Indian consensus on durability of glycemic control in type 2 diabetes management and role of oral antidiabetic drugs

The prevalence of type 2 diabetes mellitus (T2DM) is increasing in an alarming way in India as well as across the globe. In order to minimize complications, there is a need to maintain good glycemic control in patients with T2DM and long-term durable glycemic control remains a challenge. Clinically, this challenge was addressed by step-wise intensification of therapy with additional antidiabetic drugs to maintain glycemic control. Various disease and patient-related factors as well as different antidiabetic agents influenced the durability of glycemic control differently. While understanding of the factors that influenced therapeutic outcomes had evolved, there was paucity of information about the durability of glycemic control and the role of oral antidiabetic drugs (OADs) in achieving it. With an objective to understand the role of durability of glycemic response in the management of Indian patients with T2DM, 4 advisory board meetings attended by 48 physicians from across the country were conducted in Mumbai, Delhi, Kolkata and Bengaluru. There was consensus to consider durability of glycemic control as an important goal in the management of T2DM. Personalized approach in T2DM management along with early initiation of dual combination therapy were recommended to achieve durability. Age group of patients, body mass index, glycated hemoglobin levels at diagnosis, presence or absence of comorbidities and complications are important factors that need to be considered before initiating dual combination therapy for patients with T2DM.

Correlates of Insulin Selection as a First-Line Pharmacological Treatment for Gestational Diabetes

Objective The aim of this study was to investigate prenatal factors associated with insulin prescription as a first-line pharmacotherapy for gestational diabetes mellitus (GDM; compared with oral antidiabetic medication) after failed medical nutrition therapy. Methods This is a retrospective cohort study of 437 women with a singleton pregnancy and diagnosis of A2GDM (GDM requiring pharmacotherapy), delivering in a university hospital between 2015 and 2019. Maternal sociodemographic and clinical characteristics, as well as GDM-related factors, including provider type that manages GDM, were compared between women who received insulin versus oral antidiabetic medication (metformin or glyburide) as the first-line pharmacotherapy using univariable and multivariable analyses. Results In univariable analysis, maternal age, race and ethnicity, insurance, chronic hypertension, gestational age at GDM diagnosis, glucose level after 50-g glucose loading test, and provider type were associated with insulin prescription. In multivariable analysis, after adjusting for sociodemographic and clinical maternal factors, GDM characteristics and provider type, Hispanic ethnicity (0.26, 95% confidence interval [CI]: 0.09–0.73), and lack of insurance (0.34, 95% CI: 0.13–0.89) remained associated with lower odds of insulin prescription, whereas endocrinology management of GDM (compared with obstetrics and gynecology [OBGYN]) (8.07, 95% CI: 3.27–19.90) remained associated with higher odds of insulin prescription. Conclusion Women of Hispanic ethnicity and women with no insurance were less likely to receive insulin and more likely to receive oral antidiabetic medication for GDM pharmacotherapy, while management by endocrinology was associated with higher odds of insulin prescription.This finding deserves more investigation to understand if differences are due to patient choice or a health disparity in the choice of pharmacologic agent for A2GDM. Key Points

Oral Antidiabetics and Sleep Among Type 2 Diabetes Patients: Data From the UK Biobank

Previous small-scale studies have found that oral antidiabetic therapy is associated with sleep difficulties among patients with type 2 diabetes (T2D). Here, we used data from 11 806 T2D patients from the UK Biobank baseline investigation to examine the association of oral antidiabetic therapy with self-reported difficulty falling and staying asleep and daily sleep duration. As shown by logistic regression adjusted for, e.g., age, T2D duration, and HbA1c, patients on non-metformin therapy (N=815; 86% were treated with sulphonylureas) had a 1.24-fold higher odds ratio of reporting regular difficulty falling and staying asleep at night compared to those without antidiabetic medication use (N=5 366, P<0.05) or those on metformin monotherapy (N=5 625, P<0.05). Non-metformin patients reported about 8 to 10 minutes longer daily sleep duration than the other groups (P<0.05). We did not find significant differences in sleep outcomes between untreated and metformin patients. Our findings suggest that non-metformin therapy may result in sleep initiation and maintenance difficulties, accompanied by a small but significant sleep extension. The results of the present study must be replicated in future studies using objective measures of sleep duration and validated questionnaires for insomnia. Considering that most T2D patients utilize multiple therapies to manage their glycemic control in the long term, it may also be worth investigating possible interactions of antidiabetic drugs on sleep.

Cost-Effectiveness of Oral Antidiabetic Drugs: A Prospective Multicenter Study of Real-World Patients

This real-world, multicenter, prospective study aims to analyze the cost-effectiveness of prevalent oral antidiabetic drugs, including traditional Chinese medicine and its compounds, used in China. Type 2 diabetes patients initiated on one or several of the most prevalent antidiabetic drugs were recruited on the baseline and followed up over one year with no restriction on drug discontinuation, switching, and add-on. Different drugs were evaluated on their efficacy, adverse effect (AE), health-related quality of life (HRQoL), and cost. Treatments were defined as the intent-to-treat in the primary analysis and on-treatment in the sensitivity analyses. A rich set of patients’ baseline characteristics was collected and controlled using the multivariate linear model in the primary analysis and inverse probability weighting and double selection—a machine learning algorithm—in the sensitivity analyses. Estimates of “raw” outcomes, which are not adjusted by covariates and calculated as subgroup means, show that the use of Xiaoke Pill alone and in combination is among the most effective therapies with 50% and 54% of patients reaching the control target of HbA1c < 6.5%. In terms of cost, Xiaoke Pill and gliclazide, which cost participants 4,350 and 5,150 RMB per year on average, are among the least costly therapies. After adjusting patient characteristics, monotherapy and combination therapy using the Xiaoke Pill again display the best control rates, of 45% and 43% against 33% of metformin. Regarding cost, the Xiaoke Pill costs a patient 5,340 RMB per year, in sharp contrast with 8,550 RMB for metformin and 10,330 RMB for acarbose. Our study suggests that the use of Xiaoke Pill—alone or in combination—is associated with better glycemic control and lower cost than some allopathic medications such as metformin or acarbose and shows a similar incidence of hypoglycemia.

