Efficacy and safety of oral semaglutide in type 2 diabetes: A systematic review of real-world evidence.

BACKGROUND AND AIMS: Oral semaglutide has undergone global Phase 3 development programs named PIONEER and approved for therapeutic use in people with type 2 diabetes (T2D). We aim to systematically review the efficacy and safety of oral semaglutide in real-world settings. METHODS: We systematically searched the electronic databases of PubMed, Google Scholar, and ClinicalTrials.gov from inception until March 15, 2024, using several keywords with Boolean "AND". We retrieved all the available granular details of real-world studies (RWS). RESULTS: To date, results from four prospective and ten retrospective real-world studies of oral semaglutide in T2D are available. In prospective studies, the primary outcome of HbA1c reduction varied from -0.9 % to -1.6 %, weight loss varied from -4.7 kg to -8.2 kg and HbA1c target of <7 % was achieved in 30 %-64 % with oral semaglutide. In retrospective studies, HbA1c reduction varied from -0.4 % to -1.8 %, weight reduction varied from -1.4 to -9.0 kg, HbA1c target of <7 % was achieved in 32-64 %, and 30-41 % of people with T2D had ≥5 % weight loss with oral semaglutide. Gastrointestinal adverse events with oral semaglutide varied from 16 % to 50 % in prospective and 6 %-47 % in retrospective RWS. Overall, 0 %-18 % of patients had oral semaglutide discontinuation due to any cause. CONCLUSION: Oral semaglutide exhibited a reasonable reduction in HbA1c and weight in people with T2D, consistent with the findings from PIONEER trials. While no new safety issues emerged, the inherent limitations of RWS underscore the necessity of long-term investigations to comprehensively assess safety.

An overview of therapeutic options of obesity management in India: the Integrated Diabetes and Endocrinology Academy (IDEA) 2023 Congress update.

INTRODUCTION: With newer anti-obesity medications (AOMs) being introduced at a rapid pace, it is prudent to make a concise and updated clinical practice document that may help busy clinicians in daily clinical practice. A group of metabolic physicians, diabetologists, endocrinologists, and bariatric surgeons assembled during the Integrated Diabetes and Endocrine Academy 2023 Congress (IDEACON, July 2023, Kolkata, India) to compile an update of pharmacotherapeutic options for managing people with obesity in India. AREAS COVERED: After an extensive review of the literature by experts in different domains, this update provides all available information on the management of obesity, with a special emphasis on both currently available and soon-to-be-available AOMs, in people with obesity. EXPERT OPINION: Several newer AOMs have been shown to reduce body weight significantly, thus poised to make a paradigm shift in the management of obesity. While the tolerability and key adverse events associated with these AOMs appear to be acceptable in randomized controlled trials, pharmacovigilance is vital in real-world settings, given the absence of sufficiently long-term studies. The easy availability and affordability of these drugs is another area of concern, especially in developing countries like India.

Non-sugar sweeteners and health outcomes in adults without diabetes: deciphering the WHO recommendations in the Indian context.

BACKGROUND AND AIMS: A systematic review and meta-analysis conducted by the World Health Organization (WHO) assessed the health outcomes of non-sugar sweeteners (NSS) in randomized controlled trials (RCTs) and prospective cohort studies (PCSs) and reported conflicting findings. We aim to decipher these conflicting findings in RCTs and PCSs by critically reviewing their results, comparing them with previous meta-analyses, and providing a simplified interpretation including the Indian perspective. METHODS: We critically reviewed the 210-page dossier of WHO including the full text of most of the key studies of NSS included in this meta-analysis and subsequently compared it with previous meta-analyses to identify similarities and differences to address a few key questions pertaining to health outcomes associated with NSS use in adults. RESULTS: Poor health outcomes are often associated with excess sugar intake. While NSS are typically consumed as a sugar replacement, benefits are conflicting. While RCTs found some benefits in the short term, PCSs found harm associated with NSS use in the long term. CONCLUSION: The 2022 WHO meta-analysis that assessed the health outcomes of NSS is the most robust and critically analyzed document available to date. Despite the absence of any strong conclusion that suggests NSS consumption increases the risk of cardio-metabolic disorders, no firm evidence also rejects this statement. NSS could be an attractive replacement for sugar in overweight/obese people in the short term, but long-term harm cannot be fully ruled out. We suggest avoiding consuming sugar and restricting NSS intake wherever possible until long-term studies confirm or refute these findings.

