Aims/hypothesis Recently, safety data signalled an increased risk of amputations in people taking canagliflozin, a sodium −glucose cotransporter 2 (SGLT2) inhibitor. If this side effect is due to drug-induced hypovolaemia, diuretics should also increase that risk. The aim of this study was to analyse the association between diuretic use and the risk of lower limb events (LLEs) in people with type 2 diabetes. Methods SURDIAGENE (SUivi Rénal, DIAbète de type 2 et GENEtique) is a prospective observational cohort that includes people with type 2 diabetes enrolled from 2002 to 2012 and followed-up until onset of LLE, death or 31 December 2015, whichever came first. Primary outcome was the first occurrence of LLE, a composite of lower limb amputation (LLA) and lower limb revascularisation (LLR). The rates of primary outcome were compared between participants taking and not taking diuretics at baseline in a Cox-adjusted model. Results At baseline, of the 1459 participants included, 670 were taking diuretics. In participants with and without diuretics, the mean ages were 67.1 and 62.9 years and 55.8% and 59.8% were men, respectively. During a median follow-up of 7.1 years, the incidence of LLE was 1.80 per 100 patient-years in diuretic users vs 1.00 in non-users (p < 0.001). The HR for LLE in users vs non-users was 2.08 (95% CI 1.49, 2.93), p < 0.001. This association remained significant in a multivariable-adjusted model (1.49 [1.01, 2.19]; p = 0.04) and similar after considering death as a competing risk (subhazard ratio 1. 89 [1.35, 2.64]; p < 0.001). When separated, LLA but not LLR, was associated with the use of diuretics: 2.01 (1.14, 3.54), p = 0.02 and 1.05 (0.67, 1.64), p = 0.84, respectively, in the multivariable-adjusted model. Conclusions/interpretation Among people with type 2 diabetes treated with diuretics, there was a significant increase in the risk of LLE, predominantly in the risk of LLA.
It is unclear whether the frequent non-severe episodes of hypoglycaemia observed during intensive glucose control in individuals with type 1 diabetes (T1D) are associated with subsequent weight gain. We analysed the association between non-severe hypoglycaemia and weight gain in 1441 Diabetes Control and Complication Trial (DCCT) participants. Non-severe hypoglycaemia was assessed by hypo-score (ie, number of blood glucose values <70 mg/dL divided by the total number of measurements during the DCCT quarterly visits). Significant associations were observed between the hypo-score and annual and total weight gain. The annual weight gain by hypo-score tertiles was 0.8 ± 1.2 (T1), 1.3 ± 1.5 (T2) and 1.4 ± 1.3 kg/y (T3), P < .001 for T2 and T3 vs T1, and for T3 vs T2. The odds ratio for a weight gain of 1.8 kg/y was 2.14 (95% CI, 1.56-2.93) for T2, and 2.53 (95%CI, 1.85-3.45) for T3 vs T1. These differences in weight gain and in risk of weight gain remained significant after adjustment for sex, age, duration of diabetes, HbA1c at baseline and treatment arms. In conclusion, our analysis shows a significant association between non-severe hypoglycaemia and weight gain in individuals with T1D from the DCCT.
Reduced tubulo-glomerular feedback and glycosuria during hyperglycaemia indicate high renal risk for Type 1 diabetic patients. Inter-individual variability in tubulo-glomerular feedback activity determines renal risk in Type 1 diabetes.
Background In contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity. Methods and results CLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia, and Africa in 2009–2010, and followed up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischaemia, or prior revascularization procedure. Among 32 694 patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to ∼60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome (cardiovascular death, myocardial infarction, or stroke) with an adjusted hazard ratio of 1.28 (95% confidence interval 1.18, 1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest. Conclusion In patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes. ClinicalTrials identifier ISRCTN43070564
Clinical trials in patients with type 2 diabetes (T2D) showed that the incidence of lower limb amputations (LLA) was doubled in patients in canagliflozin arm compared with placebo. Whether hypovolemia favored by SGLT2 inhibition-induced diuresis could be associated with a reduced lower extremity perfusion is a potential explanation. Although we cannot test this hypothesis directly, a similar side-effect of diuretics would be a supportive argument. We tested the association between use of diuretics (recorded at baseline) and risk of LLA (any LLA occurring during follow-up) in patients with T2D from the SURDIAGENE French cohort. Unadjusted and adjusted cox models were used. Among 1468 participants (Male 58%, age 65±11 years, known diabetes duration 15±10 years), 670 (46%) were on treatment with diuretics. LLA occurred in 79 (5.4%) patients during 5.8±3.2 years of follow-up: 51 (3.5%) among diuretics users and 28 (1.9%) in non-users (p<0.001). In the unadjusted model, the risk of amputation was higher in diuretics users (hazard ratio (HR), 2.52; 95% CI, 1.59-4.02; P<0.0001). The risk remained significantly higher after adjustment for confounding variables (age, sex, BMI, HbA1c at baseline, systolic blood pressure, diabetes duration, current smoking status, cholesterol-lowering drugs use and urinary albumin to creatinine ratio): HR 2.51 (95% CI, 1.50-4.22; P=0.0005). Higher risk of LLA during follow-up was also independently associated with male sex (HR 1.80; 95% CI, 1.1-1.41; P<0.0001), higher systolic blood pressure (HR 1.02; 95% CI, 1.00-1.03; P=0.01), and higher albuminuria (HR 1.33; 95% CI, 1.18-1.50; P<0.0001). Lower risk of LLA was associated with the use of fibrate (HR 0.23; 95% CI, 0.06-0.95; P=0.04). In our prospective observational study, the use of diuretics was the highest risk factor for LLA in patients with T2D. The result supports the role of hypovolemia in the amputation risk in T2D, a potential under-recognized effect of canagliflozin. Disclosure L. Potier: Consultant; Self; Sanofi, Novo Nordisk A/S, Eli Lilly and Company. Board Member; Self; Merck Sharp & Dohme Corp. K. Mohammedi: Speaker's Bureau; Self; Novo Nordisk Inc.. Other Relationship; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Sanofi. Other Relationship; Self; Sanofi, Takeda Development Centre Europe Ltd., Boehringer Ingelheim Pharmaceuticals, Inc.. A.K. Moutairou: None. A. Bumbu: Other Relationship; Self; Sanofi, Novo Nordisk A/S. O. Matar: None. F. Schneider: None. M. Marre: Board Member; Self; Abbott. Consultant; Self; AstraZeneca. Board Member; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Eli Lilly and Company. Board Member; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; Sanofi. Board Member; Self; Servier. P. Saulnier: None. G. Velho: None. R. Roussel: Advisory Panel; Self; AbbVie Inc., Abbott, Eli Lilly and Company, Sanofi, Novo Nordisk A/S, AstraZeneca. Speaker's Bureau; Self; Servier. Consultant; Self; Bayer AG. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Research Support; Self; Amgen Inc., Sanofi, Novo Nordisk A/S, Danone Research. Stock/Shareholder; Self; Iriade. Advisory Panel; Self; Physiogenex S.A.S. S. Hadjadj: Consultant; Self; Abbott, Novo Nordisk A/S, Servier, AstraZeneca, Merck Sharp & Dohme Corp.. Board Member; Self; Valbiotis. Consultant; Self; Sanofi, Eli Lilly and Company.
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