Consensus on Bridges for Barriers to Insulin Therapy.

INTRODUCTION: Insulin is an effective, safe and well-tolerated drug for glycaemic control. However, there are significant barriers to its use. OBJECTIVE: This consensus statement aims to define these barriers and suggest bridges to overcome them. METHODS: The consensus statements are based upon deliberations of a meeting held at New Delhi, India on 20 August 2016. The expert group committee reviewed various barriers to insulin use and categorized them into various categories: patient/community-related, physician-related and drug-related. The committee further proposed recommendations, based on published literature and their clinical experience, to address each of these barriers. RESULTS: Barriers (and bridges) can be classified as patient/community, physician/provider, and drug/device. Patient and physician barriers can further be categorized as those related to perceived inadequacy, perceived high cost, and perceived lack of benefit. Drug and device barriers can similarly be classified as those linked with perceived inadequacy, perceived high cost, and perceived lack of tolerability. Such a classification allows diabetes care providers to build appropriate bridges, which in turn facilitate timely insulin usage. Patient related barriers can be bridged by education, support and counselling. Use of modern insulin regimes and social marketing can address barriers related to perceived cost and lack of benefit. Physician related barriers can be resolved by training on various aspects of diabetes care. This will also help to break drug and device barriers, by ensuring appropriate choice of regimes, preparations and delivery devices. CONCLUSIONS: The consensus statements provide an easily understandable taxonomic structure of barriers to insulin use. By using a reader-friendly rubric, and by focusing on bridges (rather than barriers alone), it promotes a proactive and positive approach to diabetes management. The consensus statement should serve as a useful pedagogic and clinical tool for diabetes care professionals, and facilitate good diabetes care across the world.

Consensus on "Basal insulin in the management of Type 2 Diabetes: Which, When and How?"

INTRODUCTION: Type 2 diabetes mellitus (T2DM) has attained epidemic proportions and continues to increase despite the availability of a number of oral antidiabetic medications and major advances made in insulin delivery since its discovery nearly a hundred years ago. One, amongst many other reasons responsible for the inability to achieve adequate glycaemic control in a substantial proportion of T2DM patients is the delayed initiation and inappropriate intensification of insulin treatment. Appropriate initiation and intensification of insulin is critical for the successful achievement of tight glycaemic control. OBJECTIVE: To provide simple and easily implementable guidelines to primary care physicians on basal insulin initiation and intensification, along with use of basal insulin in special situations (hepatic failure, renal failure and gestational diabetes mellitus). METHODS: Each consensus statement on basal insulin initiation, intensification and use of basal insulin in special situations was evaluated for dosing and titration based on established guidelines, data from approved pack inserts, prescribing information or summary of product characteristics for each insulin type, and published scientific literature. These evaluations were then factored into the national context based not only on the clinical experience of the expert committee representatives' but also based on the common therapeutic practices followed in India to successfully achieve optimal glucose control. RESULTS: Recommendations on initiation and intensification of basal insulin, and its use in special situations, have been developed. The key recommendations are to initiate basal insulin when 2 or 3 oral antidiabetic medications fail to achieve target glycaemic control, or in symptomatic patients with glycated haemoglobin value greater than 9%. Depending upon patient characteristics, any of the four available basal insulins [Neutral protamine Hagedorn (NPH), Glargine (IGlar), Detemir (IDet), Degludec (IDeg)] can be used. However, IDeg has a longer duration of action, comparatively lesser hypoglycaemia (both overall and nocturnal) and more flexibility in administration timing compared to IGlar) and IDet. Inability to maintain glycaemic control should lead to prompt intensification of basal insulin treatment by adding mealtime insulin, consisting of one to three injections of either rapid-acting insulin analog or regular insulin; depending upon patient characteristics, intensification can also be achieved by transition from basal insulin to twice daily premixed insulin analogs/premixed human insulin/insulin co-formulations. IDeg/IDet can be used in all grades of renal and hepatic impairment; and IDet has been approved for use in gestational diabetes mellitus. CONCLUSIONS: We hope that these consensus based recommendations shall be a useful reference tool for health care practitioners and help them in initiating and intensifying insulin therapy in T2DM patients in order to achieve optimal glycaemic control.

Consensus on Insulin Dose and Titration Algorithms in Ambulatory Care of Type 2 Diabetes in India.