New-onset diabetes with sodium-glucose cotransporter-2 inhibitors in prediabetes: An updated meta-analysis and possible mechanisms.

BACKGROUND AND AIMS: A recent systematic review and meta-analysis studied the effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on new-onset diabetes (NOD) in adults with prediabetes having chronic kidney disease and heart failure. In light of other large randomized controlled trials (RCTs) of SGLT2i published after this meta-analysis that also reported the NOD outcome in adults with prediabetes, it is of interest to update the NOD outcome with SGLT2i. METHODS: A systemic search in the PubMed and Embase electronic database was made until March 31, 2023, using specific MeSH keywords following PRISMA protocol. Subsequently, we conducted a meta-analysis using the random effects model while applying the inverse variance-weighted averages of pooled logarithmic hazard ratio (HR). Heterogeneity was measured using Higgins I2 and Cochrane Q statistics and publication bias was evaluated by applying funnel plots. A sensitivity exclusion analysis was additionally made. RESULTS: This meta-analysis of five RCTs (N = 6752) found a significant reduction in NOD (HR 0.81; 95% CI, 0.69-0.94; P = 0.005) with SGLT2i in adults with prediabetes without any heterogeneity (I2 = 0%). CONCLUSIONS: SGLT2i has the potential to reduce NOD in adults with prediabetes. Since no effect on HbA1c reduction was seen in adults with prediabetes in all five RCTs included in this meta-analysis, it is conceivable that reduction in NOD is not related to the masking of blood glucose exerted by SGLT2i. However, only an adequately powered trial of SGLT2i in people with prediabetes with a sufficient wash-out period will confirm these findings.

Protein restriction in adults with chronic kidney disease, with or without diabetes: Integrated Diabetes and Endocrine Academy (IDEA) consensus statement for Indian patients.

BACKGROUND AND AIMS: Most guidelines recommend protein restriction in adults with chronic kidney disease (CKD), with or without diabetes. However, advising protein restriction for every person with CKD is controversial. We aim to arrive at a consensus on this topic, especially among Indian adults with CKD. METHODS: A systematic literature search in the PubMed electronic database was undertaken using specific keywords and MeSH terms until May 1, 2022. All the retrieved literature was circulated and rigorously deliberated upon by the panel members. RESULTS: Seventeen meta-analyses that evaluated the outcomes of protein restriction in adults with CKD, with or without diabetes, met our inclusion criteria and were analyzed. A low-protein diet (LPD) in people with stages 3-5 of CKD (who are not on haemodialysis [HD]) reduces the severity of uremic symptoms and the rate of decline in glomerular filtration rate, leading to a delay in dialysis initiation. However, LPD in patients on maintenance HD may not be desirable because HD-induced protein catabolism may lead to protein-energy malnutrition. Since the average protein intake among Indians is much lower than recommended, this must be taken into consideration before recommending LPD for all Indian adults with CKD, particularly those on maintenance HD. CONCLUSION: It is essential to assess the nutritional status of people with CKD, particularly in countries like India where average daily protein intake is poor, before recommending guideline-directed protein restriction. The prescribed diet, including the quantity and quality of proteins, should be tailored to the person's habits, tastes, and needs.

Cardiovascular and Renal Outcomes With Sodium-Glucose Cotransporter-2 Inhibitors and Dipeptidyl Peptidase-4 Inhibitors Combination Therapy: A Meta-Analysis of Randomized Cardiovascular Outcome Trials.

