Prandial Insulins: A Person-Centered Choice.

PURPOSE OF REVIEW: Postprandial hyperglycemia, or elevated blood glucose after meals, is associated with the development and progression of various diabetes-related complications. Prandial insulins are designed to replicate the natural insulin release after meals and are highly effective in managing post-meal glucose spikes. Currently, different types of prandial insulins are available such as human regular insulin, rapid-acting analogs, ultra-rapid-acting analogs, and inhaled insulins. Knowledge about diverse landscape of prandial insulin will optimize glycemic management. RECENT FINDINGS: Human regular insulin, identical to insulin produced by the human pancreas, has a slower onset and extended duration, potentially leading to post-meal hyperglycemia and later hypoglycemia. In contrast, rapid-acting analogs, such as lispro, aspart, and glulisine, are new insulin types with amino acid modifications that enhance their subcutaneous absorption, resulting in a faster onset and shorter action duration. Ultra-rapid analogs, like faster aspart and ultra-rapid lispro, offer even shorter onset of action, providing better meal-time flexibility. The Technosphere insulin offers an inhaled route for prandial insulin delivery. The prandial insulins can be incorporated into basal-bolus, basal plus, or prandial-only regimens or delivered through insulin pumps. Human regular insulin, aspart, lispro, and faster aspart are recommended for management of hyperglycemia during pregnancy. Ongoing research is focused on refining prandial insulin replacement and exploring newer delivery methods. The article provides a comprehensive overview of various prandial insulin options and their clinical applications in the management of diabetes.

Role of Teplizumab, a Humanized Anti-CD3 Monoclonal Antibody, in Managing Newly Diagnosed Type 1 Diabetes: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: Teplizumab has emerged as a potential disease-modifying drug in type 1 diabetes (T1D). This meta-analysis sought to summarize the therapeutic effect of teplizumab in newly diagnosed patients with T1D. METHODS: Randomized controlled trials involving patients with T1D receiving teplizumab in the intervention arm and placebo (or no active intervention) in the control arm were searched throughout the electronic databases. The primary outcome was the change in area under the curve of C-peptide levels from baseline. RESULTS: Seven reports from 6 studies involving 834 subjects met the inclusion criteria. Compared to teplizumab, greater reductions in area under the curve of C-peptide from the baseline values were observed in the control group after 6 months (mean difference [MD] 0.07 nmol/L [0.01, 0.13], P = .02), after 12 months (MD 0.07 nmol/L [0.04, 0.11], P = .0001), after 18 months (MD 0.10 nmol/L [0.06, 0.14], P < .00001), and after 24 months (MD 0.07 nmol/L [0.01, 0.14], P = .03) of interventions. Moreover, fewer patients treated with teplizumab had a decreased C-peptide response after 6 months (odds ratio [OR] 0.21), after 12 months (OR 0.17), after 18 months (OR 0.30), and after 24 months (OR 0.12) of treatment. The preservation of endogenous insulin production was supported by reduced use of exogenous insulin with maintenance of comparable glycemic control for up to 18 months post-treatment. Teplizumab imparted higher risks of grade 3 or higher adverse events, adverse events leading to study medication discontinuation, nausea, rash, and lymphopenia. CONCLUSION: The results of the meta-analysis support teplizumab as a promising disease-modifying therapy for newly diagnosed T1D.

Glucagon-Like Peptide-1 Receptor Agonists in Post-bariatric Surgery Patients: A Systematic Review and Meta-analysis.

BACKGROUND: A significant number of patients face the issue of weight gain (WG) or inadequate weight loss (IWL) post-bariatric surgery for obesity. Several studies have been published evaluating the role of glucagon-like peptide-1 receptor agonists (GLP1RA) for weight loss post-bariatric surgery. However, no systematic review and meta-analysis (SRM) till date has evaluated the efficacy, safety and tolerability of GLP1RA in this clinical scenario. Hence, this SRM aimed to address this knowledge gap. METHODS: Databases were searched for randomized controlled trials (RCTs), case-control, cohort and observational studies involving use of GLP1RA in the intervention arm post-bariatric surgery. Primary outcome was weight loss post at least 3 months of therapy. Secondary outcomes were evaluation of body composition parameters, total adverse events (TAEs) and severe adverse events (SAEs). RESULTS: From initially screened 1759 articles, 8 studies (557 individuals) were analysed. Compared to placebo, patients receiving liraglutide had significantly greater weight loss after 6-month therapy [MD - 6.0 kg (95% CI, - 8.66 to - 3.33); P < 0.001; I2 = 79%]. Compared to liraglutide, semaglutide had significantly greater percent reduction in body weight after 6-month [MD - 2.57% (95% CI, - 3.91 to - 1.23); P < 0.001; I2 = 0%] and 12-month [MD - 4.15% (95% CI, - 6.96 to - 1.34); P = 0.004] therapy. In study by Murvelashvili et al. (2023), after 12-month therapy, semaglutide had significantly higher rates of achieving > 15% [OR 2.15 (95% CI, 1.07-4.33); P = 0.03; n = 207] and > 10% [OR 2.10 (95% CI, 1.19-3.71); P = 0.01; n = 207] weight loss. A significant decrease in fat mass [MD - 4.78 kg (95% CI, - 7.11 to - 2.45); P < 0.001], lean mass [MD - 3.01 kg (95% CI, - 4.80 to - 1.22); P = 0.001] and whole-body bone mineral density [MD - 0.02 kg/m2 (95% CI, - 0.04 to - 0.00); P = 0.03] was noted with liraglutide. CONCLUSION: Current data is encouraging regarding use of GLP1RAs for managing WG or IWL post-bariatric surgery. Deterioration of bone health and muscle mass remains a concern needing further evaluation. TRIAL REGISTRATION: The predefined protocol has been registered in PROSPERO having registration number of CRD42023473991.