INSTRUCTION: Insulin is the oldest of the currently available treatment options in Type 2 diabetes mellitus (T2DM) and is considered as the most effective glucose lowering agent. Despite this, decision on starting insulin therapy is often delayed in India as well as worldwide due to various barriers at both patient and physician levels. Appropriate insulin dosing and titration is also critical to the successful achievement of tight glycaemic control. OBJECTIVE: To provide simple and easily implementable guidelines to primary care physicians on appropriate insulin dosing and titration of various insulin regimens for both initiation and intensification. METHODOLOGY: Each insulin regimen (once daily [OD] basal, OD, twice daily and thrice daily premixed, basal-plus and basal-bolus) was presented and evaluated for dosing and titration based on established guidelines, data from approved pack inserts, and published scientific literature. These evaluations were then factored into the national context based on the expert committee representatives patient-physician experience in their clinical practice and common therapeutic practices followed in India. RESULTS: Recommendations for dosing and titration of basal, basal-plus, premixed and basal-bolus insulins were developed. The key recommendations are that insulin doses can be adjusted once or twice weekly; adjustment can be based on lowest/mean of three recent self-monitoring of plasma glucose pre-meal/fasting plasma glucose (FPG) values. The titration should be based on FPG or pre-meal value of 80-130 mg/dL and the dose should be reduced by 10-20% for patients reporting hypoglycaemia(<70mg/dL). CONCLUSIONS: The consensus based recommendations mentioned in this paper will be a useful reference tool for health care practitioners, to initiate, optimise and intensify insulin therapy and to successfully achieve optimal glucose control.

Barriers and bridges to insulin therapy: bio psychosocial classification.

Barriers to insulin therapy are a major challenge to optimal practice of primary care diabetes. The primary care practitioner has to contend with multiple barriers while trying to initiate appropriate insulin therapy in a timely manner. Proper understanding of these barriers allows for efficient bridging of them. This article proposes a bio psychosocial classification of the potential barriers to insulin therapy, and possible bridges which can be built to overcome them.

Finerenone in type 2 diabetes and renal outcomes: A random-effects model meta-analysis.

Background: The nonsteroidal mineralocorticoid antagonist finerenone is a new addition to the list of agents (angiotensin converting enzyme inhibitors and sodium glucose cotransporter 2 inhibitors) conferring renal protection to patients with diabetic kidney disease. Two recent meta-analyses using the fixed effect model in patients with chronic kidney disease (both diabetic and nondiabetic populations) came to a conflicting conclusion on the effect of finerenone on eGFR decline. This meta-analysis was undertaken exclusively in the type 2 diabetes (T2D) population to explore the robustness and heterogeneity of the effect size by conducting a random effects model meta-analysis along with draft plots and prediction intervals. Materials and methods: A database search was conducted using the Cochrane library, PubMed, and Embase to identify relevant citations. Analysis was conducted on the 14th of September 2022, using RevMan 5.4.1 and RStudio (2022.07.1, Build 554). The hazard ratio was used as the effect size for the renal composite, while the standardized mean difference (SMD) was used to estimate the effect size of eGFR decline and reduction in the urine albumin creatinine ratio (UACR). The Cochrane risk-of-bias was used to assess the quality of the studies. The primary outcome assessed was the renal composite defined as kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes. Results: A pooled population of 13,943 patients from four citations was included for analysis. The Cochrane risk of bias was used to assess the quality of the studies. There was a significant 16% reduction in the renal composite (kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes) [HR: 0.84, 95% CI 0.77-0.92, 2: 0, I2: 0%). Finerenone was also associated with reduction in UACR (SMD: -0.49, 95% CI -0.53 to -0.46, τ2: < 0.0001, I2: 0%, prediction interval: -0.57 to -0.41) and prevention of decline in eGFR (SMD: -0.32, 95% CI -0.37 to -0.27, τ2: < 0.0001, I2: 0%, prediction interval: -0.43 to -0.21) without any evidence for significant heterogeneity. Except for an increase in hyperkalaemia (RR: 2.22, 95% CI 1.93-2.24), adverse events were observed with fineronone compared to placebo (RR: 1.00, 95% CI 0.98-1.01). Conclusion: There are significant benefits in renal outcomes associated with finerenone treatment in T2D patients with established chronic kidney disease with a side effect profile comparable to placebo.

Exploring the comparative cardiovascular death benefits of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a frequentist and Bayesian network meta-analysis-based scoring.

