Angioedema associated with dipeptidyl peptidase-IV inhibitors

Background Dipeptidyl peptidase-IV (DPP-IV) inhibitors, also known as gliptins, are a class of oral antidiabetic agents. Postmarketing reports have documented the occurrence of angioedema in patients treated with gliptins and it was found that these drugs increased the risk of angioedema in patients concurrently treated with angiotensin-converting enzyme inhibitors (ACEIs). The aim of this manuscript is to provide an overview of the risk of angioedema associated with gliptins. Methods The keywords used for the literature search in the PubMed database included “angioedema” and “dipeptidyl peptidase”, “gliptins”, or the name of each DPP-IV inhibitor. Articles in English published up to December 2020 were taken into consideration. Results The available data appear to rule out a higher risk of angioedema associated with gliptin monotherapy and have revealed an increased susceptibility in patients simultaneously treated with gliptins and ACEIs. However, one single multicenter phase IV trial and case reports, even if very limited in number, have shown that angioedema can also occur during treatment with DPP-IV inhibitors without the concomitant use of ACEIs. The involvement of other drugs and drug interactions has occasionally been suggested. In a few patients, deficiency of enzymes involved in bradykinin catabolism was detected and this finding can constitute a risk factor for angioedema exacerbated by treatment with DPP-IV inhibitors. Conclusions This risk of angioedema associated with the use of gliptins has mostly been related to the concurrent administration of ACEIs, and has been considered rare, but it might be underestimated and underreported. The role of additional risk factors or drug interactions deserves further investigations. Caution should be taken when considering the use of DPP-IV inhibitors in patients treated with ACEIs or presenting with other known risk factors for angioedema.

COVID-19 and Diabetes

The prevalence of diabetes in people with coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has varied worldwide. Most of the available evidence suggests a significant increase in severity and mortality of COVID-19 in people with either type 1 (T1DM) or type 2 diabetes mellitus (T2DM), especially in association with poor glycemic control. While new-onset hyperglycemia and new-onset diabetes (both T1DM and T2DM) have been increasingly recognized in the context of COVID-19 and have been associated with worse outcome, no conclusive evidence yet suggests direct tropism of SARS-CoV-2 on the β cells of pancreatic islets. While all approved oral antidiabetic agents appear to be safe in people with T2DM having COVID-19, no conclusive data are yet available to indicate a mortality benefit with any class of these drugs, in the absence of large randomized controlled trials. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Overtreatment and undertreatment in a sample of elderly people with diabetes

Aims In older adults with type 2 diabetes (T2D), overtreatment remains prevalent and undertreatment ignored. The main objective is to estimate the prevalence and examine factors associated with potential overtreatment and undertreatment Method Observational study conducted within an administrative database of older adults with T2D who registered in 2018 at the Portuguese Diabetes Association. Participants were categorized either as potentially overtreated (HbA1c≤7.5%), appropriately on target (HbA1c≥7.5–≤9%), or potentially undertreated (HbA1c>9%). Results of 444 participants, potential overtreatment, and undertreatment were found in 60.5% and 12.6% of the study population. Taking the patients on target as a comparator, the group of potentially overtreated showed to be more males (61.3% vs.52.2%), less-obese (34.1% vs.39.2), higher cardiovascular diseases (13.7% vs.11%), peripheral vascular diseases (16.7% vs.12.8%), diabetic foot (10% vs.4.5%), and severe kidney disease (5.2% vs.4.5%). Conversely, the potentially undertreated participants were more females (64.2% vs.47.7%), obese (49% vs.39.2%), had more dyslipidemia (69% vs.63.1%), peripheral vascular disease (14.2% vs.12.8%), diabetic foot (8.9% vs.4.5%), and infections (14.2% vs.11.9%). The odds of potential overtreatment were mostly decreased by 59% of females, 73.5% in those with retinopathy, and 86.3% in insulin, 65.4% sulfonylureas, and 66.8% in SGLT2 inhibitors users. Contrariwise, an increase in the odds of potential undertreatment was more than 4.8times higher in insulin, and more than 3.1times higher in sulfonylureas users. Conclusion potential overtreatment and undertreatment in older adults with T2D in routine clinical practice should guide the clinicians to balance the use of newer oral antidiabetic agents considering its safety profile regarding hypoglycemia.

Suboptimal control for patients with type 2 diabetes in the Central Chronic Medicine Dispensing programme in South Africa

Background: In South Africa, the Central Chronic Medicine Dispensing and Distribution (CCMDD) programme allows stable patients with non-communicable diseases, including type 2 diabetes mellitus (T2DM), to collect their medication from a pick-up location near their home, thus avoiding long waiting times and travel expenses. The CCMDD programme aims at improving patient retention and adherence through better access to medicines, resulting in better health outcomes.Aim: We assessed whether patients with T2DM enrolled in CCMDD achieved the recommended targets for glycaemic, blood pressure (BP) and lipid control.Setting: City of Tshwane, South Africa.Methods: We reviewed the records of 198 T2DM patients enrolled in CCMDD and assessed their control of haemoglobin A1c (HbA1c), BP and lipids.Results: Most of the records reviewed belonged to women (64.7%), African (89.9%), hypertensive (82.7%) and to patients exclusively on oral antidiabetic agents (98.5%). Patients were, on average, 57.7 (s.d. = 12.1) years old and had participated in the CCMDD programme for, on average, 2 years. The mean HbA1c was 8% (s.d. = 2). Glycaemic control was achieved by only 29.2% of patients, and 49% of patients had HbA1c between 7% and 9%. Ninety-three patients (66%) had achieved the total cholesterol target, 57.4% achieved BP targets and 6.9% had achieved the low-density lipoprotein cholesterol target.Conclusion: A small group of patients achieved the targets for glycaemic, BP and lipid control. Despite improved accessibility to medication, the CCMDD is not synonymous of improved clinical outcomes. Future research should ascertain the factors associated with suboptimal control for these patients.

