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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)., (© 2021. The Author(s).)

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.

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: To assess the effects DPP-4i; SGLT2-i & GLP1-RA on CV death, MI, stroke and hHF. This is probably the first meta-analysis to assess the effects of these drugs on MI and stroke in totality, including non-fatal & fatal MI and stroke., Methods: Scientific databases were searched for RCTs with pre-specified inclusion criteria and each end-point from the selected 13 studies was reported as an effect size (M H odds ratio) with a 95% confidence interval P value., Results: The pooled analysis of all the 5 available CVOT with DPP-4i resulted in a neutral effect on MI, stroke, the combined end points of MI & Stroke, CV death and hHF. The pooled analysis of all the 5 available CVOTs with GLP1-RA resulted in a neutral effect on MI. However, there was a statistically significant 12% reduction in CV death (P = 0.01), 13% reduction in stroke (P = 0.02) and 11% reduction the combined end points of MI & Stroke (P = 0.001). The impact of GLP1-RA inhibitors on hHF was neutral. The pooled analysis of all the 3 available CVOTs with SGLT2-i resulted in a neutral effect on MI, stroke, the combined end points of MI & Stroke and CV death. There was however a statistically significant 28% reduction in hHF (P < 0.001)., Conclusion: DPP-4i & SGLT-2i are neutral as far as all aspects of CV outcomes are concerned except for hHF which is significantly reduced by the latter. GLP1-RA as a class reduce risk of ASCVD showing a significant reduction in MI and stroke., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.

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.

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.

Objective: To compare the changes in various glycemic parameters in insulin-naïve type 2 diabetes mellitus (DM) patients who were initiated on insulin glargine or insulin degludec in a real world setting., Methods: Retrospective data were analyzed in consecutive type 2 DM patients in a real world setting, who failed oral therapy (at least 2 oral anti-diabetic drugs) and were initiated with either insulin glargine or insulin degludec. The parameters assessed were the changes in HbA1c, fasting plasma glucose, body weight, dose of Insulin and the total number of patient reported hypoglycemic episodes up to 6 months after initiation., Result: At baseline, insulin glargine and insulin degludec groups were similar in terms of gender, age, weight, HbA1c and duration of diabetes. After 6 months follow up the change in HbA1c (-1.09 versus -1.45 P=0.124), change in FPG (-72.81mg/dl [-4mmol/L] versus -75.88mg/dl [-4.2mmol/L] P=0.755), and the change in body weight (+1.65 versus +0.85 P=0.082) were similar in glargine and degludec groups, respectively. Patients in insulin degludec group experienced significantly lesser patient reported hypoglycemic episodes (12 versus 40) and required significantly lesser dose (25.68Units versus 18.61Units per day; P=0.002) compared to insulin glargine. 41% of the patients reached HbA1C target of ≤7% with insulin glargine compared to 69% with insulin degludec within the specified time period., Conclusion: Results from this real world analysis suggest that among type 2 DM patients who were initiated on insulin degludec as compared to insulin glargine may be associated with significantly lesser patient reported hypoglycemic episodes and lesser dose of insulin while achieving similar glycemic control. This study is however limited by the retrospective nature of the data collection., (Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

The issue related to macrovascular outcomes and intensive glycemic control was hotly debated after the publication of landmark trials like ACCORD, ADVANCE, and VADT. The only benefits seem to come from intervening early on in the disease process as indicated by the 10-year UKPDS follow-up. To complicate matters USFDA made it mandatory for modern drugs to conduct cardiovascular safety trials in high-risk populations after the 2008 rosiglitazone scare. This led to all the modern group of drugs designing cardiovascular safety trials (gliptins, GLP-1 agonists, and SGLT-2 inhibitors) to meet USFDA regulatory requirements. We saw publication of the first 2 randomized trials with gliptins published a year and a half back. On the face value SAVOR TIMI and EXAMINE satisfied the primary composite CV end-points. However, issues related to significant increase in heart failure and all-cause 7-day on-treatment mortality created a lot of confusion. FDA reanalysis of these data (especially SAVOR) raises a lot of doubts as far as CV safety of these groups of drugs was concerned. Hence, all eyes were on TECOS, which was published this year. We take a microscopic look at these trials trying to understand where we stand as from now on this issue.

In the month of June 2013 the Government of India suddenly suspended three drugs for use. The suspension of the anti-diabetic agent came as a rude shock to the medical community who has been utilizing this insulin sensitizer for more than a decade. We took a close look at the controversies surrounding this agent, the current state in the global scenario and how India has reacted in this mini review. Like most of the drugs utilized in the management of medical disorders pioglitazone also has been under the scanner for quite some time. However no definitive cause and effect association with any of the adverse events namely bladder cancer, anemia, fractures and heart failure was found. The international community responded with caution and refrained from banning the drug outright except for France. The ban in India in the absence of incriminating data on the Indian population seems out of place., (Copyright © 2014. Published by Elsevier Ltd.)

Over the last few years a number of important drugs like rofecoxib, rosiglitazone, gatifloxacin (in diabetics) have lost their position in disease management. The newest controversy revolves around Pioglitazone, a thiozolidindione, which improves insulin sensitivity and is reputed to have cardioprotective actions, but is riddled with several controversies related to weight gain, distal fractures of long bones, recent reports of bladder cancer and others. There are now new groups of drugs, which have been introduced with stringent FDA approval. These include DPP-4 inhibitors, GLP-1 analogues and bromocriptine (old wine in a new bottle). Early in 2013 we are also looking at the launch of another new agent - SGLT-2 inhibitors. These newer agents are associated with not only a significant glucose lowering effect but also positive extra-glycaemic benefits principally in the areas of hypoglycaemia and weight gain. This raises a very important question - do we really need such a controversial agent when such a plethora of agents are available to us with possibly better metabolic profile than pioglitazone? This review addresses this highly contentious area dissecting the pros and cons as we see it., (Copyright © 2013. Published by Elsevier Ltd.)

Recent publications indicate a possible association between newer analogue insulin Glargine and cancer. However all these data were observational in nature and subject to lot of methodological errors. It is practically impossible to derive at a cause and effect relationship based on these observational studies. There are several confounding factors like hyperinsulinemia, obesity and smoking, which independently can be associated with cancer risk. This review looks into the recently published observational studies from the methodological point of view and whether such a negative association can indeed be drawn as a conclusion. Several methodological defects were identified in the process of scrutiny and we concluded it is not possible to conclude that there is an association between Glargine use and cancer. However long-term prospective data is required to come to definite conclusion., (Copyright © 2012 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Traditionally, treatment for type 2 diabetes (T2D) centered on the failure of insulin secretion from the beta cells of the pancreas and insulin resistance. Though effective in certain respects, these treatments are marred by multiple undesirable side effects. The discovery of the incretin defect and the role of glucagon in T2D shifted the focus to therapies that addressed not only the beta cell defect but also the alpha cell defect in the pancreas. Therapies addressing these defects, simultaneously, have switched the entire focus of T2D therapy by not only improving glycemic control but also reducing the risk of hypoglycemia and weight gain and improving outcomes. These newer modalities of treatment started off with dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RAs), and now further treatments in the form of twincretins (GLP1/GIP dual agonists) and triple agonists (GLP1/GIP/glucagon agonists) are unraveling. This article provides a summary of the evidence available with these newer antidiabetics, which address the glucagon defect in T2D. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]