Background and aims: Cardiovascular death (CV death) is the most objective component of the primary or secondary endpoint in cardiovascular outcome trials (CVOTs) conducted with sodium-glucose cotransporter 2 inhibitors (SGLT-2is). CV death is often incorporated into primary composite outcomes. It is combined with major adverse cardiovascular events (MACEs) in trials with atherosclerotic cardiovascular disease (ASCVD) at baseline and with hospitalization due to heart failure (hHF) in trials with heart failure at baseline. Unlike the primary composites, CV death reduction by itself demonstrated significant variations among the CVOTs with SGLT-2is. Moreover, the impact of the individual agents within the SGLT-2i group on the reduction in CV death has not been explored objectively. This network meta-analysis was undertaken to construct a hierarchy based on indirect pairwise comparisons and rankings among the individual agents within SGLT-2is. Methods: A Cochrane library-based web search yielded 13 randomized controlled trials for analysis. Stata/BE 17.0 and RStudio 2022.07.1 Build 554 software were used to conduct a frequentist and Bayesian network meta-analysis. The effect size was assessed based on the risk ratio (RR). Ranking of the individual agents was performed with a frequentist approach (P-score and a multidimensional scaling [MDS] rank system) and a Bayesian ranking (surface under the cumulative ranking [SUCRA]). Results: Regarding the overall data, SGLT-2is reduced the CV death risk by 12% (RR: 0.88, 95% CI 0.80-0.96). All three scoring methods resulted in empagliflozin scoring the highest. There was a 15% RR reduction in CV death (95% CI 0.71-1.02) in the ASCVD and multiple cardiovascular risk factor (MRF) groups and an 11% RR reduction in the HF group, with empagliflozin ranking the highest in the former group and dapagliflozin in the latter. Conclusions: Empagliflozin ranked the highest compared to the other SGLT-2is in the overall population and the trials including type 2 diabetes (T2D) patients with ASCVD or MRF at baseline, while dapagliflozin ranked the highest in the trials of patients with HF at baseline. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022381556, identifier CRD42022381556.

Assessing the Effects of Modern Renoprotective Agents in Preventing Progression of Renal Composite Outcomes in Patients with Type 2 Diabetes: A Network Meta-analysis.

BACKGROUND AND AIMS: Type 2 diabetes is one of the leading causes of the development and progression of diabetic kidney disease, culminating in end-stage renal disease. Approximately two decades after successful implementation of the renin-angiotensin-aldosterone blocking system, three classes of agents [sodium glucose cotransporter 2 inhibitors (SGLT-2i), glucagon-like peptide 1 receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists] have shown significant potential to confer renoprotection. This network meta-analysis was undertaken to construct a hierarchy based on indirect pairwise comparisons and rankings among and within these three classes of molecules. METHODS: A Cochrane library-based web search yielded 16 randomized controlled trials for analysis. Stata/BE 17.0 and RStudio 2022.07.1 Build 554 software were used to conduct a frequentist network meta-analysis. The effect size was assessed based on the odds ratio, and the MDS (multidimensional scaling) rank system was used to identify a hierarchy among reno-protective molecules. RESULTS: Regarding the overall data, the SGLT-2i group of agents ranked higher than the other groups in preventing the progression of renal composite events in patients with T2D. Dapagliflozin ranked the highest among individual molecules. CONCLUSIONS: The SGLT-2i group of agents, especially dapagliflozin, is best suited to complement metabolic control in preventing the progression of renal composite outcomes.

Heterogeneity in cardiovascular death or hospitalization for heart failure benefits with flozins is linked to weight.

AIMS: Cardiovascular outcome trials with sodium-glucose cotransporter 2 inhibitors (SGLT-2is) have documented a positive impact on micro- and macrovascular complications of type 2 diabetes (T2D). Most analyses suggest that these benefits are independent of achieving metabolic control. This meta-regression analysis was undertaken to explore the relationship between metabolic components positively influenced by SGLT-2is and a reduction in cardiovascular death (CV death) or hospitalization due to heart failure (hHF). METHODS AND RESULTS: A database search was conducted using the Cochrane Library to identify relevant studies. Analysis was conducted using CMA and RStudio (2022.07.1) software. The hazard ratios of the individual studies were used to compute the random effects model mean effect size for CV death or hHF, and the prediction interval was used to identify the uncertainty in the summary treatment effect. Heterogeneity was quantified using Q statistics. A pooled population of 46 969 patients from five studies was included for analysis. The Cochrane risk of bias tool was used to assess the quality of the studies. There was a significant 23% reduction in CV deaths or hHFs in the SGLT-2i arm compared with the placebo arm [hazard ratio (HR): 0.77, 95% confidence interval (CI) 0.70-0.85]. However, the prediction interval (0.57-1.05) and the Q statistics [8.06 > degrees of freedom (df) of 4] were indicative of uncertainty in the true effect or heterogeneity. Nearly 50% of the variance of the observed effects were related to the true effects (I2  = 50%). Among the moderators selected, a significant correlation of the outcomes was found with the weight variable (P < 0.01). Weight differential could explain the entire variance in true effect size (R2  = 1.00) ruling out any sampling error. CONCLUSIONS: The results of this meta-regression analysis suggest that the beneficial effects of SGLT-2is in reducing CV deaths and hHFs are related to the weight variable.

