Importance of controlling diabetes early - The concept of metabolic memory, legacy effect and the case for early insulinisation

Most of the microvascular complications of diabetes are related to the degree and the length of exposure to hyperglycaemia. New data from the follow-up studies of the Diabetes Control and Complications Trial- the Epidemiology of Diabetes Intervention and Complications Study (DCCT- EDIC), and the United Kingdom Prospective Diabetes Study (UKPDS) emphasize the role of glycemic control early in the course of the disorder and its value in prevention of later complications. The phenomenon of ongoing beneficial effects on diabetic complications after a period of improved glycemic control even if followed by a return to usual (often poorer) metabolic control has been described as representing "metabolic memory" by the DCCT/EDIC investigators and as a "legacy effect" by the UKPDS investigators. This article reviews these concepts and explores the role of early use of insulin as a tool to achieve good glycemic control in type 2 diabetes

Treatment of diabetes mellitus: Beyond glycaemic control

Type 2 diabetes mellitus has emerged as the leading metabolic disorder worldwide, affecting more than 350 million individuals as of 2007. India is the ‘diabetic capital’ of the world, with 41 million people afflicted with the disease. The clinical importance of diabetes lies mainly in its propensity to produce macrovascular and microvascular complications, leading to cardiovascular disease, cerebrovascular disease, retinopathy, nephropathy, neuropathy and foot problems, which account for considerable morbidity and mortality throughout the world

Effectiveness of exenatide in Asian Indians in clinical care setting

Background: This study reports on the effectiveness of exenatide compared to insulin glargine or NPH insulin in patients with type 2 diabetes mellitus, unable to achieve glycemic control with oral glucose-lowering therapies in a clinical care setting. Patients and Methods: Patients with type 2 diabetes mellitus (n=47) whose glycemia was not controlled adequately with oral hypoglycemic agents at maximum recommended therapeutic doses were initiated on exenatide therapy. Age-, sex-, and body mass index-matched patients receiving insulin glargine (n=54) or NPH insulin (n=23) served as controls. Data analysis included glycated hemoglobin, fasting and postprandial plasma glucose, lipid profile, body weight, and the occurrence of hypoglycemia. Results: A statistically significant reduction in glycated hemoglobin value was noted after initiating exenatide (pre-exenatide 9.7±1.4% vs. post-exenatide 8.7±1.5%; P<0.05), which was comparable to values after insulin glargine (9.8±1.1% vs. 9.0±1.5%, respectively; P<0.05) and NPH insulin (9.6±1.4% vs. 8.9±1.3%, respectively; P<0.05). Exenatide therapy was associated with net weight loss (mean, 1.6kg), but therapy with insulin glargine and NPH insulin was associated with weight gain (1.8 and 2.3kg, respectively). Conclusions: In a group of select Asian Indian type 2 diabetes patients with secondary failure to oral hypoglycemic agents seen at a diabetes center, exenatide treatment in combination with oral drug regimens resulted in significant lowering of glycated hemoglobin similar to insulin glargine or NPH insulin but with the additional benefit of weight loss, albeit a small amount

The complex exocrine-endocrine relationship and secondary diabetes in exocrine pancreatic disorders

The pancreas is a dual organ with exocrine and endocrine functions. The interrelationship of the endocrine-exocrine parts of the pancreas is a complex one, but recent clinical and experimental studies have expanded our knowledge. Many disorders primarily of the exocrine pancreas, often solely in the clinical realm of gastroenterologists are associated with diabetes mellitus (DM). Although, the DM becoming disorders are often grouped with type 2 diabetes, the pathogenesis, clinical manifestations and management differ. We review here data on the association of exocrine-endocrine pancreas, the many hormones of the pancreas and their possible effects on the exocrine functions followed by data on the epidemiology, pathogenesis, and management of DM in chronic pancreatitis, cystic fibrosis, pancreatic cancer, and clinical states after pancreatic surgery

How to detect the millions of people in India with undiagnosed diabetes cost effectively

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Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics