Efficacy and safety of fixed dose combination of Sitagliptin, metformin, and pioglitazone in type 2 Diabetes (IMPACT study): a randomized controlled trial.

BACKGROUND: Due to the progressive decline in ß-cell function, it is often necessary to utilize multiple agents with complementary mechanisms of action to address various facets and achieve glycemic control. Thus, this study aimed to evaluate the efficacy and safety of a fixed-dose combination (FDC) of metformin/sitagliptin/pioglitazone (MSP) therapy vs. metformin/sitagliptin (MS) in type 2 diabetes mellitus (T2DM). METHODS: In this phase 3, multicenter, double-blind study, patients with T2DM who exhibited inadequate glycemic control with HbA1c of 8.0-11.0% while taking ≥1500 mg/day metformin for at least 6 weeks were randomized to receive either FDC of MSP (1000/100/15 mg) or MS (1000/100 mg) per day for 24 weeks. The primary outcome measure was the change in HbA1c, and secondary outcomes included changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and body weight from baseline to 24 weeks along with safety and tolerability. RESULTS: Among the 236 patients randomized, 207 (87.71%) successfully completed the study. All baseline characteristics were comparable between the FDC of MSP and MS groups. There was a subsequent significant reduction of HbA1c in FDC of MSP (- 1.64) vs. MS (- 1.32); between groups was [- 0.32% (95% CI, - 0.59, - 0.05)], P = 0.0208. Similar reductions were found in FPG [- 13.2 mg/dL (95% CI, - 22.86, - 3.71)], P = 0.0068, and PPG [- 20.83 mg/dL (95% CI, - 34.11, - 7.55)], P = 0.0023. There were no significant changes in body weight. A total of 27 adverse effects (AEs) and one severe AE were reported, none of which were related to the study drug. CONCLUSION: The FDC of MSP demonstrated significant efficacy in managing glycemic indices and could serve as a valuable tool for physicians in the management of Indian patients with T2DM. TRIAL REGISTRATION: Clinical Trials Registry of India, CTRI/2021/10/037461.

A Prospective Observational Study to Evaluate Cardiovascular Changes in Patients of Hypothyroidism.

Introduction Hypothyroidism is a common endocrine disorder in India and is easy to diagnose based on clinical manifestations and signs. Thyroid hormone affects the cardiovascular system. Fatiguability, dyspnea, weight gain, lower limb swelling, and bradycardia are some clinical manifestations. ECG changes in hypothyroidism include sinus bradycardia, prolonged QTc interval, changes in the morphology of the T-wave, QRS duration, and low voltage. Echocardiography changes include diastolic dysfunction, asymmetrical septal hypertrophy, and pericardial effusion. This study aimed to examine the cardiovascular changes in patients with hypothyroidism. Methodology Patients with hypothyroidism and cardiovascular changes were assessed using an electrocardiogram and echocardiography. Results A total of 68 hypothyroid patients were enrolled in the study. The mean age of patients was 41.93 ± 15.36 years, and the mean BMI was 24.64 ± 4.30 kg/m2. Of 68 hypothyroid patients, 57 (83.8%) were females, and 11 (16.2%) were males. The mean thyroid-stimulating hormone (TSH) level in the study population was 11.48 ± 22.02 (mIU/mL). The most common symptoms reported among the study participants were tiredness or weakness (67.6%), followed by dyspnea (42.6%). The mean pulse rate, systolic blood pressure, and diastolic blood pressure were 81.50 ± 16.16, 112.76 ± 7.05, and 70.68 ± 7.46, respectively. Pallor was the most common sign (22.1%) among all the people who participated in the study. The most common findings on the ECG were low voltage complexes (25%) followed by inversion of the T wave (23.5%). Other ECG findings were bradycardia (10.3%), right bundle branch block (7.4%), and QRS prolongation (2.9%). Echocardiography revealed 21 (30.8%) patients with grade 1 left ventricular diastolic dysfunction and pericardial effusion in two patients (2.94%). There was a significantly greater increase in the level of TSH in study participants. Conclusion Patients with abnormal ECG and echocardiography without other cardiovascular changes should be evaluated for hypothyroidism to improve the quality of care.