The Renal Composite Benefit of Sodium Glucose Co-Transporter 2 Inhibitors Should Ideally Be Assessed Based on a Standardised Definition: A Meta-Analysis of Randomised Controlled Trials.

(1) Background: Chronic kidney disease (CKD) is extremely common against the backdrop of type 2 diabetes (T2D), accounting for nearly 30-40% of cases. The conventional management strategy relie predominantly on metabolic control and the renin-angiotensin-aldosterone system (RAAS) blockage. In the last decade, sodium glucose cotransporter 2 inhibitors (SGLT-2is) have emerged as the leading molecules preventing the development of, as well as retarding, the progression to CKD. Although the evidence in support of SGLT-2is is overwhelming, the definition of renal composite outcome in the trials varied considerably. The aim of the present meta-analysis was to explore the robustness of the renal composite benefits using a uniform definition. (2) Methods: A web-based search was conducted using the Cochrane Library to identify the relevant articles for meta-analysis. RStudio (1 July 2022, Build 554) software was used to conduct the meta-analysis. Hazard ratio (HR) was the effect size used to estimate the renal composite benefit, and prediction interval was used to detect heterogeneity. In view of the differing baseline characteristic of the trials as well as different molecules used, a random effects model was used. (3) Results: There were 12 trials including 78,781 patients, identified using the search strategy, and a five-point Cochrane risk-of-bias was used to assess quality of the publications. In the overall estimation (irrespective of the definition used for the renal composite) the HR was 0.68 (95% CI 0.60-0.76, prediction interval: 0.48-0.95) in favour of SGLT-2is, devoid of heterogeneity. While using a uniform definition of eGFR ≥ 40%decline, ESKD, or renal death, the HR was 0.64 (95% CI 0.53-0.78); using eGFR ≥ 50%decline, ESKD, or renal death the HR was 0.75 (95% CI 0.59-0.97); and with doubling of serum creatinine, renal replacement therapy, or renal death, the HR was 0.67 (95% CI 0.55-0.83) in favour of SGLT-2is. However, significant heterogeneity was encountered with all these three definitions. (4) Conclusion: There is a need to analyse the renal outcomes using a uniform definition in future trials. The presence of heterogeneity might disappear with the pooling of larger number of trials. However, if heterogeneity persists, we need to identify other clinical or laboratory attributes (in addition to SGLT-2is) responsible for the positive renal outcomes.

The cardiovascular benefits of GLP1-RAs are related to their positive effect on glycemic control: A meta-regression analysis.

BACKGROUNDS AND AIMS: Glucagon-like-peptides 1 receptor analogues (GLP1-RAs) have gained primacy in the management of type 2 diabetes (T2D).However, in contrast to the CVOT conducted with sodium glucose cotransporter-2 inhibitors (SGLT-2i)there was a significant reduction in glycated haemoglobin (HbA1c) in some of the CVOT with GLP1-RA. The aim of this analysis is to explore the possible association between cardiovascular outcome benefits with GLP1-RA and HbA1c reduction. METHODS: A Cochrane library based web search yielded 9 eligible citations for this analysis. The analysis was performed using the comprehensive meta-analysis (CMA) software.A meta-regression analysis was performed using HbA1c, weight, and systolic blood pressure reduction as moderators. RESULT: The meta-regression analysis was conducted on a pooled population of 64,236 patients. There was a significant heterogeneity associated with the MACE benefits (Q = 16.88, I2: 52.59, df = 7, p = 0.03). Among the moderators selected to explain the variance in true effects, HbA1c reduction was significant (Q = 7.00, P=<0.001, R2:1.0). Additional meta-regression analysis using 0.9% reduction of HbA1c from baseline indicated an association with MACE benefit (95% CI -0.23 to -0.02, P = 0.01, R2: 0.98). CONCLUSION: The MACE benefits associated with GLP1-RAs are dependent on the reduction of HbA1c levels.