Efficacy and Safety of Omarigliptin, a Novel Once-Weekly Dipeptidyl Peptidase-4 Inhibitor, in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

BACKGRUOUND: No recent meta-analysis has holistically analyzed and summarized the efficacy and safety of omarigliptin in type 2 diabetes mellitus (T2DM). We conducted a meta-analysis to address this knowledge gap. METHODS: Electronic databases were searched to identify randomized controlled trials (RCTs) that included patients with T2DM who received omarigliptin in the intervention arm. The control arm consisted of either a placebo (passive control group [PCG]) or an active comparator (active control group [ACG]). The primary outcome assessed was changes in hemoglobin A1c (HbA1c), while secondary outcomes included variations in glucose levels, achievement of glycemic targets, adverse events (AEs), and hypoglycemic events. RESULTS: From 332 initially screened articles, data from 16 RCTs involving 8,804 subjects were analyzed. Omarigliptin demonstrated superiority over placebo in reducing HbA1c levels (mean difference, -0.58%; 95% confidence interval, -0.75 to -0.40; P<0.00001; I2=91%). Additionally, omarigliptin outperformed placebo in lowering fasting plasma glucose, 2-hour postprandial glucose, and in the percentage of participants achieving HbA1c levels below 7.0% and 6.5%. The glycemic efficacy of omarigliptin was similar to that of the ACG across all measures. Although the omarigliptin group experienced a higher incidence of hypoglycemic events compared to the PCG, the overall AEs, serious AEs, hypoglycemia, and severe hypoglycemia were comparable between the omarigliptin and control groups (PCG and ACG). CONCLUSION: Omarigliptin has a favorable glycemic efficacy and safety profile for managing T2DM.

Impact of early initiation of ezetimibe in patients with acute coronary syndrome: A systematic review and meta-analysis.

OBJECTIVE: Scant data is available on the efficacy and safety of adding ezetimibe to high-intensity statin therapy for early and rapid reduction of low-density lipoprotein cholesterol (LDL-C) within 4-12 weeks of an acute-event in acute coronary syndrome (ACS). We undertook this meta-analysis to address this knowledge-gap. METHODS: Electronic databases were searched for RCTs involving patients with ACS receiving ezetimibe in intervention arm, and placebo/active comparator in control arm. Primary outcome was to evaluate changes in LDL-C levels post-ACS. Secondary outcomes were to evaluate alterations in other lipid parameters and adverse events. RESULTS: From initially screened 4561 articles, data from 11 studies (20,291 patients) were analyzed. Compared to controls, patients receiving ezetimibe had significantly lower LDL-C at 7-days [MD -19.55 mg/dl(95 %CI:-36.46 to -2.63);P = 0.02;I2 = 91 %], 1-month [MD-24.67 mg/dl (95 %CI:-34.59 to -14.76);P < 0.001;I2 = 81 %], 3-months [MD -18.01 mg/dl(95 %CI:-24.11 to -11.90);P < 0.001;I2 = 92 %] and 10-12 months [MD -16.90 mg/dl (95 % CI: -17.67 to -16.12); P < 0.001; I2 = 0 %] of treatment. Compared to controls, patients receiving ezetimibe had significantly lower total cholesterol at 7-days [MD-21.05 mg/dl(95 %CI:-26.73 to -15.37);P < 0.001;I2 = 0 %], 1-month [MD-25.56 mg/dl(95 %CI:-38.29 to -12.83);P < 0.001;I2 = 85 %], 3-months [MD-22.54 mg/dl(95 %CI:-36.90 to -8.19);P = 0.002;I2 = 22 %] and 12-months [MD-19.68 mg/dl(95 %CI:-20.78 to -18.59);P < 0.001;I2 = 0 %] of treatment. Death from any cause, ACS and non-fatal stroke [OR0.89(95 %CI:0.83-0.96);P = 0.002;I2 = 0 %], non-fatal myocardial infarction [OR0.86(95 %CI:0.79-0.94);P = 0.001;I2 = 0 %] and ischemic stroke [OR0.80(95 %CI:0.68-0.94);P = 0.009;I2 = 0 %] was significantly reduced in patients receiving ezetimibe. CONCLUSION: Addition of ezetimibe to high-intensity statin therapy at the time of ACS event is associated with significantly better cholesterol reduction at day-7,1-month, 3- months and 1-year of follow-up, which translates into a significantly lower recurrent cardiovascular events post an index event of ACS. CONCISE SUMMARY OF FINDINGS: Addition of ezetimibe to high-intensity statin therapy at the time of acute coronary syndrome (ACS) index event is associated with significantly better low density lipoprotein cholesterol and total cholesterol reduction at day-7, 1-month, 3-months and 1-year of follow-up, which translates into a significantly lower recurrent cardiovascular events (death from any cause, major ACS, non-fatal stroke, non-fatal myocardial infarction, and ischemic stroke) post an index event of ACS.

