The U.S. Food and Drug Administration issued a guidance for pharmaceutical industry defining preapproval and postapproval requirements for the demonstration of cardiovascular (CV) safety for all new medications developed for glycemic management in type 2 diabetes. However, results published from the studies of dipeptidyl peptidase-4 (DPP-4) inhibitors are conflicting with regard to different CV endpoints. Upcoming CV outcome studies perhaps will be able to provide additional insights related to diabetes management and help to provide the answers to some of these concerns. This article provides a brief overview regarding how various CV safety evidence of DPP-4 inhibitor evolved over time that highlights possible implication in clinical practice and translates them into effective diabetes management.

Current development around the pandemic of novel coronavirus disease 2019 (COVID-19) presents a significant healthcare resource burden threatening to overwhelm the available nationwide healthcare infrastructure. It is essential to consider, especially for resource-limited nations, strategizing the coordinated response to handle this crisis effectively and preparing for the upcoming emergence of calamity caused by this yet-to-know disease entity.Relevant epidemiological data were retrieved from currently available online reports related to COVID-19 patients. The correlation coefficient was calculated by plotting dependant variables -the number of COVID-19 cases and the number of deaths due to COVID 19 on the Y-axis and independent variables -critical-care beds per capita, the median age of the population of the country, the number of COVID-19 tests per million population, population density (persons per square km), urban population percentage, and gross domestic product (GDP) expense on health care -on the X-axis.After analyzing the data, both the fatality rate and the total number of COVID-19 cases were found to have an inverse association with the population density with the variable -the number of cases of COVID-19 -achieving a statistical significance (p-value 0.01). The negative correlation between critical care beds and the fatality rate is well-justified, as intensive care unit (ICU) beds and ventilators are the critical elements in the management of complicated cases. There was also a significant positive correlation between GDP expenses on healthcare by a country and the number of COVID-19 cases being registered (p-value 0.008), although that did not affect mortality (p-value 0.851). This analysis discusses the overview of various epidemiological determinants possibly contributing to the variation in patient outcomes across regions and helps improve our understanding to develop a plan of action and effective control measures in the future.

BackgroundDespite conventional insulin treatment being considered an effective approach for glycemic regulation during renal dysfunction, there is still a major clinical need for better insulin therapy to stabilize fluctuations in glucose levels.AimThe aim of this study was to assess the impact of mealtime fast-acting insulin aspart therapy on glycemic variability as compared to regular human insulin therapy in advanced chronic kidney disease (CKD) patients with type 2 diabetes (T2D).MethodsData from eight patients were retrospectively collected after analyzing 57 patients' data between July 2019 and October 2019. All T2D patients with stage 4 CKD were switched to mealtime fast-acting insulin aspart on account of recurrent hypoglycemic events. The continuous glucose monitoring data of the first four days were analyzed to calculate the mean amplitude of glucose excursions (MAGE) as well as five other glycemic variability indices, namely, standard deviation, mean, continuous overall net glycemic action, average daily risk range, and J index.ResultsThe primary endpoint of 24-h MAGE significantly decreased from 7.01 ± 2.59 to 4.19 ± 1.06 mg/dL (p = 0.012) when short-acting regular human insulin (RHI) therapy was replaced with mealtime fast-acting insulin aspart therapy. However, no significant change was observed in 24-h mean glucose levels and other indices of glucose variability. Significant reduction in 24-h and night-time hypoglycemic events was reported in patients after therapy switch during the four-day follow-up period.ConclusionsThe present study demonstrated an improvement in glycemic variability with the administration of fast-acting insulin aspart as compared to RHI, suggesting that modern bolus insulin replacement might prove to be a useful therapeutic strategy in type 2 diabetes patients with advanced CKD. Further clinical studies will be required to confirm the benefits of this therapeutic approach.Relevance for patientsThe safety and effectiveness of fast-acting insulin aspart in CKD patients have not yet been established. The clinical effectiveness and better safety profile of newer mealtime insulin therapy may prompt a reconsideration of its use in patients with an advanced stage of renal dysfunction, leading to better adherence and improved quality of life.

Background: Recent studies suggested that the increased risk of heart failure by DPP-4 inhibitors may have an interconnection with patients' baseline eGFR. We decided to investigate the effect of DPP-4 inhibitors and the degree of renal function on cardiovascular (CV) safety in type 2 diabetes (T2D) patients. Materials and Methods: Systemic search of literature that examined the DPP-4 inhibitors and reported cardiovascular outcomes in diabetes patients with renal impairment were performed. Studies were examined for inclusion criteria: Randomized controlled trials with reduced renal function taking DPP-4 inhibitors alone or in combination with other anti-diabetes agents reporting evaluable CV events for at least 24 weeks. Result: Analysis of four CV outcome studies (11,789 patients with eGFR ≤60 ml/min/1.73m 2 ) did not find any increase in primary composite endpoints with DPP-4 inhibitors in patients stratified by baseline renal function. Rate of hospitalization due to heart failure (hHF) is found to be non-inferior to placebo group in patients with renal insufficiency (RR 1.07; 95% CI, 0.96-1.20 P = 0.26). In moderate renal dysfunction, there is a significant increase in heart failure risk compared to placebo. (RR 1.27; 95% CI, 1.033 -1.5 8; P = 0.024). Conclusion: Treatment with DPP-4 inhibitors did not affect the risk of cardiovascular events regardless of baseline renal function, however, an increase in the risk of hHF in moderate renal function in T2D patients with high CV risk merits careful consideration. Further research would be necessitated to reach definitive conclusion to understand the effect of declining renal function on CV safety of DPP-4 inhibitors.

Empagliflozin (SGLT2 inhibitor) and linagliptin (DPP-4 inhibitor) is a Fixed Dose Combination (FDC) with limited real-world evidence. We assessed the efficacy of this novel FDC in the real world Indian setting by analyzing the mean change in 12-week values of the glycemic (HbA1c and FPG) and extra-glycemic parameters (SBP, DBP, eGFR and body weight) as compared to the baseline values at the point of initiation of FDC in 498 patients. (Table). The patients enrolled were independently naïve to both DPP IV inhibitor and SGLT2 inhibitor therapy. Unpaired t test and ANOVA were utilised for statistical analysis. The mean age was 61 years (SD ± 7.6). The ongoing treatment in 20% (n=100), 43% (n=214), 38% (n=189), 26% (n=127) were metformin (M), combination of M and sulfonylureas (SU), combination of M, SU and voglibose, and insulin, respectively. The mean change in HbA1c, FPG, SBP, DBP, eGFR and body weight was -1.1%, -45 mg/dl, -12 mmHg, -5 mmHg, 5 mL/min/1.73m2, -5 kg (p<0.0001), respectively. 23.9 % patients (n=119) achieved HbA1c < 7%. 36.8% (n=183) patients achieved FPG reductions ≥100mg/dl. Six patients reported clinically evident hypoglycaemia which was managed symptomatically. There was a meaningful change and a substantial quantum of improvement in glycemic, metabolic and renal parameters. The results need to be validated through a long-term larger study. Disclosure A. Gupta: None. M. Khalse: None. A. Bhargava: None.