Topical Esmolol Hydrochloride as a Novel Treatment Modality for Diabetic Foot Ulcers: A Phase 3 Randomized Clinical Trial.

Importance: Preclinical and phase 1/2 studies with esmolol hydrochloride suggest its potential role in treatment of diabetic foot ulcers (DFUs). Objective: To study the efficacy of topical esmolol for healing of uninfected DFUs. Design, Setting, and Participants: A randomized, double-blind, multicenter, phase 3 clinical trial was conducted from December 26, 2018, to August 19, 2020, at 27 referral centers across India. Participants included adults with DFUs. Interventions: Participants were randomized after a run-in phase (1 week) to receive esmolol, 14%, gel with standard of care (SoC), SoC only, or vehicle with SoC (3:3:1 proportion) for 12 weeks (treatment phase) and followed up subsequently until week 24. Main Outcomes and Measures: The primary outcome was the proportion of wound closure within the 12-week treatment phase in the esmolol with SoC and SoC only groups. Analysis was conducted using an intention-to-treat safety evaluable population, full analysis set or efficacy-evaluable population, and per-protocol population comparing the esmolol plus SoC and SoC only treatment groups. Results: In the study, 176 participants (122 men [69.3%]; mean [SD] age, 56.4 [9.0] years; mean [SD] hemoglobin A1c level, 8.6% [1.6%]) with DFUs classified as University of Texas Diabetic Wound Classification system grade IA and IC (mean [SD] ulcer area, 4.7 [2.9] cm2) were randomized to the 3 groups. A total of 140 participants were analyzed for efficacy. The proportion of participants in the esmolol with SoC group who achieved target ulcer closure within 12 weeks was 41 of 68 (60.3%) compared with 30 of 72 (41.7%) participants in the SoC only group (odds ratio [OR], 2.13; 95% CI, 1.08-4.17; P = .03). A total of 120 participants completed the end of study visit which were analyzed. Target ulcer closure by the end of the study (week 24) was achieved in 44 of 57 (77.2%) participants in the esmolol with SoC group and 35 of 63 (55.6%) participants in the SoC only group (OR, 2.71; 95% CI, 1.22-5.99; P = .01). The median time for ulcer closure was 85 days for the esmolol with SoC group and was not estimable for SoC only group. Significant benefits of Esmolol with SoC were seen in patients with factors that impede the healing of DFU. Treatment-emergent adverse events were noted in 18.8% of the participants, but most (87.3%) of these events were not attributable to the study drug. Conclusions and Relevance: In this multicenter, randomized, double-blind clinical trial, the addition of esmolol to SoC was shown to significantly improve the healing of DFUs. With these results, topical esmolol may be an appropriate addition to SoC for treating DFUs. Trial Registration: ClinicalTrials.gov Identifier: NCT03998436; Clinical Trial Registry, India CRI Number: CTRI/2018/11/016295.

Major complications following central neuraxial block - A multi-centre observational study in Maharashtra (MGMM CNB Study).

Background and Aims: Major complications of central neuraxial block (CNB) are rare and their incidence in India is not known. This information is essential for explaining risk and medico-legal concerns. The present multi-centre study in Maharashtra was conducted to provide insight into the characteristics of rare complications following this popular anaesthetic technique. Methods: Data were collected from 141 institutes to study the clinical profile of CNB. Incidence of complications like vertebral canal haematoma, abscess, meningitis, nerve injury, spinal cord ischaemia, fatal cardiovascular collapse, and drug errors was collected over one year. Complications were reviewed by audit committee to assess causation, severity, and outcome. 'Permanent' injury was defined as death or neurological symptoms persisting for more than six months. Results: Spinal anaesthesia (SA) was the most frequently used CNB in 88.76% patients. Bupivacaine and an adjuvant were used in 92.90% and 26.06% patients, respectively. Eight major complications (four neurological and four cardiac arrests) were reported in patients receiving SA. In seven of eight instances, SA was responsible or contributory for complication. The pessimistic incidence of complications (included cases where CNB was responsible; contribution was likely, unlikely and could not be commented) was 8.69/lakh and optimistic incidence (included cases where CNB was responsible or contribution was likely) was 7.61/lakh. 'Pessimistically' and 'optimistically' there were three deaths including one death due to quadriplegia following epidural haematoma after SA. Five out of eight patients recovered completely (62.5%). As only eight patients had complications of different types, it was difficult to establish statistical correlation of major complications with demographic or clinical parameters. Conclusion: This study was reassuring and suggested that the incidence of major complications following CNB was low in Maharashtra.

