Hypoglycaemia among adults with Type 2 Diabetes mellitus in a Family Medicine Clinic

Background: The prevalence of Diabetes mellitus (DM) is increasing worldwide. The complications of DM arising from hyperglycaemia are well documented and. However, there is a lack of data, poor awareness and information on hypoglycaemia in DM. Objective: To describe the prevalence and factors associated with hypoglycaemia among patients with Type 2 Diabetes mellitus (DM). Methods: This was a retrospective study of the clinical records of patients with Type 2 DM at the Family Medicine Clinic of a Nigerian teaching hospital from January 2019 to January 2020. The sociodemographic and clinical characteristics, including hypoglycaemia, Glycosylated Haemoglobin (HbA1c), Fasting and Random blood glucose, were retrieved. Results: A total number of 570 patients were assessed, with a prevalence of 43 (7.5%) of hypoglycaemia. The mean age of the patients in the study was 58.2±10.9 years (range: 36-83 years). Metformin (557; 97.7%), Sulphonylureas (377; 66.1%), Dipeptidylpeptidase -4 inhibitors (137; 24.0%) and insulin (72; 12.6%) were the most prescribed anti-diabetic medications. hypoglycaemiaA majority (29; 67.4%) of the hypoglycaemia episodes occurred in the morning, while most (24; 55.8%) of the episodes of hypoglycaemia were mild. Mean age (t= 2.35; p = 0.019), presence of hypertension (X2 = 6.92, p = 0.008) and dyslipidaemia (X2 = 7.86, p = 0.005) were associated with hypoglycaemia. Conclusions: The prevalence of hypoglycaemia in the Outpatient clinic was low, while the presence of comorbidities (hypertension and dyslipidaemia) and age were associated with hypoglycaemia. There is a need for patient education and Self-Monitoring of Blood Glucose (SMBG) to prevent complications of hypoglycaemia. hypoglycaemia

Cost-Effectiveness of Dipeptidylpeptidase-4 Inhibitors Added to Metformin in Patients With Type 2 Diabetes in China

PurposeDipeptidylpeptidase-4 (DPP-4) inhibitors, including linagliptin, alogliptin, saxagliptin, sitagliptin, and vildagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM) patients in China. This study assessed the economic outcomes of different DPP-4 inhibitors in patients with T2DM inadequately controlled with metformin in the Chinese context.Materials and MethodsIn this study, the validated Chinese Outcomes Model for T2DM (COMT) was conducted to project economic outcomes from the perspective of Chinese healthcare service providers. Efficacy and safety, medical expenditure, and utility data were derived from the literature, which were assigned to model variables. The primary outputs of the model included the lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analysis was conducted to assess the potential uncertainties of parameters.ResultsOf the five competing strategies, alogliptin 25 mg strategy yielded the most significant health outcome, which associated with improvements in discounted QALY of 0.007, 0.014, 0.011, and 0.022 versus linagliptin 5 mg, saxagliptin 5 mg, sitagliptin 100 mg and vildagliptin50 mg, respectively. The sitagliptin 100 mg strategy was the cheapest option. The ICER of alogliptin 25 mg against sitagliptin 100 mg strategy was $6,952 per additional QALY gained, and the rest of the strategies were dominated or extended dominated. The most influential parameters were the cost of DPP-4 inhibitors and their treatment efficacy.ConclusionsThese results suggested that alogliptin was a preferred treatment option compared with other DPP-4 inhibitors for Chinese patients whose T2DM are inadequately controlled on metformin monotherapy.

Anti-Diabetic Drugs GLP-1 Agonists and DPP-4 Inhibitors may Represent Potential Therapeutic Approaches for COVID-19

: The fast spread of coronavirus 2019 (COVID-19) calls for immediate action to counter the associated significant loss of human life and deep economic impact. Certain patient populations like those with obesity and diabetes are at higher risk for acquiring severe COVID-19 disease and have a higher risk of COVID-19 associated mortality. In the absence of an effective and safe vaccine, the only immediate promising approach is to repurpose an existing approved drug. Several drugs have been proposed and tested as adjunctive therapy for COVID-19. Among these drugs are the glucagon-like peptide-1 (GLP-1) 2 agonists and the dipeptidylpeptidase-4 (DPP-4) inhibitors. Beyond their glucose-lowering effects, these drugs have several pleiotropic protective properties, which include cardioprotective effects, anti-inflammatory and immunomodulatory activities, antifibrotic effects, antithrombotic effects, and vascular endothelial protective properties. This narrative review discusses these protective properties and addresses their scientific plausibility for their potential use as adjunctive therapy for COVID-19 disease.