Orforglipron, a novel non-peptide oral daily glucagon-like peptide-1 receptor agonist as an anti-obesity medicine: A systematic review and meta-analysis.

Background: Orforglipron is a novel once-daily oral non-peptide glucagon-like peptide-1 receptor agonist with several recently published randomized controlled trials (RCTs) evaluating its role in diabetes and obesity. No meta-analysis has analyzed the efficacy and safety of orforglipron; this meta-analysis aimed to address this knowledge gap. Methods: A systematic search was conducted in electronic databases to identify RCTs that included individuals with obesity who were administered orforglipron and compared to either a placebo or an active comparator. The primary outcome of interest was the percent change in body weight. Results: From 12 initially screened articles, data from three RCTs involving 774 people were analyzed with a follow-up duration of up to 36 weeks. Compared to placebo, patients receiving orforglipron 12 mg/day (mean difference (MD), MD -5.48%, 95% CI [-7.64, -3.33], p < 0.01), 24 mg/day (MD -8.51%, 95% confidence interval (CI) [-9.88, -7.14], p < 0.01), 36 mg/day (MD -8.84%, 95% CI [-11.68, -6.00], p < 0.01) and 45 mg/day (MD -8.24%, 95% CI [-12.84, -3.63], p < 0.01) had a significantly greater percent reduction in body weight. The percentage of patients being able to achieve >15% weight loss from baseline was significantly higher with orforglipron 24 mg/day [Odds ratio (OR) 21.90 (95% CI [4.06, 118.15], p = 0.0003), 36 mg/day (OR 17.43, 95% CI [3.18, 95.66], p = 0.001) and 45 mg/day (OR 23.17, 95% CI [4.37, 123.03], p = 0.0002). Total but not severe adverse events were significantly higher with all the doses of orforglipron compared to placebo, with the hazard ratios being higher with higher doses. Gastrointestinal side-effects were predominant side effects, being dose-dependent, with nausea, vomiting, constipation, and gastroesophageal reflux being the predominant ones. Conclusion: Orforglipron at 24-45 mg/day doses is an effective weight loss medication. The efficacy versus side effect profile suggests that 24-36 mg/day is the most optimal dose for orforglipron as an anti-obesity medicine.

Safety and tolerability of sodium glucose cotransporter-2 inhibitors in children and young adults: A systematic review and meta-analysis.

Purpose: Sodium glucose co-transporter-2 inhibitors (SGLT2i) have been evaluated in children with type-2 diabetes (T2DM), Type-1 diabetes (T1DM) and several other non-diabetic conditions. Potential tolerability issues have been preventing us from routinely using SGLT2i in children with diabetes. No meta-analysis till date has evaluated the safety and tolerability of SGLT2i in children. This systematic review and meta-analysis aimed to address this knowledge-gap. Methods: Databases were searched for randomized controlled trials (RCTs), case-control and cohort studies involving children receiving SGLT2i in intervention-arm. Primary outcome was occurrence of treatment-emergent adverse events (TAEs). Secondary outcomes were evaluation of glycaemic efficacy and occurrence of severe adverse-events (SAEs), hypoglycaemia, ketosis, genital or urinary infections and any other adverse-events. Results: From initially screened 27 articles, data from 4 RCT (258 children) was analyzed. In children with T2DM, occurrence of TAEs [OR 1.77(95%CI:0.93-3.36);P=0.08;I2=0%], SAEs [OR 0.45(95%CI:0.08-2.54);P=0.37;I2=0%], ketoacidosis [OR 0.33(95%CI:0.01-8.37);P=0.50], urinary tract infections [OR 2.34(95%CI:0.44-12.50);P=0.32;I2=0%] and severe hypoglycaemia [OR 4.47(95%CI:0.21-96.40);P=0.34] were comparable among SGLTi group and placebo. Compared to placebo, T2DM children receiving SGLTi had significantly lower HbA1C at 24-26 weeks [MD -0.79%(95%CI:-1.33--0.26);P=0.004;I2=0%]. In T1DM children, ß-hydroxybutyrate levels were significantly higher in SGLTi group compared to placebo [MD 0.11mmol/L(95%CI:0.05-0.17);P=0.0005;I2=53%]. In T1DM, there was not a single report of SAE, ketoacidosis, severe hypoglycaemia among both groups, with time in range considerably greater in SGLT2i group (68%±6% vs. 50%±13%;P<0.001). Conclusion: This study provides us with reassuring data on safety of use of SGLT2i in children and young adults.

Trabecular bone score in adults with type 1 diabetes: a meta-analysis.