Platelet derived exosomes disrupt endothelial cell monolayer integrity and enhance vascular inflammation in dengue patients.

Background: Thrombocytopenia is the most notable phenomenon in dengue. Activation status of platelets and interaction of platelets with endothelium contribute towards dengue disease pathogenesis. Platelets are the major cell types known to release extracellular vesicles, especially exosomes in circulation. However, the role of platelet derived exosomes (PLT-EXOs) in endothelial dysfunction during dengue infection remains unknown. Methods: In this study, we recruited 28 healthy subjects and 69 dengue patients categorized as WS- (n=31), WS+ (n=29) and SD (n=9). Platelets were isolated from platelet rich plasma of dengue patients and their activation was assessed by flow cytometry. PLT-EXOs were isolated by ultracentrifugation method. Western blot analyses were performed to characterize the exosomes. Exosome uptake experiment was carried out to see the internalization of exosomes inside endothelial cells (HUVECs). To observe the effect of exosomes on endothelial cells, exosomes were added on HUVECs and expression of adherens and tight junctional proteins were examined by immunofluorescence assay and western blot. Expression levels of vascular injury markers were measured in the culture supernatants of Exosome-HUVEC coculture and sera of dengue patients by MSD-multiplex assay. Results: As compared to healthy subjects, CD41/CD61 expression was significantly reduced (p<0.0001) and CD62p expression was significantly increased (p<0.0001) on platelets in dengue patients. PLT-EXOs isolated from the dengue patients showed higher expression of CD63 and CD9 proteins than the healthy subjects. With in-vitro immunofluorescence assays, we illustrated the internalization of PLT-EXOs by the HUVECs and observed disruption of endothelial cell monolayer integrity in the presence of PLT-EXOs from WS+ and SD patients. Furthermore, the significant reduction in the expressions of ZO-2, VE-Cadherin and CD31 in endothelial cells following exposure to PLT-EXOs from the dengue patients provide direct evidence of PLT-EXOs mediated vascular permeability. PLT-EXOs stimulated the release of inflammatory markers CRP, SAA, sVCAM-1 and sICAM-1 in the supernatants of HUVEC cells. Importantly, significantly higher levels of CRP, sVCAM-1 and sICAM-1 in the sera of severe than mild dengue patients (p<0.0001) suggest their role in disease severity. Conclusions: In summary, our data suggest that PLT-EXOs promote vascular leakage via release of proinflammatory mediators and compromise vascular barrier integrity in dengue patients.

A Comparative Study of efficacy and safety of different Sodium Glucose Co-transporter 2 (SGLT-2) Inhibitors in the Management of Patients with Type II Diabetes Mellitus.