Safety of Dipeptidylpeptidase-4 Inhibitors in Older Adults with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

BackgroundWe aim to assess the safety of dipeptidylpeptidase-4 inhibitors (DPP4s) in older type 2 diabetes patients with inadequate glycaemic control. MethodsWe included RCTs in older (≥65 years) patients with type 2 diabetes. The intervention group was treated with any DPP4. A systematic search in MEDLINE and EMBASE was performed in December 2020. For assessing risk of bias, the RoB 2 tool was applied. The quality of evidence was assessed using GRADE. We pooled outcomes using random-effects meta-analyses. ResultsWe identified 16 RCTs that included 19,317 patients with a mean age >70 years. The mean HbA1c ranged between 7.1g/dl and 10.0g/dl.Adding DPP4s to standard alone care may increase mortality slightly (RR 1.04; 0.89-1.21). Adding DPP4s to standard care increases the risk for hypoglycaemia (RR 1.08; 95%CI 1.01-1.16), but difference in overall adverse events is negligible.DPP4s added to standard care likely reduce mortality compared to sulfonylureas (RR 0.88; 0.75-1.04). DPP4s probably reduce the risk for hypoglycaemia compared to sulfonylureas (magnitude of effect not quantifiable because of heterogeneity) but difference in overall adverse events is negligible.There is insufficient evidence on hospitalizations, falls, fractures, renal impairment, and pancreatitis. Conclusion There is no evidence that DPP4s in addition to standard care decrease mortality but DPP4s increase hypoglycaemia risk. Second-line therapy in older patients should be considered cautiously because even in drugs with a good safety profile like DPP4s. In the case second-line treatment is necessary, DPP4s appear to be superior to sulfonylureas. RegistrationPROSPERO: CRD42020210645

Macroalgal protein hydrolysates from Palmaria palmata influence the ‘incretin effect’ in vitro via DPP-4 inhibition and upregulation of insulin, GLP-1 and GIP secretion

Purpose This study investigated metabolic benefits of protein hydrolysates from the macroalgae Palmaria palmata, previously shown to inhibit dipeptidylpeptidase-4 (DPP-4) activity in vitro. Methods Previously, Alcalase/Flavourzyme-produced P. palmata protein hydrolysate (PPPH) improved glycaemia and insulin production in streptozotocin-induced diabetic mice. Here the PPPH, was compared to alternative Alcalase, bromelain and Promod-derived hydrolysates and an unhydrolysed control. All PPPH’s underwent simulated gastrointestinal digestion (SGID) to establish oral bioavailability. PPPH’s and their SGID counterparts were tested in pancreatic, clonal BRIN-BD11 cells to assess their insulinotropic effect and associated intracellular mechanisms. PPPH actions on the incretin effect were assessed via measurement of DPP-4 activity, coupled with GLP-1 and GIP release from GLUTag and STC-1 cells, respectively. Acute in vivo effects of Alcalase/Flavourzyme PPPH administration on glucose tolerance and satiety were assessed in overnight-fasted mice. Results PPPH’s (0.02–2.5 mg/ml) elicited varying insulinotropic effects (p < 0.05–0.001). SGID of the unhydrolysed protein control, bromelain and Promod PPPH’s retained, or improved, bioactivity regarding insulin secretion, DPP-4 inhibition and GIP release. Insulinotropic effects were retained for all SGID-hydrolysates at higher PPPH concentrations. DPP-4 inhibitory effects were confirmed for all PPPH’s and SGID counterparts (p < 0.05–0.001). PPPH’s were shown to directly influence the incretin effect via upregulated GLP-1 and GIP (p < 0.01–0.001) secretion in vitro, largely retained after SGID. Alcalase/Flavourzyme PPPH produced the greatest elevation in cAMP (p < 0.001, 1.7-fold), which was fully retained post-SGID. This hydrolysate elicited elevations in intracellular calcium (p < 0.01) and membrane potential (p < 0.001). In acute in vivo settings, Alcalase/Flavourzyme PPPH improved glucose tolerance (p < 0.01–0.001) and satiety (p < 0.05–0.001). Conclusion Bioavailable PPPH peptides may be useful for the management of T2DM and obesity.