Type 1 diabetes mellitus (T1DM) is associated with a disproportionately high fracture rate despite a minimal decrease in bone mineral density. Though trabecular bone score (TBS), an indirect measure of bone architecture, is lower in adults with T1DM, the modest difference is unlikely to account for the large excess risk and calls for further exploration. INTRODUCTION: Fracture rates in type 1 diabetes mellitus (T1DM) are disproportionately high compared to the modestly low bone mineral density (BMD). Distortion of bone microarchitecture compromises bone quality in T1DM and is indirectly measured by trabecular bone score (TBS). TBS could potentially be used as a screening tool for skeletal assessment; however, there are inconsistencies in the studies evaluating TBS in T1DM. We performed this meta-analysis to address this knowledge gap. METHODS: An electronic literature search was conducted using PubMed, Scopus, and Web of Science resources (all-year time span) to identify studies relating to TBS in T1DM. Cross-sectional and retrospective studies in adults with T1DM were included. TBS and BMD data were extracted for pooled analysis. Fracture risk could not be analyzed as there were insufficient studies reporting it. RESULT: Data from six studies were included (T1DM: n = 378 and controls: n = 286). Pooled analysis showed a significantly lower TBS [standardized mean difference (SMD) = - 0.37, 95% CI - 0.52 to - 0.21; p < 0.00001] in T1DM compared to controls. There was no difference in the lumbar spine BMD (6 studies, SMD - 0.06, 95% CI - 0.22 to 0.09; p = 0.43) and total hip BMD (6 studies, SMD - 0.17, 95% CI - 0.35 to 0.01; p = 0.06) in the case and control groups. CONCLUSIONS: Adults with T1DM have a lower TBS but similar total hip and lumbar spine BMD compared to controls. The risk attributable to the significant but limited difference in TBS falls short of explaining the large excess propensity to fragility fracture in adults with T1DM. Further studies on clarification of the mechanism and whether TBS is suited to screen for fracture risk in adults with T1DM are necessary.

Hyperprolactinemia Due to Prolactinoma has an Adverse Impact on Bone Health with Predominant Impact on Trabecular Bone: A Systematic Review and Meta-Analysis.

BACKGROUND: No meta-analysis has holistically analysed and summarized the effect of prolactin excess due to prolactinomas on bone mineral metabolism. We undertook this meta-analysis to address this knowledge-gap. METHODS: Electronic databases were searched for studies having patients with hyperprolactinemia due to prolactinoma and the other being a matched control group. The primary outcome was to evaluate the differences in BMD Z-scores at different sites. The secondary outcomes of this study were to evaluate the alterations in bone mineral density, bone mineral content and the occurrence of fragility fractures. RESULTS: Data from 4 studies involving 437 individuals was analysed to find out the impact of prolactinoma on bone mineral metabolism. Individuals with prolactinoma had significantly lower Z scores at the lumbar spine [MD -1.08 (95 % CI: -1.57 - -0.59); P < 0.0001; I2 = 54 % (moderate heterogeneity)] but not at the femur neck [MD -1.31 (95 % CI: -3.07 - 0.45); P = 0.15; I2 = 98 % (high heterogeneity)] as compared to controls. Trabecular thickness of the radius [MD -0.01 (95 % CI: -0.02 - -0.00); P = 0.0006], tibia [MD -0.01 (95 % CI: -0.02 - -0.00); P=0.03] and cortical thickness of the radius [MD -0.01 (95 % CI: -0.19 - -0.00); P = 0.04] was significantly lower in patients with prolactinoma as compared to controls. The occurrence of fractures was significantly higher in patients with prolactinoma as compared to controls [OR 3.21 (95 % CI: 1.64 - 6.26); P = 0.0006] Conclusion: Bone mass is adversely affected in patients with hyperprolactinemia due to prolactinoma with predominant effects on the trabecular bone.

Role of Novel Glucagon-like Peptide-1 Receptor Analogue Polyethylene Glycol Loxenatide in Type 2 Diabetes: A Systematic Review and Meta-analysis.

Background: Polyethylene glycol loxenatide (peg-loxenatide) is a novel glucagon-like peptide-1 receptor agonist developed and available for clinical use in China. This meta-analysis was performed as no meta-analysis has analysed the efficacy and safety of peg-loxenatide in type 2 diabetes (T2DM). Methods: Electronic databases were systematically reviewed for RCTs having patients living with T2DM receiving peg-loxenatide in treatment arm and placebo/any other diabetes medicine in control arm. The primary outcome was to evaluate changes in glycated haemoglobin. The secondary outcomes were to evaluate alterations in weight, blood pressure, fasting glucose, prandial glucose, lipids, and adverse events. Results: Data from four trials (718 patients) were analysed. Over 12-24 weeks of clinical use, HbA1c was significantly lower in patients receiving standard-dose peg-loxenatide (100 mcg/week) {MD -0.95% [95% confidence interval (CI): -1.19 to -0.71]; P < 0.01; I2 = 76%} and high-dose peg-loxenatide (200 mcg/week) [MD -1.15% (95% CI: -1.47 to -0.82); P < 0.01; I2 = 90%], as compared to placebo. Standard-dose peg-loxenatide was not associated with increased occurrence of nausea [RR 2.87 (95% CI: 0.56 to 14.72); P = 0.21; I2 = 10%], vomiting [RR 4.73 (95% CI: 0.53 to 41.88); P = 0.16; I2 = 0%], and anorexia [RR 0.78 (95% CI: 0.18 to 3.28); P = 0.73; I2 = 0%]. Occurrence of nausea [RR 16.85 (95% CI: 3.89 to 72.92); P < 0.01; I2 = 10%], vomiting [RR 15.90 (95% CI: 2.99 to 84.55); P < 0.01; I2 = 0%], and anorexia [RR 3.85 (95% CI: 1.24 to 11.88); P = 0.02; I2 = 0%] was significantly higher with high-dose peg-loxenatide, as compared to placebo. Conclusion: Peg-loxenatide (100 mcg/week) is the most appropriate dose for clinical use as it is associated with good glycaemic efficacy with minimal gastro-intestinal side effects.