The Current and Potential Therapeutic Use of Metformin—The Good Old Drug

Metformin, one of the oldest oral antidiabetic agents and still recommended by almost all current guidelines as the first-line treatment for type 2 diabetes mellitus (T2DM), has become the medication with steadily increasing potential therapeutic indications. A broad spectrum of experimental and clinical studies showed that metformin has a pleiotropic activity and favorable effect in different pathological conditions, including prediabetes, type 1 diabetes mellitus (T1DM) and gestational diabetes mellitus (GDM). Moreover, there are numerous studies, meta-analyses and population studies indicating that metformin is safe and well tolerated and may be associated with cardioprotective and nephroprotective effect. Recently, it has also been reported in some studies, but not all, that metformin, besides improvement of glucose homeostasis, may possibly reduce the risk of cancer development, inhibit the incidence of neurodegenerative disease and prolong the lifespan. This paper presents some arguments supporting the initiation of metformin in patients with newly diagnosed T2DM, especially those without cardiovascular risk factors or without established cardiovascular disease or advanced kidney insufficiency at the time of new guidelines favoring new drugs with pleotropic effects complimentary to glucose control. Moreover, it focuses on the potential beneficial effects of metformin in patients with T2DM and coexisting chronic diseases.

Turning Foes to Friends: Knocking Down Diabetes Associated SGLT2 Transporters and Sustaining Life

Background: The discovery of Sodium-Glucose co-transporter-2 (SGLT2) inhibitors had rewritten the treatment of diabetes mellitus with an impressive fall in the incidence of death and associated complications. Introduction: The SGLT2 inhibitors by inhibiting the SGLT2 in the proximal nephron, helps in reducing the reabsorption of approximately 90% of the filtered glucose and increased urinary glucose excretion (UGE). Methods: The literature related to SGLT2 inhibitors has been thoroughly explored from various available public domains and reviewed extensively for this article. Detailed and updated information related to SGLT2 inhibitors with a major focus on the recently approved Ertuglifolzin is structured in this review. Result: The present review is an effort to understand the management of diabetes mellitus over the past few decades with a special focus on the role of SGLT2 receptor in the causes of therapeutic and preventive strategies for diabetes mellitus. Pragmatic placement of the currently available Canagliflozin, Dapagliflozin, and Empagliflozin as oral antidiabetic agents has been done. Well accommodated stereochemistry and a high docking score of Ertugliflozin in ligand-receptor simulation studies attribute to its high potency. Conclusion: This review highlights the unique mechanism of SGLT2 Inhibitors coupled with pleiotropic benefits on weight and blood pressure, which make it an attractive choice of therapy to diabetic patients, not controlled by other medications.

Development and Validation of a Method for Simultaneous Estimation of Sitagliptin and Ertugliflozin in Rat Plasma by LC–MS method

Background: The development of sound bioanalytical LC-MS (liquid chromatography-mass spectroscopy) method(s) is of paramount importance during the process of drug discovery, development and culminating in a marketing approval. The use of oral antidiabetic agents has been increased significantly from last decades and till now no bioanalytical method is available for quantitation of sitagliptin (SG) and ertugliflozin (EG) in biological matrix which can be applied to pharmacokinetic studies using LC-MS/MS. Objective: To develop a new, rapid and sensitive LC–MS/MS method for the simultaneous estimation of sitagliptin (SG) and ertugliflozin (EG) in rat plasma by liquid–liquid extraction method (LLE) using deutereated sitagliptin (SGd6) and ertugliflozin (EGd6). Method: Chromatographic separation was carried out on a reverse phase Waters, Xetrra C18 (150mm x 4.6mm, 2μm) column using mixture of acetonitrile and OPA buffer (50:50v/v) at a flow rate of 1ml/min in isocratic mode. Quantification was achieved using an electrospray ion interface operating in positive mode, under multiple reaction monitoring (MRM) conditions. Results: The method showed excellent linearity over the concentration range of 5.00- 75.00pg/mL for sitagliptin and 0.75- 11.35pg/mL ertugliflozin. The intra-batch and inter batch precision (%CV) was ≤ 4.3% and matrix effect (%CV) was 0.02% and 0.12% for sitagliptin at HQC and LQC, respectively. Matrix effect (%CV) was 0.08% and 0.33% for ertugliflozin at HQC and LQC, respectively. Conclusion: The simplicity of the method allows for application in laboratories, presents a valuable tool for pharmacokinetic studies. The particular assay has been proficiently put on pharmacokinetic study in rats subjects.