OBJECTIVE: The cardiovascular (CV) and renal benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in people with type 2 diabetes are well known. However, similar beneficial effects of SGLT2i in combination with dipeptidyl peptidase-4 inhibitors (DPP4i) are unknown. It is of interest to explore a trial-level meta-analysis to fill this knowledge gap. METHODS: A literature search was conducted in the PubMed and Embase databases until January 31, 2023. All CV outcome trials (CVOTs) reporting the CV and renal outcomes of SGLT2i with or without background DPP4i therapy against the placebo were retrieved. A meta-analysis was subsequently conducted by applying the inverse variance-weighted averages of pooled logarithmic hazard ratio using primarily random-effects analysis. RESULTS: This meta-analysis showed that the beneficial 3-point major adverse cardiovascular events composite (3 CVOTs; N = 32 418), the composite of CV death or heart failure hospitalization (hHF) (4 CVOTs; N = 37 687), hHF (3 CVOTs; N = 27 545), CV death (4 CVOTs; N = 34 565), and renal outcomes (2 CVOTs; N = 25 406) with SGLT2i were similar with or without background DPP4i therapy against the placebo (Pheterogeneity = .71, .07, .87, .72, and .25; respectively). However, against the placebo, the summary estimates for the 3-point major adverse cardiovascular events composite, hHF, and renal outcomes were stronger with SGLT2i alone, whereas the summary estimates for CV death or hHF composite were larger with SGLT2i with background DPP4i therapy. CONCLUSION: Beneficial CV and renal effects of SGLT2i are similar against the placebo regardless of background DPP4i therapy.

Will lobeglitazone rival pioglitazone? A systematic review and critical appraisal.

BACKGROUND AND AIMS: Lobeglitazone (LGZ), a newly researched thiazolidinedione (TZD) thought to have lesser side effects compared with pioglitazone (PGZ), has been recently approved for the treatment of type 2 diabetes (T2D) in India. We aim to conduct an updated systematic review of LGZ to critically appraise its efficacy and safety in the context of PGZ. METHODS: A systematic literature search was carried out in the electronic database of PubMed until Jan 15, 2023, using specific keywords and MeSH terms. All studies which evaluated LGZ in people with T2D were retrieved and data were synthesized with regard to its efficacy and safety. A comparative critical appraisal was additionally made in the context of PGZ in T2D. RESULTS: Four randomized controlled, one prospective observational, and two real-world studies have evaluated the safety and efficacy of LGZ against placebo or active comparators either as monotherapy or in combination therapy. HbA1c reduction with LGZ 0.5 mg was superior to the placebo but similar to PGZ 15 mg and sitagliptin (SITA) 100 mg. Weight gain with LGZ was significantly higher compared to placebo and SITA but similar to PGZ. Edema was more frequently observed with LGZ compared to placebo, PGZ, and SITA. CONCLUSION: No substantial evidence is yet available that suggests LGZ could be a better alternative to PGZ both in the context of glycemic or extra-glycemic effects. At least in the short-term, adverse events of LGZ are indifferent from PGZ. More data is additionally needed to claim any advantage of LGZ over PGZ.

Noninsulin-based antihyperglycemic medications in patients with diabetes and COVID-19: A systematic review and meta-analysis.

