Lower limb events in individuals with type 2 diabetes: evidence for an increased risk associated with diuretic use
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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.
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.
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.
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.
KeywordsDiuretics Lower limb amputation Lower limb revascularisation Type 2 diabetes
Canagliflozin Cardiovascular Assessment Study
Lower limb amputation
Lower limb event
Lower limb revascularisation
Peripheral arterial disease
Sodium−glucose cotransporter 2
SUivi Rénal, DIAbète de type 2 et GENEtique
We thank: all participants included and followed-up in the cohort study for their kind participation in this research; the nurses and technicians who contributed to this clinical study; and E. Gand for her help with data management.
The independent adjudication committee for the SURDIAGENE study includes:
J. M. Halimi (Chairman Tours, France), G. Ducrocq (Paris, France), R. Roussel (Paris, France), P. Llatty (Poitiers, France), V. Rigalleau (Bordeaux, France), C. Hulin (Poitiers, France), D. Montaigne (Lille, France) and P. Zaoui (Grenoble, France).
Some of the data were presented as an abstract at the EASD meeting in 2018 (session 7, abstract 12).
LP had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. LP, RR, KM and SH made substantial contributions to conception and design of the study. All authors made substantial contributions to acquisition, analysis or interpretation of data and gave final approval of the version to be published. LP and RR drafted the manuscript and all the authors made critical revision of the manuscript for important intellectual content.
The SURDIAGENE study was supported by grants from the French Ministry of Health (Programme Hospitalier de Recherche Clinique [PHRC]-Poitiers 2004) and the Association Française des Diabetiques (AFD) (Research Grant 2003). The sponsors had no role in the: design or conduct of the study; collection, management, analysis or interpretation of the data; preparation, review or approval of the manuscript; or decision to submit the manuscript for publication.
Duality of interest
LP reports grants, personal fees and non-financial support from Novo Nordisk and Sanofi, personal fees and non-financial support from Eli Lilly and non-financial support from Servier. RR reports grants, personal fees and non-financial support from Sanofi, personal fees and non-financial support from MSD, grants from Amgen, personal fees from Physiogenex, AstraZeneca, Janssen, Eli Lilly, Abbott, Medtronic, Novo Nordisk and Servier and grants from Novo Nordisk. AB reports non-financial support from Sanofi, Novo Nordisk and Elivie. MM reports personal fees from Abbott, Intarcia, Eli Lilly, MSD, Novo Nordisk, Sanofi and Servier, grants from Novo Nordisk, Sanofi, Servier, MSD and Novartis and non-financial support from Novo Nordisk. KM reports personal fees and non-financial support from Novo Nordisk and Sanofi and non-financial support from VitalAir. SH reports personal fees and non-financial support from AstraZeneca, Bristol-Myers Squibb, Janssen, MSD and Sanofi, personal fees from Abbott, Boehringer Ingelheim, Eli Lily, Novartis, Novo Nordisk, Servier and Takeda. All support was outside the submitted work and modest. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.
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