Dipeptidyl Peptidase-4 Inhibitor Administration Is Associated with Higher Eosinophil Counts and Batter Clinical Outcomes in Patients with Aorta Intramural Hematoma

Objectives Investigating whether dipeptidyl peptidase-4 (DPP-4) inhibitors could influence clinical outcomes in intramural hematoma (IMH) patients with diabetes mellitus (DM). Methods IMH patients who received a "wait and watch strategy" were included. Cox proportional hazard models were constructed to identify potential risk factors. A Kaplan–Meier survival analysis was used to estimate all-cause and aorta-related mortality during the follow-up period. Results From January 2000 to December 2020, 1094 IMH patients were divided into group A (n=572, IMH patients without DM), group B (n=191, IMH patients with DM and receiving oral antidiabetic drugs [without admission of DDP-4 inhibitors]) and group C (n=331, IMH patients with DM and receiving oral antidiabetic drugs [including admission of DDP-4 inhibitors]). Group C had the lowest rate of aorta-related adverse events (6.4%), aorta-related mortality (1.2%) and reintervention (5.2%). Cox proportional hazard models revealed that lower eosinophil count (per 0.1, hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.73, P< 0.001) and thicker hematoma thickness (HR, 1.22; 95% CI, 1.06-1.39, P <0.001) were associated with higher occurrences of aorta-related adverse events. Lower eosinophil count (per 0.1, HR, 0.24; 95% CI, 0.15-0.40, P <0.001), larger descending aorta diameters (HR, 1.12; 95% CI, 1.02-1.23, P <0.021), and thicker hematoma thickness (HR, 3.25; 95% CI, 2.36-4.46, P <0.001) were also associated with increased aorta-related mortality. Kaplan-Meier survival analysis revealed a significant decrease in all-cause and aorta-related mortality in group C ( P <0.001). Conclusions DPP-4 administration influences progression of IMH patients with DM, leading to a lower rate of aorta-related adverse events, aorta-related mortality, and reinterventions.

Critical Assessment of In Vitro Screening of α-Glucosidase Inhibitors from Plants with Acarbose as a Reference Standard

Postprandial hyperglycemia is treated with the oral antidiabetic drug acarbose, an intestinal α-glucosidase inhibitor. Side effects of acarbose motivated a growing number of screening studies to identify novel α-glucosidase inhibitors derived from plant extracts and other natural sources. As “gold standard”, acarbose is frequently included as the reference standard to assess the potency of these candidate α-glucosidase inhibitors, with many outperforming acarbose by several orders of magnitude. The results are subsequently used to identify suitable compounds/products with strong potential for in vivo efficacy. However, most α-glucosidase inhibitor screening studies use enzyme preparations obtained from nonmammalian sources (typically Saccharomyces cerevisiae), despite strong evidence that inhibition data obtained using nonmammalian α-glucosidase may hold limited value in terms of identifying α-glucosidase inhibitors with actual in vivo hypoglycemic potential. The aim was to critically discuss the screening of novel α-glucosidase inhibitors from plant sources, emphasizing inconsistencies and pitfalls, specifically where acarbose was included as the reference standard. An assessment of the available literature emphasized the cruciality of stating the biological source of α-glucosidase in such screening studies to allow for unambiguous and rational interpretation of the data. The review also highlights the lack of a universally adopted screening assay for novel α-glucosidase inhibitors and the commercial availability of a standardized preparation of mammalian α-glucosidase.

Metformin strengthens uroepithelial immunity against E. coli infection

Urinary tract infection frequently caused by E. coli is one of the most common bacterial infections. Increasing antibiotic resistance jeopardizes successful treatment and alternative treatment strategies are therefore mandatory. Metformin, an oral antidiabetic drug, has been shown to activate macrophages in the protection against certain infecting microorganisms. Since epithelial cells often form the first line of defense, we here investigated the effect on uroepithelial cells during E. coli infection. Metformin upregulated the human antimicrobial peptides cathelicidin LL-37 and RNase7 via modulation of the TRPA1 channel and AMPK pathway. Interestingly, metformin stimulation enriched both LL-37 and TRPA1 in lysosomes. In addition, metformin specifically increased nitric oxide and mitochondrial, but not cytosolic ROS. Moreover, metformin also triggered mRNA expression of the proinflammatory cytokines IL1B, CXCL8 and growth factor GDF15 in human uroepithelial cells. The GDF15 peptide stimulated macrophages increased LL-37 expression, with increased bacterial killing. In conclusion, metformin stimulation strengthened the innate immunity of uroepithelial cells inducing enhanced extracellular and intracellular bacterial killing suggesting a favorable role of metformin in the host defense.