A Meta-Analysis of the Effect of Sodium Glucose Cotransporter-2 Inhibitors on Metabolic Parameters in Patients With Polycystic Ovary Syndrome.

Objective: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women of childbearing age and is associated with multiple morbidities. However, treatment for this condition is mainly applied for symptomatic relief and does not address the complex pathophysiology of this condition. This meta-analysis was conducted on the usage of sodium-glucose cotransporter 2 inhibitors (SGLT-2is) in PCOS because this group of drugs presents an attractive strategy to address the metabolic and hormonal defects by managing the pathophysiological defects observed in this syndrome. Methods: We included prospective trials that enrolled patients with established PCOS and compared an SGLT-2i group versus a control group with at least 2 weeks of follow-up. The standardized mean difference (SMD) was used for effect size estimation from individual studies and was pooled using the fixed effect model. Results: We included four trials with a pooled population of 158 patients with documented PCOS who received either an SGLT-2i or standard management. From a metabolic perspective, significant improvements were observed in the reduction in body weight (SMD: -0.68, 95% CI -1.16 to -0.19, <0.01), fasting plasma glucose (FPG) (SMD: -0.59, 95% CI -0.99 to -0.19, P<0.01), and insulin resistance as assessed with the HOMA-IR (SMD: -0.39, 95% CI -0.76 to -0.03, P=0.03). In addition, a significant improvement was noted in dehydroepiandrosterone sulphate (DHEAS) levels (SMD: -0.55, 95% CI -0.94 to -0.16, P<0.01). Conclusion: SGLT-2i use is associated with salutary outcomes of metabolic and anthropometric markers of PCOS and likely favourable hormonal effects. Clinical Trial Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021268564], PROSPERO 2021 CRD42021268564.

The role of oral semaglutide in managing type 2 diabetes in Indian clinical settings: Addressing the unmet needs.

AIMS: Despite their established benefits, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) remain underutilized for type 2 diabetes mellitus (T2DM) management, which indicates that subcutaneous injection is an unfavorable mode of delivery from the patient's perspective. This review summarizes existing challenges related to medication adherence and the use of antihyperglycemia injectables, revisits the established safety and efficacy of oral semaglutide, and explores its features and considerations for use among the Indian T2DM population. METHODS: We performed a literature search using MEDLINE and the National Institutes of Health Clinical Trials Registry from July 1, 2016, to July 1, 2021, to identify publications on oral semaglutide approval, T2DM treatment guidelines, and clinical evidence for oral drug formulation. RESULTS: Oral semaglutide is the first oral GLP-1 RA approved for T2DM patients based on phase 3, randomized PIONEER trials. The multitargeted action of this drug offers glycemic control, weight control, and cardiovascular, renal, and additional benefits, including patient convenience and enhanced medication adherence. In addition to achieving glycemic control, the cost of semaglutide is reported to be lower than other GLP-1 RA in the West, thus potentially mitigating the economic burden that appears to be high among the Indian population. CONCLUSIONS: Currently, there is no data available on oral semaglutide in Indian clinical settings. However, significant improvements in glycemic control, cardiac and renal benefits, as well as weight loss across clinical trials should encourage clinicians to prioritize oral semaglutide over other antidiabetic agents.

Peptidyl-arginine deiminase: an additional marker of rheumatoid arthritis.

