inflammation are prominent in cachexia but the potential effect of antidiabetic agents especially those belonging to biguanide, DPP4 inhibitors and SGLT2 on the heart are not studied till now. In present study, the effect of metformin, vildagliptin, teneligliptin, dapagliflozin and empagliflozin on cardiovascular complications associated with cancer cachexia by using B16F1 induced metastatic cancer cachexia and urethane-induced cancer cachexia was studied. These antidiabetic agents proved to be beneficial against cachexia-induced atrophy of the heart, preserved ventricular weights, maintained cardiac hypertrophic index, preserved the wasting of cardiac muscles assessed by HE staining, Masson trichrome staining, periodic acid Schiff staining and picro-Sirius red staining. Altered cardiac gene expression was attenuated after treatment with selected antidiabetics, thus preventing cardiac atrophy. Also, antidiabetic agents treatment improved the serum creatinine kinase MB, Sodium potassium ATPase and collagen in the heart. Reduction in blood pressure and heart rate was observed after treatment with antidiabetic agents. Results of our study show that the selected antidiabetics prove to be beneficial in attenuating the cardiac atrophy and helps in regulation of hemodynamic stauts in cancer cachexia-induced cardiovascular complications. Our study provides some direction towards use of selected antidiabetic agents in the management of cardiovascular complications associated with cancer cachexia and the study outcomes can be useful in desiging clinical trials.

Effects of new hypoglycemic drugs on cardiac remodeling: a systematic review and network meta-analysis.

BACKGROUND: In recent years, the incidence of diabetes mellitus has been increasing annually, and cardiovascular complications secondary to diabetes mellitus have become the leading cause of death in diabetic patients. Considering the high incidence of type 2 diabetes (T2DM) combined with cardiovascular disease (CVD), some new hypoglycemic agents with cardiovascular protective effects have attracted extensive attention. However, the specific role of these regimens in ventricular remodeling remains unknown. The purpose of this network meta-analysis was to compare the effects of sodium glucose cotransporter type 2 inhibitor (SGLT-2i), glucagon-like peptide 1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 inhibitor (DPP-4i) on ventricular remodeling in patients with T2DM and/or CVD. METHODS: Articles published prior to 24 August 2022 were retrieved in four electronic databases: the Cochrane Library, Embase, PubMed, and Web of Science. This meta-analysis included randomized controlled trials (RCTs) and a small number of cohort studies. The differences in mean changes of left ventricular ultrasonic parameters between the treatment and control groups were compared. RESULTS: A total of 31 RCTs and 4 cohort studies involving 4322 patients were analyzed. GLP-1RA was more significantly associated with improvement in left ventricular end-systolic diameter (LVESD) [MD = -0.38 mm, 95% CI (-0.66, -0.10)] and LV mass index (LVMI) [MD = -1.07 g/m2, 95% CI (-1.71, -0.42)], but significantly decreased e' [MD = -0.43 cm/s 95% CI (-0.81, -0.04)]. DPP-4i was more strongly associated with improvement in e' [MD = 3.82 cm/s, 95% CI (2.92,4.7)] and E/e'[MD = -5.97 95% CI (-10.35, -1.59)], but significantly inhibited LV ejection fraction (LVEF) [MD = -0.89% 95% CI (-1.76, -0.03)]. SGLT-2i significantly improved LVMI [MD = -0.28 g/m2, 95% CI (-0.43, -0.12)] and LV end-diastolic diameter (LVEDD) [MD = -0.72 ml, 95% CI (-1.30, -0.14)] in the overall population, as well as E/e' and SBP in T2DM patients combined with CVD, without showing any negative effect on left ventricular function. CONCLUSION: The results of the network meta-analysis provided high certainty to suggest that SGLT-2i may be more effective in cardiac remodeling compared to GLP-1RA and DPP-4i. While GLP-1RA and DPP-4i may have a tendency to improve cardiac systolic and diastolic function respectively. SGLT-2i is the most recommended drug for reversing ventricular remodeling in this meta-analysis.

Cardiovascular and Renal Outcomes With Sodium-Glucose Cotransporter-2 Inhibitors and Dipeptidyl Peptidase-4 Inhibitors Combination Therapy: A Meta-Analysis of Randomized Cardiovascular Outcome Trials.