Prevention of Type 1 Diabetes: Current Perspective.

People living with type 1 Diabetes (T1D) and their families have poor perception of health related quality of life. Therapies for T1D are becoming better with time, but they still involve a lot of effort. Prevention of T1D, if successful, has potential to change lives of millions of families across the globe. Type 1 diabetes is an autoimmune disease with underlying genetic predisposition for autoimmunity against beta cell antigens upon exposure to an environmental trigger. Identifying underlying primary antigen responsible for initiating autoimmune cascade, avoiding environmental trigger and modifying immunity has all been used as strategies for preventing or delaying onset of type 1 diabetes. Primary prevention for type 1 diabetes is hindered by difficulty in identifying at-risk population and also due to lack of effective preventive strategy. Secondary prevention, in children with presence of autoimmunity, has recently received a boost with approval of Teplizumab, an immunity modifying drug by its Anti-CD3 action. Application of preventive strategies would also change based on country specific incidence, prevalence and availability of health resources. In current review, an update on preventive strategies for type 1 diabetes is being discussed as well as their applicability in Indian context.

Efficacy and Safety of Novel Thiazolidinedione Rivoglitazone in Type-2 Diabetes a Meta-Analysis.

No meta-analysis has analyzed the safety and efficacy of rivoglitazone in type-2 diabetes (T2DM). We undertook this meta-analysis to address this knowledge gap. Electronic databases were searched for RCTs involving T2DM patients receiving rivoglitazone in the intervention arm, and placebo/active comparator in the control arm. The primary outcome was to evaluate changes in HbA1c. Secondary outcomes were to evaluate alterations in glucose, lipids, and adverse events. From initially screened 24 articles, data from 3 RCTs (3591 patients) that fulfilled all criteria was analzsed. HbA1c was significantly lower with standard-dose (1 mg/d) [MD-0.86% (95%CI:-1.11--0.61); P < 0.01; I2 = 87%] and high-dose (1.5-2 mg/d) [MD-0.97%(95%CI:-1.03--0.90); P < 0.01; I2 = 19%] rivoglitazone compared to placebo. When compared to pioglitazone (30-45 mg/d), HbA1c lowering was comparable with standard-dose [MD 0.05%(95%CI:-0.01 - 0.11); P = 0.08; I2 = 11%], but superior with high-dose [MD -0.11%(95%CI:-0.18- -0.04); P < 0.01; I2 = 0%] rivoglitazone. Triglycerides were significantly lower with standard-dose [MD-17.95 mg/dl (95%CI:-34.23--1.66); P = 0.03; I2 = 0%] and high-dose [MD-40.41 mg/dl (95%CI:-72.90- -7.93);P = 0.01;I2 = 71%] rivoglitazone compared to placebo. Adiponectin significantly improved with standard-dose [MD 7.94 ng/ml (95%CI: 5.48-10.39); P < 0.01;I2 = 98%] and high-dose [MD 13.82 ng/ml (95%CI: 8.16-19.48); P < 0.01; I2 = 100%] rivoglitazone compared to placebo. hsCRP was significantly lower with standard-dose [MD -1.00 mg/L (95% CI: -1.20 - -0.80); P < 0.01; I2 = 6%] and high-dose [MD -1.50 mg/L (95%CI:-1.59- -1.40); P < 0.01; I2 = 0%] rivoglitazone compared to placebo. Treatment-emergent adverse events with standard-dose [Risk ratio (RR) 1.16 (95%CI: 0.84 -1.60); P = 0.38; I2 = 0%] and high-dose [RR1.34 (95%CI: 0.99-1.83); P = 0.06; I2 = 0%] rivoglitazone was comparable to placebo. Severe adverse events with standard-dose [RR1.88 (95%CI: 0.69-5.12);P = 0.22;I2 = 0%] and high-dose [RR 1.27 (95% CI: 0.45 - 3.59); P = 0.68; I2 = 0%] rivoglitazone was comparable to placebo. This meta-analysis highlights the good glycaemic efficacy and safety of both standard and high-dose rivoglitazone, and appears to be better than lobeglitazone in T2DM.

Optimal use of once weekly icodec insulin in type-2 diabetes: An updated meta-analysis of phase-2 and phase-3 randomized controlled trials.