BACKGROUND: Antibodies against cyclic citrullinated peptide (anti-CCP) were thought to be more specific than rheumatoid factor (RF) for the diagnosis of rheumatoid arthritis (RA). The determination of anti-CCP in addition to RF could be helpful in the serological diagnosis and monitoring of patients with RA. Citrullination of proteins involves the enzymatic conversion of protein containing arginine residues to citrulline residues by the enzyme peptidylarginine deiminase (PAD). The present investigation was undertaken to estimate serum PAD enzyme activity in RA patients with a view to find its importance as a new diagnosis marker in a rheumatology clinic. METHODS: The activity of the PAD enzyme was measured by spectrophotometric method at 530 nm in sera of control subjects and in patients of RA (Group I: RF negative and CCP positive: Group II: both RF and CCP positive) in terms of citrulline formation using benzoyl-arginine ethyl ester (BAEE) as substrate. Anti-CCP and RF were also estimated in two groups by enzyme immunoassay and immunoturbidimetry for comparison. Clinical variables (duration of morning stiffness, swollen and tender joint counts, patient's assessment of pain) and C-reactive protein were also evaluated. RESULTS: A marked increase in PAD enzyme activity (p < 0.001) was noted in RA patients in comparison to controls and the level diminished appreciably along with two known serological markers (anti-CCP and RF) after six months of disease modifying antirheumatic drug (DMARD) treatment. The Group II RA patients showed much higher enzyme activity than Group I RA patients. However, clinical variables did not differ significantly between the two Groups of RA patients. CONCLUSIONS: We conclude that determination of PAD enzyme activity may be used as an additional marker for monitoring disease progression and regression along with anti-CCP and RF in patients with RA. Moreover, this method is rapid, sensitive, and inexpensive and can be adopted in a laboratory having modest facilities.

A Target HbA1c Between 7 and 7.7% Reduces Microvascular and Macrovascular Events in T2D Regardless of Duration of Diabetes: a Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: The target glycated haemoglobin (HbA1c) at which micro- and macrovascular benefits may be derived in type 2 diabetes (T2D) has never been clearly outlined. This meta-analysis was conducted on 15 randomized controlled trials to highlight the association of HbA1c range with outcomes. METHODS: The association of different HbA1c cluster (intention-to-treat (ITT) and end-of-study [EOS]) ranges (≤ 6.5%, 6.6-7.0%, 7.1-7.7%) with micro- and macrovascular complications and also the combined effect of T2D duration (< 10 years or ≥ 10 years) and HbA1c levels was assessed. RESULTS: An intensive glucose-lowering strategy resulted in a significant 17% (95% CI: 0.73-0.93, P < 0.01) reduction in retinopathy, 18% reduction in macroalbuminuria (95% CI 0.62-0.83, P < 0.01), 32% reduction in end-stage renal disease (ESRD) (95% CI 0.36-0.92, P = 0.02) and 13% reduction in non-fatal myocardial infarction (NFMI) (95% CI 0.78-0.96, P < 0.01). Based on HbA1c achieved at EOS, a significant 46% reduction in retinopathy, 52% reduction in macroalbuminuria, 36% reduction in (NFS) non-fatal stroke and a 22% reduction in all-cause mortality (ACM) were observed in the group with HbA1c in the 7.1-7.7% range. In the cohort, with diabetes duration ≥ 10 years, reduction of HbA1c to ≤ 7.0% and significant improvements in new-onset retinopathy (24%) and macroalbuminuria (30%) were offset by an increase in ACM (21%) and NFMI (17%). CONCLUSION: Contrasting with most recommendations, this meta-analysis including recent studies suggests that the optimal HbA1c range for T2D is 7.1-7.7% regardless of diabetes duration.

A meta-analysis of the effects of glucagon-like-peptide 1 receptor agonist (GLP1-RA) in nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes (T2D).

Treatment options for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D), two conditions which coexist, are limited though weight loss is an important strategy to improve outcomes in either disease. Glucagon-like peptide 1 receptor agonist (GLP1-RA) present a novel option to treat this dual disease by their salutary effects on glycaemic control and weight reduction. Eight randomized controlled trials on T2D and NAFLD from the Cochrane Library, Embase, and PubMed were included in this meta-analysis. The Comprehensive Meta-Analysis Software version 3 was used to calculate the effect size. In a pooled population of 615 patients-297 on GLP1-RA and 318 in the control arm, GLP1-RA produced a significant improvement in alanine aminotransferase [standardised mean difference (SDM), - 0.56, 95% CI - 0.88 to - 0.25, P < 0.01], aspartate aminotransferase (SDM, - 0.44, SE, 95% CI - 0.64 to - 0.24, P < 0.01), gamma glutaryl transaminase (SDM, - 0.60, 95% CI - 0.86 to - 0.34, P < 0.01) and reduction in liver fat content (LFC) (SDM, - 0.43, 95% CI - 0.74 to - 0.12, P < 0.01), as well as glycosylated haemoglobin (SDM, - 0.40, 95% CI, - 0.61 to - 0.19, P < 0.01) and weight (SDM, - 0.66, 95% CI, - 0.88 to - 0.44, P < 0.01), in comparison to standard of care or placebo. Significant improvement in biopsy resolution was also seen in the GLP1-RA arm (Rate Ratio, 6.60, 95% CI 2.67 to 16.29, P < 0.01). This is possibly the first meta-analysis conducted exclusively in patients with T2D and NAFLD which presents a strong signal that GLP1-RA, improve liver function and histology by improving glycaemia, reducing body weight and hepatic fat, which in turn reduces hepatic inflammation.Trial Registration: PROSPERO (ID: CRD42021228824).