OBJECTIVE: The cardiovascular (CV) and renal benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in people with type 2 diabetes are well known. However, similar beneficial effects of SGLT2i in combination with dipeptidyl peptidase-4 inhibitors (DPP4i) are unknown. It is of interest to explore a trial-level meta-analysis to fill this knowledge gap. METHODS: A literature search was conducted in the PubMed and Embase databases until January 31, 2023. All CV outcome trials (CVOTs) reporting the CV and renal outcomes of SGLT2i with or without background DPP4i therapy against the placebo were retrieved. A meta-analysis was subsequently conducted by applying the inverse variance-weighted averages of pooled logarithmic hazard ratio using primarily random-effects analysis. RESULTS: This meta-analysis showed that the beneficial 3-point major adverse cardiovascular events composite (3 CVOTs; N = 32 418), the composite of CV death or heart failure hospitalization (hHF) (4 CVOTs; N = 37 687), hHF (3 CVOTs; N = 27 545), CV death (4 CVOTs; N = 34 565), and renal outcomes (2 CVOTs; N = 25 406) with SGLT2i were similar with or without background DPP4i therapy against the placebo (Pheterogeneity = .71, .07, .87, .72, and .25; respectively). However, against the placebo, the summary estimates for the 3-point major adverse cardiovascular events composite, hHF, and renal outcomes were stronger with SGLT2i alone, whereas the summary estimates for CV death or hHF composite were larger with SGLT2i with background DPP4i therapy. CONCLUSION: Beneficial CV and renal effects of SGLT2i are similar against the placebo regardless of background DPP4i therapy.

Tetrazoles and Related Heterocycles as Promising Synthetic Antidiabetic Agents.

Tetrazole heterocycle is a promising scaffold in drug design, and it is incorporated into active pharmaceutical ingredients of medications of various actions: hypotensives, diuretics, antihistamines, antibiotics, analgesics, and others. This heterocyclic system is metabolically stable and easily participates in various intermolecular interactions with different biological targets through hydrogen bonding, conjugation, or van der Waals forces. In the present review, a systematic analysis of the activity of tetrazole derivatives against type 2 diabetes mellitus (T2DM) has been performed. As it was shown, the tetrazolyl moiety is a key fragment of many antidiabetic agents with different activities, including the following: peroxisome proliferator-activated receptors (PPARs) agonists, protein tyrosine phosphatase 1B (PTP1B) inhibitors, aldose reductase (AR) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, G protein-coupled receptor (GPCRs) agonists, glycogen phosphorylases (GP) Inhibitors, α-glycosidase (AG) Inhibitors, sodium glucose co-transporter (SGLT) inhibitors, fructose-1,6-bisphosphatase (FBPase) inhibitors, IkB kinase ε (IKKε) and TANK binding kinase 1 (TBK1) inhibitors, and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). In many cases, the tetrazole-containing leader compounds markedly exceed the activity of medications already known and used in T2DM therapy, and some of them are undergoing clinical trials. In addition, tetrazole derivatives are very often used to act on diabetes-related targets or to treat post-diabetic disorders.

Insight into Structure Activity Relationship of DPP-4 Inhibitors for Development of Antidiabetic Agents.

This article sheds light on the various scaffolds that can be used in the designing and development of novel synthetic compounds to create DPP-4 inhibitors for the treatment of type 2 diabetes mellitus (T2DM). This review highlights a variety of scaffolds with high DPP-4 inhibition activity, such as pyrazolopyrimidine, tetrahydro pyridopyrimidine, uracil-based benzoic acid and esters, triazole-based, fluorophenyl-based, glycinamide, glycolamide, ß-carbonyl 1,2,4-triazole, and quinazoline motifs. The article further explains that the potential of the compounds can be increased by substituting atoms such as fluorine, chlorine, and bromine. Docking of existing drugs like sitagliptin, saxagliptin, and vildagliptin was done using Maestro 12.5, and the interaction with specific residues was studied to gain a better understanding of the active sites of DPP-4. The structural activities of the various scaffolds against DPP-4 were further illustrated by their inhibitory concentration (IC50) values. Additionally, various synthesis schemes were developed to make several commercially available DPP4 inhibitors such as vildagliptin, sitagliptin and omarigliptin. In conclusion, the use of halogenated scaffolds for the development of DPP-4 inhibitors is likely to be an area of increasing interest in the future.

New antidiabetic therapy and HFpEF: light at the end of tunnel?

New antidiabetic therapy that includes sodium-glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors showed significant benefit on cardiovascular outcomes in patients with and without type 2 diabetes mellitus, and this was particularly confirmed for SGLT2 inhibitors in subjects with heart failure (HF) with reduced ejection fraction (HFrEF). Their role on patients with HF with preserved ejection fraction (HFpEF) is still not elucidated, but encouraging results coming from the clinical studies indicate their beneficial role. The role of GLP-1R agonists and particularly DPP-4 inhibitors is less clear and debatable. Findings from the meta-analyses are sending positive message about the use of GLP-1R agonists in HFrEF therapy and revealed the improvement of left ventricular (LV) diastolic function in HFpEF. Nevertheless, the relevant medical societies still consider their effect as neutral or insufficiently investigated in HF patients. The impact of DPP-4 inhibitors in HF is the most controversial due to conflicting data that range from negative impact and increased risk of hospitalization due to HF, throughout neutral effect, to beneficial influence on LV diastolic dysfunction. However, this is a very heterogeneous group of medications and some professional societies made clear discrepancy between saxagliptin that might increase risk of HF hospitalization and those DPP-4 inhibitors that have no effect on hospitalization. The aim of this review is to summarize current clinical evidence about the effect of new antidiabetic medications on LV diastolic function and their potential benefits in HFpEF patients.