BACKGROUND: Patients with diabetes are more likely to suffer COVID-19 complications. Using noninsulin antihyperglycemic medications (AGMs) during COVID-19 infection has proved challenging. In this study, we evaluate different noninsulin AGMs in patients with COVID-19. METHODS: We searched Medline, Embase, Web of Science, and Cochrane on 24 January 2022. We used the following keywords (COVID-19) AND (diabetes mellitus) AND (antihyperglycemic agent). The inclusion criteria were studies reporting one or more of the outcomes. We excluded non-English articles, case reports, and literature reviews. Study outcomes were mortality, hospitalization, and intensive care unit (ICU) admission. RESULTS: The use of metformin rather than other glucose-lowering medications was associated with statistically significant lower mortality (risk ratio [RR]: 0.60, 95% confidence interval [CI]: 0.47, 0.77, p < .001). Dipeptidyl peptidase-4 inhibitor (DPP-4i) use was associated with statistically significantly higher hospitalization risk (RR: 1.44, 95% CI: 1.23, 1.68, p < .001) and higher risk of ICU admissions and/or mechanical ventilation vs nonusers (RR: 1.24, 95% CI: 1.04, 1.48, p < .02). There was a statistically significant decrease in hospitalization for SGLT-2i users vs nonusers (RR: 0.89, 95% CI: 0.84-0.95, p < .001). Glucagon-like peptide-1 receptor agonist (GLP-1RA) use was associated with a statistically significant decrease in mortality (RR: 0.56, 95% CI: 0.42, 073, p < 0.001), ICU admission, and/or mechanical ventilation (RR: 0.79, 95% CI: 0.69-0.89, p < .001), and hospitalization (RR: 0.73, 95% CI: 0.54, 0.98, p = .04). CONCLUSIONS: AGM use was not associated with increased mortality. However, metformin and GLP-1RA use reduced mortality risk statistically significantly. DPP-4i use was associated with a statistically significant increase in the risk of hospitalization and admission to the ICU.

Efficacy and safety of imeglimin in type 2 diabetes: A systematic review and meta-analysis of randomized placebo-controlled trials.

BACKGROUND & AIMS: Imeglimin is a novel new oral compound recently approved for treating type 2 diabetes (T2D) in India. We conducted a systematic review and meta-analysis to evaluate the efficacy of imeglimin in people with T2D in the approved dose of 1000 mg twice daily (BID). METHODS: We systematically searched the database of PubMed until December 20, 2022, and retrieved all published double-blind, randomized, placebo-controlled trials (RCTs) conducted with imeglimin 1000 mg BID, using appropriate keywords and MeSH terms. A meta-analysis was conducted to study the HbA1c lowering effect of imeglimin 1000 mg BID in people with T2D using the Comprehensive meta-analysis (CMA) software Version 3, Biostat Inc. Englewood, NJ, USA. RESULTS: Of the seven Phase 2 studies and three Phase 3 studies conducted so far, only three published double-blind RCTs have reported the efficacy and safety of imeglimin 1000 mg BID against the placebo. Our meta-analysis using the random-effects model from two monotherapy studies (n = 360) showed imeglimin 1000 mg BID reduce HbA1c significantly (Δ -0.9%, 95% Confidence Interval [CI], -1.1 to -0.74%; P < 0.0001) against the placebo, without any heterogeneity (I2 = 0%). The pooled meta-analysis from all three RCTs (n = 574) found a significant reduction in HbA1c with imeglimin 1000 mg BID (Δ -0.79%; 95% CI, -1.00 to -0.59%; P < 0.0001) compared to placebo with high heterogeneity. CONCLUSIONS: This meta-analysis found a significant HbA1c lowering effect of imeglimin in people with T2D with an acceptable tolerability profile. Still, larger and longer studies are needed.

Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement.