BACKGROUND: Previously published meta-analysis have analysed data from 3 small phase-2 randomized controlled trials (RCTs). Since then, 5 big phase-3 RCTs have been published on use of icodec in type-2 diabetes (T2D). This updated systematic review aimed to establish the best practices and safety of icodec in T2D. METHODS: Databases were searched for RCTs involving T2D patients receiving icodec. Primary outcome was change in HbA1c. Secondary outcomes were alterations in glycaemic parameters and adverse events. RESULTS: Data from 8 studies (4317 patients) was analysed. Compared to other basal insulins, icodec had comparable HbA1c lowering at 16-weeks [MD-0.19 %(95%CI: 0.58-0.20); P = 0.35; I2 = 92 %], better HbA1c lowering at 26-weeks [MD-0.19 %(95%CI: 0.35-0.013); P = 0.02; I2 = 94 %] and 52-weeks [MD -0.28 %(95%CI: 0.45-0.12); P = 0.0008; I2 = 100 %]. Percentage of participants achieving HbA1c<7 % with icodec was higher at 16-weeks [OR2.37(95%CI:1.05-5.35); P = 0.04], comparable at 26-weeks [OR1.38(95%CI:0.91-2.11); P = 0.13; I2 = 80 %], and higher at 52-weeks [OR1.55(95%CI:1.30-1.85); P < 0.00001; I2 = 0 %]. Percentage of participants achieving HbA1c<7 % without level 2/3 hypoglycaemia was higher with icodec at 26-weeks [OR1.37(95%CI:1.10-1.71); P = 0.004; I2 = 28 %] and 52-weeks [OR1.48(95%CI:1.24-1.77); P < 0.001; I2 = 0 %]. At 26-weeks, injection-site reactions was higher with icodec [OR1.95(95%CI:1.06-3.56); P = 0.03; I2 = 0 %]. At 26-weeks level-1 hypoglycemia [OR1.40(95%CI:1.02-1.94); P = 0.04; I2 = 58 %], but not level-2/3 hypoglycaemia was higher with icodec. Subset analysis revealed increased occurrence of level-1 [OR 4.19 (95 % CI: 3.20-5.50); P < 0.00001] and level-2 [OR 3.97 (95 % CI: 3.04-5.18); P < 0.00001] hypoglycaemia in participants who received one-time additional 50 % icodec loading dose as compared to those who did not. At 26-weeks, weight-gain was significantly higher with icodec [MD0.61 kg(95%CI:0.38-0.84); P < 0.00001; I2 = 98 %]. CONCLUSION: Icodec insulin is well tolerated with glycaemic efficacy similar to all other available basal insulins.

Impact of early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors in patients with acute coronary syndrome: A systematic review meta-analysis.

OBJECTIVE: Scant data is available on the efficacy and safety of proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) for early and rapid reduction of low-density lipoprotein cholesterol (LDL-C) within 4-8 weeks of an acute event in patients with acute coronary syndrome (ACS). We undertook this meta-analysis to address this knowledge-gap. METHODS: Electronic databases were searched for RCTs involving patients with ACS receiving PCSK9i in intervention arm, and placebo/active comparator in control arm. Primary outcome was to evaluate changes in 1-month LDL-C post ACS. Secondary outcomes were to evaluate alterations in other lipid parameters and adverse events. RESULTS: From initially screened 194 articles, data from 3 studies was analyzed. After 4-weeks therapy, patients receiving PCSK9i had lower LDL-C [MD -0.95 mmol/L (95%CI:-1.51 to -0.40); P = 0.0007; I2 = 96%, total cholesterol (TC) [MD-1.05 mmol/L (95%CI:-1.83 to -0.27); P = 0.009; I2 = 94%] and triglycerides (TG) [MD-0.27 mmol/L (95%CI:-0.44 to -0.10); P = 0.002; I2 = 0%] compared to controls. After 4-8 weeks therapy, patients receiving PCSK9i has lower apolipoprotein B [MD-27.74% (95%CI:-42.59 to -12.89); P = 0.0003; I2 = 89%] as compared to controls. High density lipoprotein cholesterol (HDL-C) [MD 0.05 mmol/L (95%CI:-0.00-0.11); P = 0.05; I2 = 0%], lipoprotein(a) [MD-20.63 mmol/L (95%CI:-41.86- 0.59); P = 0.06; I2 = 54%] and apolipoprotein A1 [MD 0.02 g/L (95%CI:-0.02-0.07); P = 0.32; I2 = 0%] were comparable between groups. Hospital readmission for ACS was significantly lower in group receiving PCSK9i compared to controls [OR0.25 (95%CI:0.07-0.85); P = 0.03; I2 = 0%]. Occurrence of cardiac death [OR3.75 (95%CI:0.41-34.22); P = 0.24; I2 = 0%], serious adverse events [OR0.71 (95% CI:0.13-3.83); P = 0.69; I2 = 70%] and total adverse events [OR1.01 (95%CI: 0.19-5.30); P = 0.99; I2 = 92%] was comparable between groups. CONCLUSION: PCSK9i are highly effective in early reduction of LDL-C along with reduction of early hospital readmissions post-ACS.

Verapamil improves One-Year C-Peptide Levels in Recent Onset Type-1 Diabetes: A Meta-Analysis.