BACKGROUND: There are a handful of sodium glucose co-transporter 2 (SGLT2) inhibitors available in the global and Indian markets to manage type II diabetes mellitus (T2DM). However, head-to-head comparison between different SGLT2 inhibitors is scarce. Therefore, the present study was aimed to analyze the effect of different SGLT2 inhibitors on glycemic control and body weight in Indian patients with T2DM. METHODS: This was a prospective, interventional, nonrandomized study that included patients (N = 480) of either sex, aged ≥30 years, with inadequately controlled T2DM having HbA1c > 8.5%, and were receiving either Canagliflozin, Empagliflozin, Dapagliflozin or Remogliflozin on the background of triple-drug therapy. In this study, patients were evaluated for HbA1c, fasting blood sugar (FBS), post-prandial blood sugar (PPBS), body weight, and systolic and diastolic blood pressure at baseline, 12 and 24 weeks. RESULTS: A total of 480 patients who received either Canagliflozin (n = 120), Empagliflozin (n = 120), Dapagliflozin (n = 120), or Remogliflozin (n = 120) were included in this study. There was a significant reduction in levels of HbA1c, FBS, PPBS, body weight, systolic blood pressure (SBP), and diastolic blood pressure (DBP) at week 12 and 24 in all treatment groups. The difference in mean values of glycemic parameters and body weight was comparable across the treatment groups at week 12 and 24 but was not significant. Out of all 480 patients, 10 patients (2.08%) reported urinary tract infection (UTI), and five (1.04%) reported genital mycotic infection. All the five patients were females and treatment for UTI and mycotic infection was provided as required. Rest of the patients tolerated the therapy well. CONCLUSION: Overall observations indicate that all the four SGLT2 inhibitors are effective in reducing HbA1c, FBS, PPBS, body weight SBP, and DBP. Therefore, gliflozins can be the best choice to start early in patients with inadequately controlled T2DM receiving triple-drug therapy which helps in controlling the parameters of glycemia and significantly reducing the body weight. Hence SGLT2 Inhibitors could be considered as an add-on to all antidiabetic agents currently used for the management of diabetes in Indian setting.

Evaluation of Teneligliptin a DPP4 Inhibitor in Terms of Efficacy and Safety with Respect to QT/QTc Prolongation in Patients with Type II Diabetes Mellitus (T2DM).

INTRODUCTION: Low risk of hypoglycemia and weight neutrality have increased the administration of dipeptidyl peptidase 4 (DPP-4) inhibitors in patients with T2DM in clinical practice. Currently Teneligliptin is prescribed as a second or third add on to the standard treatment with other classes of oral hypoglycemic agents (OHAs) to achieve targeted glycemic control in type 2 DM patients. METHODS: An open label, interventional, single arm, 12 weeks study was conducted on160 patients with type 2 DM at MGM Medical College, Aurangabad with Teneligliptin 20 mg once a day as add on to the ongoing standard treatment with other classes of OHAs. Changes in glycemia parameters like FBS, PPBS HbA1C, body weight were assessed and twelve lead ECG was recorded with safety assessment at baseline and follow-up visits.. The QTc was calculated by using the Bazett's formula (QTc=QT/√RR).The study was conducted with an objective to assess efficacy and safety of Teneligliptin with respect to QT/QTc prolongation in patients with T2DM. RESULTS: A significant reduction was seen in the glycemic parameters like FBS, PPBS HbA1C from the baseline values (P<0.001) but no significant change in the QT interval (P=0.9563) and QTc interval (P=0.5594) from the baseline to the end of study at12 weeks. CONCLUSION: Tenelegliptin is a promising new drug to help to achieve targeted glycemic control in patients with T2DM without prolonging the QT/QTc interval.

Prevalance of Microalbuminuria in Non Diabetic Ischemic Heart Disease Patients.

