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Aims/hypothesis: Older adults are under-represented in trials, meaning the benefits and risks of glucose-lowering agents in this age group are unclear. The aim of this study was to assess the safety and effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in people with type 2 diabetes aged over 70 years using causal analysis., Methods: Hospital-linked UK primary care data (Clinical Practice Research Datalink, 2013-2020) were used to compare adverse events and effectiveness in individuals initiating SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i). Analysis was age-stratified: <70 years (SGLT2i n=66,810, DPP4i n=76,172), ≥70 years (SGLT2i n=10,419, DPP4i n=33,434). Outcomes were assessed using the instrumental variable causal inference method and prescriber preference as the instrument., Results: Risk of diabetic ketoacidosis was increased with SGLT2i in those aged ≥70 (incidence rate ratio compared with DPP4i: 3.82 [95% CI 1.12, 13.03]), but not in those aged <70 (1.12 [0.41, 3.04]). However, incidence rates with SGLT2i in those ≥70 was low (29.6 [29.5, 29.7]) per 10,000 person-years. SGLT2i were associated with similarly increased risk of genital infection in both age groups (incidence rate ratio in those <70: 2.27 [2.03, 2.53]; ≥70: 2.16 [1.77, 2.63]). There was no evidence of an increased risk of volume depletion, poor micturition control, urinary frequency, falls or amputation with SGLT2i in either age group. In those ≥70, HbA 1c reduction was similar between SGLT2i and DPP4i (-0.3 mmol/mol [-1.6, 1.1], -0.02% [0.1, 0.1]), but in those <70, SGLT2i were more effective (-4 mmol/mol [4.8, -3.1], -0.4% [-0.4, -0.3])., Conclusions/interpretation: Causal analysis suggests SGLT2i are effective in adults aged ≥70 years, but increase risk for genital infections and diabetic ketoacidosis. Our study extends RCT evidence to older adults with type 2 diabetes., (© 2024. The Author(s).)

Importance: Neuropathic pain (NP) has important clinical and socioeconomic consequences for individuals and society. Increasing evidence indicates that genetic factors make a significant contribution to NP, but genome-wide association studies (GWASs) are scant in this field and could help to elucidate susceptibility to NP., Objective: To identify genetic variants associated with NP susceptibility., Design, Setting, and Participants: This genetic association study included a meta-analysis of GWASs of NP using 3 independent cohorts: ie, Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS); Generation Scotland: Scottish Family Health Study (GS:SFHS); and the United Kingdom Biobank (UKBB). Data analysis was conducted from April 2018 to December 2019., Exposures: Individuals with NP (ie, case participants; those with pain of ≥3 months' duration and a Douleur Neuropathique en 4 Questions score ≥3) and individuals with no pain (ie, control participants) with or without diabetes from GoDARTS and GS:SFHS were identified using validated self-completed questionnaires. In the UKBB, self-reported prescribed medication and hospital records were used as a proxy to identify case participants (patients recorded as receiving specific anti-NP medicines) and control participants., Main Outcomes and Measures: GWAS was performed using linear mixed modeling. GWAS summary statistics were combined using fixed-effect meta-analysis. A total of 51 variants previously shown to be associated with NP were tested for replication., Results: This study included a total of 4512 case participants (2662 [58.9%] women; mean [SD] age, 61.7 [10.8] years) and 428 489 control participants (227 817 [53.2%] women; mean [SD] age, 62.3 [11.5] years) in the meta-analysis of 3 cohorts with European descent. The study found a genome-wide significant locus at chromosome 12q23.1, which mapped to SLC25A3 (rs369920026; odds ratio [OR] for having NP, 1.68; 95% CI, 1.40-2.02; P = 1.30 × 10-8), and a suggestive variant at 13q14.2 near CAB39L (rs7992766; OR, 1.09; 95% CI, 1.05-1.14; P = 1.22 × 10-7). These mitochondrial phosphate carriers and calcium binding genes are expressed in brain and dorsal root ganglia. Colocalization analyses using expression quantitative loci data found that the suggestive variant was associated with expression of CAB39L in the brain cerebellum (P = 1.01 × 10-14). None of the previously reported variants were replicated., Conclusions and Relevance: To our knowledge, this was the largest meta-analyses of GWAS to date. It found novel genetic variants associated with NP susceptibility. These findings provide new insights into the genetic architecture of NP and important information for further studies.