Meta-analysis of the effects of sodium glucose cotransporter 2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes.

BACKGROUND AND AIM: Sodium glucose cotransporter 2 inhibitors (SGLT-2i), by way of their unique mode of action, present an attractive strategy for the treatment of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), which often coexist and may lead to severe complications. However, the evidence for treatment with SGLT-2i is limited to small heterogeneous studies. Therefore, this meta-analysis was conducted to deduce the effects of SGLT-2i in NAFLD with type 2 diabetes (T2D). METHODS: A web-based search identified nine randomized controlled trials from the Cochrane Library, Embase, and PubMed for this meta-analysis. The Comprehensive Meta-Analysis Software version 3 was used to calculate the effect size. RESULT: The outcomes of interest were analyzed from a pooled population of 11 369 patients-7281 on SGLT-2i and 4088 in the control arm. SGLT-2i therapy produced a statistically significant improvement in alanine aminotransferase [standardised mean difference (SDM), -0.21, 95% confidence interval (CI), -0.32 to -0.10, P < 0.01], aspartate aminotransferase (Standardised mean difference (SDM), -0.15, 95% CI, -0.24 to -0.07, P < 0.01), and liver fat as measured by proton density fat fraction (SDM, -0.98, 95% CI, -1.53 to -0.44, P < 0.01) in comparison to standard of care or placebo. In addition, there was a significant reduction in glycosylated hemoglobin (SDM, -0.37, 95% CI, -0.60 to -0.14, P < 0.01) and weight (SDM, -0.58, 95% CI, -0.93 to -0.23, P < 0.01) in the SGLT-2i arm. CONCLUSION: This meta-analysis provides a convincing signal that SGLT-2i have a salutary effect on NAFLD in type 2 diabetes (T2D), probably driven by an improvement of glycemia and body weight, which in turn attenuates hepatic inflammation and hepatic fat accumulation.

Assessing the need for pioglitazone in the treatment of patients with type 2 diabetes: a meta-analysis of its risks and benefits from prospective trials.

The safety and usefulness of pioglitazone (Pio) is repeatedly called into question due to the contradictory information available about it. A meta-analysis and risk benefit assessment was conducted to address the various points of debate regarding Pio. Electronic database search (Cochrane library, Embase & PubMed) resulted in 10 citations eligible for this meta-analysis (prospective, randomised studies), which was conducted using CMA software version 3 (Biostat Inc., Englewood, NJ, USA). The meta-analysis was registered with PROSPERO (ID: CRD42019122403) and compared pioglitazone with a control (anti-hyperglycemic agents without pioglitazone) in patients with either established cardiovascular disease or having high cardiovascular risk. Sensitivity and subgroup analysis were conducted to differentiate the effect of Pio against active controls and placebo. The use of Pio compared to the control group that did not use Pio resulted in a 14% and 23% significant reduction in odds of major adverse cardiac events (MACE: MH-OR, 0.86; 95% CI 0.75-0.98), and stroke (MH-OR, 0.77; 95% CI 0.60-0.99), respectively. This reduction in stroke was not significant in comparison to placebo on subgroup analysis. However, Pio significantly increased odds of heart failure (HF) (MH-OR, 1.47; 95% CI 1.26-1.71) as well as hospitalization for heart failure (hHF) (MH-OR, 1.48; 95% CI 1.21-1.81). In addition, the use of Pio was associated with a significant increase in odds of fractures in women (MH-OR, 2.05; 95% CI 1.28-3.27) and anaemia (MH-OR, 2.56; 95% CI 1.55-4.21). Pio has no significant effect on bladder cancer nor macular oedema. Pio has salutary effects on MACE. The positive effects are completely offset by the harm they seem to cause by way of heart failure, fractures, and anaemia. Pio should therefore be reserved for treatment of T2D with high CV risk or established cardiovascular (CV) disease only in selected patients where other antidiabetics are precluded and not routinely.