OBJECTIVES: 46, XY difference/disorder of sex development (DSD) is a relatively uncommon group of heterogeneous disorders with varying degree of underandrogenization of male genitalia. Such patients should be approached systematically to reach an aetiological diagnosis. However, we lack, at present, a clinical practice guideline on diagnostic approach in 46, XY DSD from this part of the globe. Moreover, debate persists regarding the timing and cut-offs of different hormonal tests, performed in these cases. The consensus committee consisting of 34 highly experienced endocrinologists with interest and experience in managing DSD discussed and drafted a consensus statement on the diagnostic approach to 46, XY DSD focussing on relevant history, clinical examination, biochemical evaluation, imaging and genetic analysis. CONTENT: The consensus was guided by systematic reviews of existing literature followed by discussion. An initial draft was prepared and distributed among the members. The members provided their scientific inputs, and all the relevant suggestions were incorporated. The final draft was approved by the committee members. SUMMARY: The diagnostic approach in 46, XY DSD should be multidisciplinary although coordinated by an experienced endocrinologist. We recommend formal Karyotyping, even if Y chromosome material has been detected by other methods. Meticulous history taking and thorough head-to-toe examination should initially be performed with focus on external genitalia, including location of gonads. Decision regarding hormonal and other biochemical investigations should be made according to the age and interpreted according to age-appropriate norms Although LC-MS/MS is the preferred mode of steroid hormone measurements, immunoassays, which are widely available and less expensive, are acceptable alternatives. All patients with 46, XY DSD should undergo abdominopelvic ultrasonography by a trained radiologist. MRI of the abdomen and/or laparoscopy may be used to demonstrate the Mullerian structure and/or to localize the gonads. Genetic studies, which include copy number variation (CNV) or molecular testing of a candidate gene or next generation sequencing then should be ordered in a stepwise manner depending on the clinical, biochemical, hormonal, and radiological findings. OUTLOOK: The members of the committee believe that patients with 46, XY DSD need to be approached systematically. The proposed diagnostic algorithm, provided in the consensus statement, is cost effective and when supplemented with appropriate genetic studies, may help to reach an aetiological diagnosis in majority of such cases.

Role and Significance of Dietary Protein in the Management of Type 2 Diabetes and Its Complications in India: An Expert Opinion.

BACKGROUND: Obesity, prediabetes, and type 2 diabetes mellitus (T2DM) pose a triple burden in India. Almost two-thirds of people with diabetes (PWD) in India are found to have suboptimal glycemic, blood pressure, and lipid control. Medical nutrition therapy (MNT) in diabetes has emphasized on the amount and type of carbohydrates for years. However, protein, an important macronutrient in diabetes management, needs to be focused upon, especially in India, where the consumption is found to be lower than the recommendations provided by most guidelines. AIM: An expert committee attempted to review the role of dietary protein in the management of T2DM, arrive at a consensus on the significance of increasing dietary protein for various benefits, and offer practical guidance on ways to improve protein intake among Indians. METHODOLOGY: A total of 10 endocrinologists and diabetologists, one nephrologist, and three registered dietitians representing four zones of India formed the expert committee. An in-depth review of literature in the Indian context was carried out, and the draft document was shared with the expert committee, and their views were incorporated into the same. The expert committee then assembled virtually to deliberate on various aspects of the role of protein in T2DM management. The experts from various specialties gave their valuable inputs and suggestions from their extensive personal clinical experience and research work, which helped to reach a consensus on the role and significance of protein in the management of T2DM and its complications in India. RESULTS: There is abundant evidence that MNT is essential for the prevention and management of T2DM and its complications. Experts agreed that increasing protein intake offers myriad health benefits, namely reducing glycemic variability, improving glycemic control, increasing insulin sensitivity, improvement in lipid profile and immunity, and helping in weight management and preservation of muscle mass in PWD. The expert committee suggested aiming for an increase in protein intake by at least 5-10% of the current intake in lieu of carbohydrates in PWD. Experts also highlighted the need for more data quantifying the unmet protein needs in the Indian PWD, especially among vegetarians. Randomized controlled trials to study the effect of protein in diabetes complications such as cardiovascular disease (CVD) and diabetic kidney disease (DKD) and comorbid conditions such as sarcopenia among the Indian population are also warranted. CONCLUSION: Increasing protein quantity and quality in the diets of Indian PWD could significantly contribute to positive health outcomes. Increased protein intake, preferably through dietary sources to meet the requirements and, when required using diabetes-specific protein supplements (DSPS), is recommended in the prevention and control of T2DM.