Meta-analysis studying the role of verapamil in improving C-peptide in people with recent-onset type-1 diabetes (T1DM) has not been conducted to date. We undertook this meta-analysis to address this knowledge gap. Electronic databases were systematically reviewed for RCTs having individuals with T1DM receiving verapamil in the treatment arm and placebo in the control arm over the standard of care. The primary outcome was to evaluate changes in the C-peptide area under the curve (AUC) at a one-year follow-up. Secondary outcomes were to assess alterations in C-peptide AUC, glycated hemoglobin (HbA1c), blood pressure, heart rate, and side effects at different time intervals over a one-year follow-up. From the initially screened 27 articles, data from two RCTs (112 patients) satisfied the inclusion criteria and were analyzed. Compared to placebo, C-peptide AUC in individuals receiving verapamil was not different at three months [MD 0.17 nmol/L (95%CI: -0.05-0.38); P = 0.13; I2 = 86%] but significantly higher at 1-year [MD 0.27 nmol/L (95%CI: 0.19-0.35); P < 0.01; I2 = 12%]. The verapamil arm showed similar changes in HbA1C at three months [MD 0.23% (95%CI: -0.43-0.90); P = 0.49; I2 = 88%] and 1-year [MD 0.18% (95% CI: -0.74 - 1.10); P = 0.70; I2 = 89%] compared to placebo. Occurrence of treatment-emergent adverse events [Risk ratio (RR) 1.90 (95%CI: 0.52-6.91); P = 0.33; I2 = 63%], serious adverse events [RR 1.40 (95%CI: 0.50-3.93); P = 0.53], constipation [RR4.11 (95%CI: 0.93-18.13); P = 0.06; I2 = 0%], headache [RR0.48 (95%CI: 0.16-1.43); P = 0.19; I2 = 0%], severe hypoglycemia [RR 0.87 (95%CI: 0.06 - 13.51); P = 0.92] were comparable across groups. Verapamil was well tolerated, and its use over one year was associated with significant improvements in C-peptide AUC though the HbA1c remained unchanged.

Semaglutide and cancer: A systematic review and meta-analysis.

BACKGROUND: French national health care insurance system database has suggested 1-3 years use of glucagon like peptide-1 receptor agonists (GLP1RA) (exenatide, liraglutide and dulaglutide) may be linked with increased occurrence of thyroid cancer. Similar data on semaglutide is not-available. Hence, we undertook this systematic review to look at the safety of semaglutide focussing on different cancers. METHODS: Databases were searched for randomized controlled trials (RCTs) and real-world studies involving patients receiving semaglutide in the intervention-arm. Primary outcome was to evaluate the occurrence of pancreatic and thyroid cancers. Secondary outcomes were to the evaluate occurrence of any other malignancies or severe adverse-events. RESULTS: Data from 37 RCTs and 19 real-world studies having 16,839 patients in placebo-control group, 16,550 patients in active-control group and 13,330 patients in real-world studies were analysed. Compared to placebo, occurrence of pancreatic cancer [OR 0.25 (95%CI: 0.03-2.24); P = 0.21], thyroid cancer [OR 2.04 (95%CI: 0.33-12.61); P = 0.44; I2 = 0%] and all neoplasms (benign, malignant and otherwise unspecified) [OR 0.95 (95%CI:0.62-1.45); P = 0.82; I2 = 0%] was similar in the semaglutide group. Compared to active controls, occurrence of pancreatic cancer [OR 0.40 (95%CI:0.09-1.87); P = 0.26; I2 = 0%], thyroid cancer [OR 1.19 (95%CI:0.15-9.66); P = 0.87; I2 = 0%] and all neoplasms (benign, malignant and otherwise unspecified) [OR 0.91 (95% CI: 0.44-1.89); P = 0.79; I2 = 0%] were similar in the semaglutide group. Real-world data analysis revealed single case each of pancreatic cancer and B-cell lymphoma. CONCLUSION: Semaglutide use in RCTs and real-world studies was not associated with an increased risk of any types of cancer, and this conclusion is supported by a high grade of evidence.

Nebulised magnesium sulphate as an adjuvant to the treatment of acute exacerbation of COPD: A systematic review and meta-analysis of randomised controlled trials with trial sequential analysis.

The purpose of this meta-analysis was to evaluate the efficacy of nebulised magnesium in the treatment of acute exacerbation of COPD. PubMed and Embase databases were searched for randomised controlled trials comparing any dose of nebulised magnesium sulphate with placebo for treatment of acute exacerbation of COPD, published from database inception till 30 June 2022. Bibliographic mining of relevant results was performed to identify any additional studies. Data extraction and analyses were done independently by review authors and any disagreements were resolved through consensus. Meta-analysis was done using a fixed-effect model at clinically significant congruent time points reported across maximum studies to ensure comparability of treatment effect. Four studies met the inclusion criteria, randomly assigning 433 patients to the comparisons of interest in this review. Pooled analysis showed that nebulised magnesium sulphate improved pulmonary expiratory flow function at 60 minutes after initiation of intervention compared to placebo [median difference (MD) 9.17%, 95% confidence interval (CI) 2.94 to 15.41]. Analysis of expiratory function in terms of standardised mean differences (SMD) revealed a small yet significant positive effect size (SMD 0.24, 95% CI 0.04 to 0.43). Among the secondary outcomes, nebulised magnesium sulphate reduced the need for ICU admission (risk ratio 0.52, 95% CI 0.28 to 0.95), amounting to 61 fewer ICU admissions per 1000 patients. No difference was noted in the need for hospital admission, need for ventilatory support, or mortality. No adverse events were reported. Nebulised magnesium sulphate improves pulmonary expiratory flow function and reduces the need for ICU admission in patients with acute exacerbation of COPD.