Translating the statistical benefits of SGLT-2 inhibitors on cardio-renal outcomes into clinical practice.

BACKGROUND/OBJECTIVES: This study aims to analyze the positive outcomes observed in cardiovascular outcomes trials conducted with sodium-glucose co-transporter inhibitors and determine their statistical and clinical significance. METHODS: A literature search conducted using the Cochrane library resulted in five citations - randomized controlled trials (RCTs), identified for analysis. Positive cardio-renal outcomes from the five RCTs were analyzed in accordance with a pre-defined strategy which included the hierarchical flow chart, presence of a persuasive p-value (p < 0.001), and number needed to treat (NNT) estimation calculated from the absolute risk reduction (ARR) reported. RESULTS: Only four instances fulfilled these stringent criteria - reduction of cardiovascular (CV) death with empagliflozin in T2DM patients with established atherosclerotic cardiovascular disease (eASCVD) (p < 0.001; NNT 45), reduction in cardiorenal outcomes with canagliflozin in a pooled T2DM population with macroalbuminuria (p < 0.00001; NNT 22), as well as reduction in the composite of CV death or hospitalization for heart failure (hHF) (p < 0.001; NNT 30) and also reduction in hHF or CV death with dapagliflozin in T2DM with heart failure with reduced ejection fraction (HFrEF) (p < 0.001; NNT 21). CONCLUSIONS: Statistically positive outcome results must be interpreted in the context of associated clinical benefits and not in isolation.

Is it Worth CANVASing for CREDENCE? A Benefit-risk Analysis.

BACKGROUND AND AIMS: A number of significant positive and negative signals emerged from the CANVAS Program and CREDENCE trial with the use of canagliflozin. These signals are confusing. A Likelihood of being Helped of Harmed (LHH) analysis was conducted to determine the risk, benefit ratio associated with canagliflozin use and address the signals as a continuum. MATERIALS AND METHODS: LHH was calculated from the number needed to treat (NNT) and number needed to harm (NNH) available from the absolute risk reductions reported with the outcomes of interest, in these two trials. RESULTS: In the CANVAS Program, LHH for major adverse cardiovascular events (MACE) points at a significant benefit with canagliflozin use in comparison to amputation (1.65), fractures (1.65) and euglycaemic diabetic ketoacidosis (euDKA) (16.67) risks. Only genital fungal infections were significant more in both sexes (0.21-M and 0.1-F) when LHH was matched against the positive outcomes. In contrast, the hHF benefits were outweighed by amputation (0.95) and fracture risks (0.95). In CREDENCE trial, the LHH for Primary composite, Renal composite and MACE, all supported the benefits in comparison to any adverse events encountered in the trial. The LHH from pooled data (CANVAS Program and CREDENCE trial) was in favour of all the benefits (hHF and renal composites) except for MACE matched against amputation (0.66). CONCLUSION: The outcome benefits were in favour of canagliflozin in comparison to all reported adverse events, when hHF and renal composite were under consideration, in both the individual and pooled LHH analysis. However, the MACE benefits were overwhelmed by amputation risk in the pooled analysis.

Redefining Cardiovascular (CV) Death as a Primary Endpoint Component in Cardiovascular Outcome Trials.

Sodium-Glucose cotransporter-2 inhibitors (SGLT-2i) and Glucagon-like peptide 1 receptor agonists (GLP1-RA) have revolutionised the approach for modern management of type 2 diabetes in view of their outcome altering abilities. An objective component of the primary endpoints used in the Cardiovascular Outcome Trials (CVOT) is cardiovascular (CV) death. However, the reason behind the decrease in CV deaths (compared to the placebo arm) appear to arise from divergent underlying processes. A recent meta-analysis of SGLT-2i and GLP1-RA indicated that the reduction in CV death associated with the former is predominantly due to its impact on heart failure (HF), while the association with the latter is due to its effect on atherosclerotic cardiovascular disease (ASCVD). A Pearson's product- moment correlation coefficient (r) analysis was performed on SGLT-2i exposed to CVOTs, exploring the strength of the association between CV death and hospitalisation for HF (hHF) and myocardial infarction (MI). The strength of association was strongest with hHF and negative with MI. In view of these findings, it has been proposed that future CVOTs should use a more objective definition of CVD, defining well in advance the anticipated impact on CVD (either as a consequence of the reduction in HF or ASCVD).