Gadag Ischemic heart disease (IHD) is atherosclerotic narrowing of coronary arteries that is often asymptomatic early in the course of the disease but may lead to stable or unstable angina, and/or myocardial infarction with the progressive thickening or plaque rupture of the wall of the coronary arteries. Ischemic heart disease has now become one of the leading causes of death worldwide, accounting for more than 7.3 million deaths in 2008 alone. Microalbuminuria is a widely recognized, strong and independent risk marker of cardiovascular disease among individuals with diabetes, which as a marker of IHD in nondiabetics is currently under international debate. MATERIAL: In a cross-sectional study, 100 clinically diagnosed IHD patients were recruited, by using standard questionnaire demographic data, drug usage, disease history and physical examination were noted. Absence of diabetes mellitus was documented by no history of diabetes mellitus and evaluating serum blood glucose and HbA1c. Presence of microalbuminuria was confirmed by microalbumin quantitative estimation. OBSERVATION: The mean age of the patients was 54.23 ± 14.44 years, ranging between 27 to 82 years. There was male predominance (84%) compared to females (16%). 51% of patients were smokers while 25% were alcoholics. Hypertension was reported to be the most prevalent comorbidity followed by Hyperhomocysteinemia and Hypothyroidism. The presence of microalbuminuria was found among 43 out of total 100 patients. Therefore, the incidence of microalbuminuria was 43%. There was no significant difference in the means of BSL, HbA1c and creatinine noted among the groups based on presence or absence of microalbuminuria. A significant positive association between presence of comorbidities and abnormal triglyceride level with presence of microalbuminuria was reported, while smoking status, alcoholic status and abnormal serum cholesterol level were not associated significantly with presence of microalbuminuria. CONCLUSION: In the present study higher prevalence of microalbuminuria was reported among non-diabetic IHD patients, which might be caused due to presence of hypertension. Therefore, the present study recommends estimating urine microalbumin to identify high-risk individuals for IHD, for primary prevention of it.

Efficacy and Safety of Empagliflozin as Add on in Patients with Type II Diabetes Mellitus (DM) Inadequately Controlled on Triple Drug Combination.

OBJECTIVES: Diabetes mellitus (DM) refers to a group of metabolic disorders characterized by hyperglycemia resulting from insulin resistance, insulin action or both. Despite availability of various treatment modalities it is difficult to achieve the desired glycemic control in many patients. In such patients new class of anti-diabetic agent sodium-glucose co-transporter II (SGLT2) inhibitors has been approved by FDA. SGLT-2 inhibitor Empagliflozin has been associated with HbA1c reduction and weight loss in a broad range of patients with type 2 Diabetes Mellitus (T2DM). METHODS: An open label, interventional, single arm, 24 weeks study was done on 120 patients who were inadequately controlled on three oral hypoglycaemic agents and reluctant to take insulin therapy. Empagliflozin 25 mg once a day was added to ongoing triple drug therapy. Changes in glycemic parameters like fasting blood sugar levels, post-prandial blood sugar levels, HbA1C, body weight, systolic and diastolic blood pressure and safety profile were assessed at baseline, three months and sixth months. Study was conducted at MGM medical college and hospital, Aurangabad in collaboration with Department of Medicine. RESULTS: Our study revealed Empagliflozin 25 mg once daily when used as add on to ongoing triple drug therapy has shown 3.02 % reduction in HbA1c and 3.83 kg reduction in bodyweight. CONCLUSION: Empagliflozin a SGLT 2 inhibitor is a promising drug for reduction in HbA1c value and body weight in patients with T2DM who are inadequately controlled on triple drug therapy and are reluctant to insulin therapy.

Efficacy and Safety of Canagliflozin in Patients with Type II Diabetes Mellitus Inadequately Controlled on Triple Drug Therapy.

OBJECTIVE: Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has been associated with HbA1c reduction and weight loss in a broad range of patients with type 2 diabetes mellitus (T2DM). This analysis evaluated changes in HbA1c and body weight in patients who were inadequately responding to maximum dose of three oral hypoglycemic agents and reluctant to take insulin therapy. METHODS: In this open label interventional single arm study, patients aged 18 to 65 years (N=118) received Canagliflozin 100 mg for in addition to an ongoing triple drug oral hypoglycemic agents (OHA) regimen for a period of 12 weeks. The said population was inadequately responding to maximum dose of three oral hypoglycemic agents and was reluctant to take insulin therapy. Percent change from baseline in HbA1c and body weight was evaluated in the study. RESULTS: Canagliflozin 100 mg additional dose above a triple OHA provided significant HbA1c reduction by 1.9% and weight reduction by 3.01kg over 12 weeks from baseline. Canagliflozin was generally well tolerated, with 2.54% of the patient population reporting Urinary tract infection (UTI) who were withdrawn from study and given appropriate treatment. CONCLUSION: Canagliflozin 100 mg (One tablet) administered to patients in addition to the inadequately controlled triple drug OHAs who were reluctant for an insulin therapy provided a significant reduction in HbA1c and body weight over 12 weeks. Canagliflozin a SGLT 2 inhibitor is a promising new drug in patients with T2DM in patients who are inadequately controlled on triple therapy and are reluctant to insulin therapy.