SGLT2i as a First-line Antihyperglycemic in the Management of Type 2 Diabetes in the Context of Indians: A Systematic Review and Consensus.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been used for almost a decade and have proven to be effective not only in managing Type 2 diabetes (T2D), but their cardio and renal protective features make them very useful in managing patients with risk of multiple comorbidities. This systematic review was undertaken by the authors because there is no evidence currently available in India that has studied the suitability of SGLT2i as a first-line agent in patients newly diagnosed with T2D in India. MATERIALS AND METHODS: First, literature was searched to identify features that are considered important when deciding on a first-line agent for managing T2D. A total of 5 broad topics were identified-glycemic control, extra glycemic effects, antihyperglycemic combination therapy, safety, and cost-effectiveness. These domains had further subheadings, and a total of 16 domains were identified. Metformin is the drug of choice as a first-line agent in such situations and has been considered the gold standard for evaluating the effects of SGLT2i across these domains. A systematic literature review on each domain was conducted to compare SGLT2i with the gold standard in Indian patients newly diagnosed with T2D. Evidence was graded (levels of evidence (LoE)-A, B, and C), and recommendations (class of recommendation (CoR)-I, II, and III) were classified by the expert group as defined in the methodology. RESULTS: According to the systematic reviews conducted, 11 domains had Level A evidence, 2 domains (impact on lipids and gut microbiome) had Level B, and 3 domains had Level C (ß-cell function, renal protection, and glycemic variability) evidence. Based on evidence and expert opinion, the authors recommend SGLT2i as a first-line agent for managing newly diagnosed patients with T2D with a Class I recommendation for 13 domains and Class II for the remaining 3 (impact on lipids, gut microbiome, and ß-cell function). Although a poorer level of evidence (Level C) was available for the glycemic variability domain, the authors still reported this as Class I recommendations according to their expert opinion and consensus. CONCLUSION: This article advocates adopting SGLT2 inhibitors as the primary treatment choice for treating patients with newly diagnosed T2D in India.

Cardiorenal disease management in type 2 diabetes: An expert consensus.

BACKGROUND AND AIM: The interplay between cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes (T2D) is well established. We aim at providing an evidence-based expert opinion regarding the prevention and treatment of both heart failure (HF) and renal complications in people with T2D. METHOD: ology: The consensus recommendations were developed by subject experts in endocrinology, cardiology, and nephrology. The criteria for consensus were set to statements with ≥80% of agreement among clinicians specialized in endocrinology, cardiology, and nephrology. Key expert opinions were formulated based on scientific evidence and clinical judgment. RESULTS: Assessing the risk factors of CVD or CKD in people with diabetes and taking measures to prevent HF or kidney disease are essential. Known CVD or CKD among people with diabetes confers a very high risk for recurrent CVD. Metformin plus lifestyle modification should be the first-line therapy (unless contraindicated) for the management of T2D. Glucagon-like peptide 1 (GLP-1) agonists can be preferred in people with atherosclerotic cardiovascular disease (ASCVD) or with high-risk indicators, along with sodium-glucose cotransporter-2 inhibitors (SGLT2i), whereas SGLT2i are the first choice in HF and CKD. The GLP-1 agonists can be used in people with CKD if SGLT2i are not tolerated. CONCLUSION: Current evidence suggests SGLT2i as preferred agents among people with T2D and HF, and for those with T2D and ASCVD. SGLT2i and GLP-1RA also lower CV outcomes in those with diabetes and ASCVD, and the treatment choice should depend on the patient profile.

"Risk assessment for periodontal disease associated tooth loss among rural and urban population of 35-44, 45-54, 55-64 and 65-74 years age groups of Barabanki district, Uttar Pradesh, India: An epidemiological study.