The effect of DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors on cardiorenal outcomes: a network meta-analysis of 23 CVOTs.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose co-transporter-2 (SGLT-2) inhibitors reduce cardiorenal outcomes. We performed a network meta-analysis to compare the effect on cardiorenal outcomes among GLP-1 RAs, SGLT-2 inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS: We searched the PUBMED, Embase and Cochrane databases for relevant studies published up until 10 December 2021. Cardiovascular and renal outcome trials reporting outcomes on GLP-1RA, SGLT-2 inhibitors and DPP-4 inhibitors in patients with or without type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE); other outcomes were cardiovascular and total death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure (HHF), and renal outcome. RESULTS: Twenty-three trials enrolling a total number of 181,143 participants were included. DPP-4 inhibitors did not lower the risk of any cardiorenal outcome when compared with placebo and were associated with higher risks of MACE, HHF, and renal outcome when compared with the other two drug classes. SGLT-2 inhibitors significantly reduced cardiovascular (RR = 0.88) and total (RR = 0.87) death, as compared with DPP-4 inhibitors, while GLP-1 RA reduced total death only (RR = 0.87). The comparison between GLP-1RA and SGLT-2 inhibitors showed no difference in their risks of MACE, nonfatal MI, nonfatal stroke, CV and total death; SGLT-2 inhibitors were superior to GLP-1RA in reducing the risk of HHF and the renal outcome (24% and 22% lower risk, respectively). Only GLP-1RA reduced the risk of nonfatal stroke (RR = 0.84), as compared with placebo. There was no head-to-head trial directly comparing these antidiabetic drug classes. CONCLUSIONS: SGLT-2 inhibitors and GLP-1RA are superior to DPP-4 inhibitors in reducing the risk of most cardiorenal outcomes; SGLT-2 inhibitors are superior to GLP-1RA in reducing the risk of HHF and renal events; GLP-1RA only reduced the risk of nonfatal stroke. Both SGLT-2 inhibitors and GLP-1RA should be the preferred treatment for type 2 diabetes and cardiorenal diseases.

Beneficial effects of dipeptidyl peptidase-4 inhibitors in diabetic Parkinson's disease.

Dipeptidyl peptidase 4 (DPP4) inhibitors are widely used hypoglycaemic agents and improve glucose metabolism by enhancing the bioavailability of active glucagon-like peptide-1. In this study, we hypothesized that treatment with DPP4 inhibitors may have beneficial effects on nigrostriatal dopamine and longitudinal motor performance in diabetic patients with Parkinson's disease. We classified 697 drug naive patients with de novo Parkinson's disease who had undergone dopamine transporter imaging into three groups according to a prior diagnosis of diabetes and use of DPP4 inhibitors: diabetic patients with Parkinson's disease being treated with (n = 54) or without DPP4 inhibitors (n = 85), and non-diabetic patients with Parkinson's disease (n = 558). Diabetic patients with Parkinson's disease being treated with DPP4 inhibitors had a higher baseline dopamine transporter availability in the anterior (2.56 ± 0.74 versus 2.10 ± 0.50; P = 0.016), posterior (1.83 ± 0.69 versus 1.40 ± 0.50; P < 0.001), and ventral putamina (1.72 ± 0.58 versus 1.35 ± 0.37; P = 0.001) than that in diabetic patients with Parkinson's disease without DPP4 inhibitors. Additionally, diabetic patients with Parkinson's disease being treated with DPP4 inhibitors had higher dopamine transporter availability in the posterior putamen than that in non-diabetic patients with Parkinson's disease (1.83 ± 0.69 versus 1.43 ± 0.59; P < 0.001). After adjusting for age, sex, disease duration, and vascular risk factors, linear regression models showed that a prior treatment of DPP4 inhibitors remained independently and significantly associated with dopamine transporter availability in the anterior (ß = -0.186, P = 0.012; ß = -0.207, P = 0.003), posterior (ß = -0.336, P < 0.001; ß = -0.286, P < 0.001), and ventral putamina (ß = -0.204, P = 0.005; ß = -0.250, P < 0.001). A linear mixed model revealed that the diabetic group with Parkinson's disease being treated with DPP4 inhibitors had a slower longitudinal increase in levodopa-equivalent dose than the other groups (P = 0.003). Survival analyses showed that the rate of levodopa-induced dyskinesia was significantly lower in the diabetic group with a prior treatment with DPP4 inhibitors than the diabetic group without DPP4 inhibitors (hazard ratio = 0.194, P = 0.037). These findings suggest that DPP4 inhibitors may confer beneficial effects on the baseline nigrostriatal dopamine degeneration and long-term motor outcomes in diabetic patients with Parkinson's disease and may extend its role into non-diabetic patients with Parkinson's disease.