Study of Saroglitazar in Treatment Of Pre-diabetes with Dyslipidemia: STOP-D.

Objectives: Patients with prediabetes are not only at increased risk of progression to type 2 diabetes, but they are also at high risk of developing cardiovascular risk compared to normoglycemic people. Further, prediabetes is also often associated with abnormal lipid levels (dyslipidemia). We therefore aimed to evaluate the effect of Saroglitazar in patients with prediabetes and dyslipidemia. Methods: This was a prospective, single centre, single arm study involving patients with pre-diabetes and dyslipidemia. Subjects with baseline HbA1c 5.7-6.4% and dyslipidemia (Total cholesterol > 200mg/dl, LDL-C > 130 mg/dl, triglycerides > 150 mg/dl and HDL< 40 mg/dl) were enrolled in this study. Subjects with on-going medications affecting blood glucose or lipids were excluded from the study. Saroglitazar 4mg once daily was administered for a period of 24 weeks. The primary outcome was change in serum triglycerides and secondary outcome parameters included changes in other lipid parameters and HbA1c levels at 24 weeks follow-up. Results: Forty patients with prediabetes and dyslipidemia were enrolled in the study. At 24 weeks follow-up, serum triglycerides was significantly reduced from 348 ± 86.98 mg/dl to 216.4 ± 72.34 mg/dl (P <0.0001). HbA1c was significantly reduced from 6.3 ± 0.16 % to 5.5 ± 0.30 % after 24 weeks of Saroglitazar therapy (P<0.0001). There were significant improvements observed in other lipid parameters at 24 weeks follow-up period. Saroglitazar was found to be safe and well tolerated, no serious adverse event reported during entire study period. Conclusion: Saroglitazar is safe and effective in prediabetes with dyslipidemia by exerting its dual lipid lowering and glycemic actions.

Autoimmune Polyglandular Syndrome Type 2 with Alopecia Universalis and Hypoparathyroidism.

A 46 years old female, presented with severe fatigue, nypotension ana hyperpigmentation. Her basal serum cortisol level at 8 a.m. was < 1.0 µg/dl which suggested a diagnosis of Addison's disease. An association with latent autoimmune diabetes of adult and autoimmune hypothyroidism led to a diagnosis of Polyglandular Autoimmune Syndrome type II (PAS II). She also had alopecia universalis and hypoparathyroidism which are very rare in PAS type II syndrome. On treatment with hydrocortisone and fludrocortisone there was drastic improvement in the clinical features.

Effect of Tectona grandis Linn. seeds on hair growth activity of albino mice.

The seeds of Tectona grandis Linn. are traditionally acclaimed as hair tonic in the Indian system of medicine. Studies were therefore undertaken in order to evaluate petroleum ether extract of T. grandis seeds for its effect on hair growth in albino mice. The 5% and 10% extracts incorporated into simple ointment base were applied topically on shaved denuded skin of albino mice. The time required for initiation of hair growth as well as completion of hair growth cycle was recorded. Minoxidil 2% solution was applied topically and served as positive control. The result of treatment with minoxidil 2% is 49% hair in anagenic phase. Hair growth initiation time was significantly reduced to half on treatment with the extracts compared to control animals. The treatment was successful in bringing a greater number of hair follicles (64% and 51%) in anagenic phase than standard minoxidil (49%). The results of treatment with 5% and 10% petroleum ether extracts were comparable to the positive control minoxidil.