Aim: The aim of the study was to assess the risk for periodontal disease-associated tooth loss among rural and urban population of Barabanki district, Uttar Pradesh, India. Materials and Methods: A cross-sectional study was done on 1200 urban and rural adults (632 males and 568 females) aged 35-74 years. Data were collected, followed by clinical examination for missing teeth. One-way analysis of variance with Bonferroni post hoc test, Chi-square test, and Student's t-test were used for statistical analysis. Statistical significance was set at P ≤ 0.05. Results: The mean number of periodontal disease-associated tooth loss in the study population was 4.2 ± 7.4. A significant association was found between the place of residence and tooth loss (3.5 ± 6.8 urban; 4.7 ± 7.8 rural), with rural adults showing greater tooth loss compared to urban adults (P < 0.01). Tooth loss increased significantly with age, ranging from mean number of 1.2 teeth in 35-44 years old to 11.5 teeth among 65-74 years old (P < 0.001). Gender showed a significant difference (P < 0.01) in tooth loss between males (4.7 ± 7.7) and females (3.6 ± 6.9). A significant association for tooth loss was also found with respect to the level of education and socioeconomic status (P < 0.001). A decrease in the mean number of missing teeth with increasing education and better socioeconomic status was observed, which was statistically significant (P < 0.001). Conclusion: The insights gained illustrate that tooth loss was 57% in rural and urban Barabanki district population, and the significant risks identified were age, illiterate, marital status, and low socioeconomic status.

Finerenone in diabetic kidney disease: A systematic review and critical appraisal.

BACKGROUND & AIMS: Finerenone is a novel non-steroidal mineralocorticoid antagonist (MRA) recently approved for the treatment of chronic kidney disease (CKD) in people with type 2 diabetes (T2D). We aim to conduct a systematic review of finerenone to know the efficacy and safety of finerenone in CKD with or without T2D. METHODS: A systematic search in the electronic database of PubMed and Google Scholar was made from inception until September 09, 2022, using several MeSH keywords related to finerenone. Ongoing trials were additionally searched from ClinicalTrials.Gov. RESULTS: Five phase 2 and three phase 3, randomized, double-blind, placebo- or active-controlled studies of finerenone have been published to date and several other randomized and real-world studies of finerenone are currently undergoing. CONCLUSIONS: In short-term studies in patients with CKD and reduced ejection heart failure, with or without T2D, finerenone 20 mg appears to have a better renal outcome compared with spironolactone and a better mortality outcome compared with eplerenone, with significantly lesser hyperkalemia compared to both spironolactone and finerenone. In long-term studies in patients with CKD and T2D, finerenone 10/20 mg significantly reduces the progression of renal disease and reduced CV endpoints (especially heart failure hospitalization) compared to placebo. Finerenone has no effect on HbA1c, body weight, and sexual side effects including gynecomastia, and has only a modest effect on blood pressure. However, hyperkalemia leading to drug withdrawal was significantly higher with finerenone compared to placebo. Safety data in real-world settings is a pressing priority.

Renin-angiotensin system blockers-SGLT2 inhibitors-mineralocorticoid receptor antagonists in diabetic kidney disease: A tale of the past two decades!

Several pharmacological agents to prevent the progression of diabetic kidney disease (DKD) have been tested in patients with type 2 diabetes mellitus (T2DM) in the past two decades. With the exception of renin-angiotensin system blockers that have shown a significant reduction in the progression of DKD in 2001, no other pharmacological agent tested in the past two decades have shown any clinically meaningful result. Recently, the sodium-glucose cotransporter-2 inhibitor (SGLT-2i), canagliflozin, has shown a significant reduction in the composite of hard renal and cardiovascular (CV) endpoints including progression of end-stage kidney disease in patients with DKD with T2DM at the top of renin-angiotensin system blocker use. Another SGLT-2i, dapagliflozin, has also shown a significant reduction in the composite of renal and CV endpoints including death in patients with chronic kidney disease (CKD), regardless of T2DM status. Similar positive findings on renal outcomes were recently reported as a top-line result of the empagliflozin trial in patients with CKD regardless of T2DM. However, the full results of this trial have not yet been published. While the use of older steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone in DKD is associated with a significant reduction in albuminuria outcomes, a novel non-steroidal MRA finerenone has additionally shown a significant reduction in the composite of hard renal and CV endpoints in patients with DKD and T2DM, with reasonably acceptable side effects.