Hypoglycemia Associated With Drug–Drug Interactions in Patients With Type 2 Diabetes Mellitus Using Dipeptidylpeptidase-4 Inhibitors

Background: Dipeptidylpeptidase-4 inhibitors (DPP-4i′s) are considered to be safe for patients with type 2 diabetes mellitus (T2DM). However, little is known about drug–drug interactions between DPP-4i′s and concurrent medications.Methods: Data on patients using DPP-4i′s for T2DM during 2011–2017 were retrieved from Chang Gung Research database provided by Chang Gung Memorial Hospital. Patients were excluded if they were aged &lt;30 years or &gt;90 years; had incomplete demographic data; had insulinoma; or had records of concomitant insulin use. A generalized estimating equation–based Poisson model was employed for statistical analysis. The primary outcome was hypoglycemia events.Results: We retrieved data on a total of 97,227 patients using DPP-4i′s. After patients were excluded according to the mentioned criteria, the remaining 77,047 DPP-4i users were studied (mean age 64 ± 12 years, men 54.4%). The most common medications coprescribed with DPP4is over all person-quarters were acetaminophen, simvastatin, fluvastatin, and colchicine (all &gt;20,000 person-quarters). The combinations of a DPP-4i with bumetanide, captopril, colchicine, acetaminophen, cotrimoxazole, and pantoprazole were associated with an increased risk of hypoglycemia. Compared with the ratios observed for person-quarters of DPP-4i use alone (reference category), the adjusted prevalence ratios per 100 person-years of hypoglycemia for person-quarters of DPP-4i use in combination with bumetanide, captopril, colchicine, acetaminophen, cotrimoxazole, and pantoprazole were 2.44 (95% confidence interval [CI], 1.78–3.36), 2.97 (95% CI, 2.26–3.90), 1.87 (95% CI, 1.44–2.42), 2.83 (95% CI, 2.44–3.29), 2.27 (95% CI, 1.27–4.04), and 3.03 (95% CI, 1.96–4.68), respectively.Conclusion: Among patients taking DPP-4i′s for T2DM, concurrent use of such inhibitors with bumetanide, captopril, acetaminophen, and pantoprazole was associated with an increased risk of hypoglycemia compared with the use of DPP-4i′s alone. Physicians prescribing DPP-4i′s should consider the potential risks associated with their concomitant use with other drugs.

Molecular modelling as a tool for designing dipeptidylpeptidase-4 inhibitors

Dipeptidyl peptidase-4 (DPP-4) is a relatively new target for the treatment of type-2 diabetes mellitus (T2DM). Most of the inhibitors designed to date have not relied on modelling studies to guide their lead optimization efforts. In our previous work, we designed compounds that retain the (R)-3-amino-4-(2,4,5-trifluorophenyl)butanamido S1-pocket binding moiety of sitagliptin, but have S2-pocket binding moieties that are more hydrophobic than the triazolopiperazine. In an effort to understand how Vina docking algorithm can be integrated in discovering new inhibitors of DPP-4; we designed, synthesized and evaluated new compounds that vary in the hydrophobic properties of the S2-pocket binding groups. Our results indicate that the minimum binding energy predicted from the docking studies was not reliable in designing more active candidates. However, visualizing the binding modes of each compound and modifying it to target neighboring key residues in the active site is a more effective implementation of the docking in the design of new compounds. Compounds in this study displayed IC50 values ranging from 0.37 µM to 11 µM.