Objectives: Several small studies indicate the sulphonamide component of the drug sulfasalazine lowers HbA 1c. We investigated reduction of HbA 1c following incident prescription of sulfasalazine and related aminosalicylates, lacking the sulphonamide group, in an observational cohort., Research Design and Methods: Individuals in the Scottish Care Information Diabetes Collaboration (SCI-Diabetes) with type 2 diabetes and incident prescription for an aminosalicylate drug (sulfasalazine, mesalazine, olsalazine or balsalazide) were identified. Baseline and 6-month HbA 1c were required for eligibility, to calculate HbA 1c response. To investigate association with haemolysis, change in components of full blood count was assessed. Paired t-tests compared difference in baseline and treatment HbA 1c measures and other clinical variables., Results: In all, 113 individuals treated with sulfasalazine and 103 with mesalazine (lacking the sulphonamide group) were eligible, with no eligible individuals treated with olsalazine or balsalazide. Baseline characteristics were similar. Mean (SD) HbA 1c reduction at 6 months was -9 ± 16 mmol/mol (-0.9 ± 1.4%) (p < 0.0001) in those taking sulfasalazine with no reduction in those taking mesalazine (2 ± 16 mmol/mol (0.2 ± 1.4%). Sulfasalazine but not mesalazine was associated with a mean (SD) increase in mean cell volume of 3.7 ± 5.6 fl (p < 0.0001) and decrease in red cell count of -0.2 ± 0.4 × 10 -12 /L (p < 0.0001)., Conclusions: In this observational, population-based study, sulfasalazine initiation was associated with a 6-month reduction in HbA 1c . This correlated with haematological changes suggesting haemolytic effects of sulfasalazine. Haemolysis is proposed to contribute to HbA 1c lowering through the sulphonamide pharmacophore. This suggests that HbA 1c is not a reliable measure of glycaemia in individuals prescribed sulfasalazine., (© 2020 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Objective: To evaluate the association between metformin use and anemia risk in type 2 diabetes, and the time-course for this, in a randomized controlled trial (RCT) and real-world population data., Research Design and Methods: Anemia was defined as a hemoglobin measure of <11 g/dL. In the RCTs A Diabetes Outcome Progression Trial (ADOPT; n = 3,967) and UK Prospective Diabetes Study (UKPDS; n = 1,473), logistic regression was used to model anemia risk and nonlinear mixed models for change in hematological parameters. In the observational Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) population ( n = 3,485), discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk., Results: In ADOPT, compared with sulfonylureas, the odds ratio (OR) (95% CI) for anemia was 1.93 (1.10, 3.38) for metformin and 4.18 (2.50, 7.00) for thiazolidinediones. In UKPDS, compared with diet, the OR (95% CI) was 3.40 (1.98, 5.83) for metformin, 0.96 (0.57, 1.62) for sulfonylureas, and 1.08 (0.62, 1.87) for insulin. In ADOPT, hemoglobin and hematocrit dropped after metformin initiation by 6 months, with no further decrease after 3 years. In UKPDS, hemoglobin fell by 3 years in the metformin group compared with other treatments. At years 6 and 9, hemoglobin was reduced in all treatment groups, with no greater difference seen in the metformin group. In GoDARTS, each 1 g/day of metformin use was associated with a 2% higher annual risk of anemia., Conclusions: Metformin use is associated with early risk of anemia in individuals with type 2 diabetes, a finding consistent across two RCTs and replicated in one real-world study. The mechanism for this early fall in hemoglobin is uncertain, but given the time course, is unlikely to be due to vitamin B 12 deficiency alone., (© 2020 by the American Diabetes Association.)

Aims: Predicting likely durability of glucose-lowering therapies for people with type 2 diabetes (T2D) could help inform individualised therapeutic choices., Methods: We used data from UKPDS patients with newly-diagnosed T2D randomised to first-line glucose-lowering monotherapy with chlorpropamide-glibenclamide-basal insulin or metformin. In 2339 participants who achieved one-year HbA 1c values <7.5% (<59 mmol/mol)-we assessed relationships between one-year characteristics and time to monotherapy-failure (HbA 1c  ≥ 7.5% or requiring second-line therapy). Model validation was performed using bootstrap sampling., Results: Follow-up was median (IQR) 11.0 (8.0-14.0) years. Monotherapy-failure occurred in 72%-82%-75% and 79% for those randomised to chlorpropamide-glibenclamide-basal insulin or metformin respectively-after median 4.5 (3.0-6.6)-3.7 (2.6-5.6)-4.2 (2.7-6.5) and 3.8 (2.6- 5.2) years. Time-to-monotherapy-failure was predicted primarily by HbA 1c and BMI values-with other risk factors varying by type of monotherapy-with predictions to within ±2.5 years for 55%-60%-56% and 57% of the chlorpropamide-glibenclamide-basal insulin and metformin monotherapy cohorts respectively., Conclusions: Post one-year glycaemic durability can be predicted robustly in individuals with newly-diagnosed T2D who achieve HbA 1c values  < 7.5% one year after commencing traditional monotherapies. Such information could be used to help guide glycaemic management for individual patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)