Once-weekly basal insulin icodec: Looking ONWARDS from pharmacology to clinical trials.

BACKGROUND AND AIMS: Insulin icodec is currently the most advanced candidate insulin suitable for once-weekly administration. We aim to conduct a systematic review of the literature to find out the efficacy and safety of insulin icodec in patients with diabetes mellitus. METHODS: We systematically searched the electronic database of PubMed, and Google Scholar from inception until August 20, 2022, using MeSH keywords. Ongoing trials of insulin icodec were additionally searched from the ClinicalTrials.Gov. We retrieved all the available granular details of phase 1 to phase 3 studies of insulin icodec in both type 1 and type 2 diabetes. RESULTS: Phase 1 study showed insulin icodec having a half-life of 196 h (>1 week) while a steady state is achieved after 3 to 4 weekly injections. Phase 2 studies compared once-weekly icodec to insulin glargine (U-100) and found a similar glucose control with no significantly greater hypoglycemia risks. Top-line results from the five phase 3 studies reported better glucose control with once-weekly icodec compared to both once-daily insulin glargine (ONWARDS 1) and once-daily degludec (in both ONWARDS 2 and 4) with similar rates of hypoglycemia in type 2 diabetes, although there was a higher hypoglycemic event with insulin icodec in type 1 diabetes (ONWARDS 6) compared to once-daily degludec despite a similar glycemic control. CONCLUSION: A brighter prospect of once-weekly insulin icodec is on the card in particular in type 2 diabetes in terms of reducing injection pricks by >85% vs. once-daily basal insulin analogs, although few unknowns still exist.

Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes.

Both GLP-1 receptor agonists (GLP-1RA) and SGLT-2 inhibitors (SGLT-2I) are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure (SBP) modestly. Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c, body weight, and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects. Since several agents from each class of these drugs have shown an improvement in cardiovascular (CV) and renal outcomes in their respective cardiovascular outcome trials (CVOT), combination therapy is theoretically expected to have additional CV and renal benefits. In this comprehensive opinion review, we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone, although body weight lowering was nearly additive and the SBP lowering was more than additive. Our additional meta-analysis of CV outcomes with GLP-1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone, against placebo. Interestingly, a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials. Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.

Relook at DPP-4 inhibitors in the era of SGLT-2 inhibitors.

SGLT-2 inhibitors (SGLT-2Is) have significantly improved cardio-renal outcomes and are preferred agents in people with cardiovascular diseases, heart failure, and diabetic kidney disease. Similarly, GLP-1 receptor agonists (GLP-1RAs) have significantly improved atherosclerotic cardiovascular outcomes. To this end, DPP-4 inhibitors (DPP-4Is) are cardiac-neutral drugs. While long-acting GLP-1RAs have shown a favorable HbA1c lowering compared to DPP-4Is, there is no clinically meaningful HbA1c lowering difference between SGLT-2Is vs DPP-4Is. Moreover, the glucose-lowering potential of SGLT-2Is gets compromised with a progressive decline in renal functions, unlike DPP-4Is. Furthermore, the HbA1c lowering potential of DPP-4Is is favorable in people with T2DM having a modest baseline HbA1c (8.0%-8.5%) compared with SGLT-2Is which lowers HbA1c larger in a background of higher baseline HbA1c (> 8.5%-9.0%). These findings suggest that the role of DPP-4Is in the management of type 2 diabetes mellitus cannot be completely ignored even in the era of SGLT-2Is.