Role of novel sodium glucose co-transporter-2 inhibitor enavogliflozin in type-2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Enavogliflozin is a novel sodium glucose co-transporter-2 inhibitor (SGLT2i) developed in South Korea. This meta-analysis was done as no meta-analysis has analysed the efficacy and safety of enavogliflozin in type-2 diabetes (T2DM). METHODS: Electronic databases were systematically reviewed for randomized controlled trials having patients with T2DM receiving enavogliflozin in treatment-arm, and placebo/any other medicine in control-arm. Primary outcome was to evaluate changes in glycosylated haemoglobin (HbA1C). Secondary outcomes were to evaluate alterations in fasting glucose (FPG), 2-h post prandial glucose (2-h PPG), blood pressure (BP), weight, lipids, and adverse events. RESULTS: Data from 4 trials (684 patients) was analysed for clinical outcomes over 12-24 weeks clinical use. Compared to placebo, patients receiving enavogliflozin had significantly lower HbA1c [MD -0.76%(95% CI: 0.93 to -0.60); P < 0.00001; I2 = 97%], FPG [MD -2.12 mmol/l(95%CI: 2.47 to -1.77); P < 0.00001; I2 = 91%], body-weight [MD-1.37 kgs (95% CI: 1.73-1.00); P < 0.00001; I2 = 89%], systolic BP [MD-4.99 mm Hg (95%CI: 7.83 to -2.16); P = 0.0006; I2 = 47%], diastolic BP [MD-3.09 mm Hg(95%CI: 3.38 to -2.81); P < 0.00001; I2 = 0%]. Treatment emergent adverse-events [OR1.16(95%CI:0.64-2.09); P = 0.63; I2 = 0%], serious adverse events [OR1.81(95%CI:0.37-8.83); P = 0.46; I2 = 0%], urinary infections [OR1.37(95%CI:0.09-20.61); P = 0.82; I2 = 33%] and genital infections [OR 3.07(95%CI:0.31-29.88); P = 0.33; I2 = 0%] were comparable. Compared to dapagliflozin, patients receiving enavogliflozin had significantly lower HbA1c [MD-0.06%(95%CI: 0.07-0.05); P < 0.00001; I2 = 0%], FPG [MD-0.19 mmol/l(95%CI: 0.21 to -0.17); P < 0.00001; I2 = 0%], body-weight [MD-0.20 kgs(95%CI: 0.24 to -0.15); P < 0.00001; I2 = 0%], diastolic BP [MD -0.92 mm Hg (95%CI: 1.36 to -0.48); P < 0.0001; I2 = 91%] and significantly higher urine glucose creatinine ratio [MD 16.69 g/g (95%CI:16.11-17.26); P < 0.00001; I2 = 0%]. CONCLUSION: Enavogliflozin is a well tolerated and effective SGLT2i for T2DM and may be superior to dapagliflozin with regard to certain clinical aspects over 6 months clinical use.

Efficacy and safety of luseogliflozin in improving glycaemic and non-glycaemic outcomes in type-2 diabetes: A meta-analysis.

BACKGROUND & AIMS: No meta-analysis is available analysing the role of luseogliflozin in type-2 diabetes. We undertook this meta-analysis to address this knowledge-gap. METHODS: Electronic databases were searched for RCTs involving diabetes patients receiving luseogliflozin in intervention arm, and placebo/active comparator in control arm. Primary outcome was to evaluate changes in HbA1c. Secondary outcomes were to evaluate alterations in glucose, blood pressure, weight, lipids, and adverse events. RESULTS: From initially screened 151 articles, data from 10 RCTs involving 1304 patients was analysed. Individuals receiving luseogliflozin 2.5 mg/d had a significantly lower HbA1c [MD -0.76% (95% CI: 1.01 to -0.51); P < 0.01; I2 = 83%], fasting glucose [MD -26.69 mg/dl (95% CI: 35.41 to -17.96); P < 0.01; I2 = 80%], systolic blood pressure [MD -4.19 mm Hg (95% CI: 6.31 to -2.07); P < 0.01; I2 = 0%], body-weight [MD -1.61 kg (95% CI: 3.14 to -0.08); P = 0.04; I2 = 0%], triglycerides PCG [MD -12.60 mg/dl (95% CI: 24.25 to -0.95); P = 0.03; I2 = 0%], uric acid [MD -0.48 mg/dl (95% CI: 0.73 to -0.23); P < 0.01; I2 = 49%] and alanine aminotransferase [MD -4.11 IU/L (95% CI: 6.12 to -2.10); P < 0.01; I2 = 0%] compared to placebo. Occurrence of treatment-emergent adverse-events [RR 0.93 (95% CI: 0.72-1.20); P = 0.58; I2 = 0%], severe adverse-events [RR 1.19 (95% CI: 0.40-3.55); P = 0.76; I2 = 0%], hypoglycaemia [RR 1.56 (95% CI: 0.85-2.85); P = 0.15; I2 = 0%] and genital infections [RR 1.42 (95% CI: 0.48-4.18); P = 0.53; I2 = 0%] were not increased with luseogliflozin. Cardiovascular outcome trials are lacking and are urgently required. CONCLUSION: Luseogliflozin has good glycaemic and non-glycaemic benefits similar to other SGLT2 inhibitors and is well tolerated.