CorrespondenceSGLT2 inhibitors and amputations in the US FDA Adverse Event Reporting System
References (4)
- B Neal et al.
Canagliflozin and cardiovascular and renal events in type 2 diabetes
N Engl J Med
(2017) - GP Fadini et al.
SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA Adverse Event Reporting System
Diabetologia
(2017)
Cited by (113)
Sodium-Glucose Cotransporter-2 Inhibitors and Lower-Extremity Amputation
2023, American Journal of CardiologyLower-limb peripheral arterial disease and amputations in people with diabetes: Risk factors, prognostic value and management
2023, Presse MedicaleLower-limb peripheral arterial disease (PAD), is a common manifestation of systemic atherosclerosis, resulting from a partial or complete obstruction of at least one lower-limb arteries. PAD is a major endemic disease with an excess risk of major cardiovascular events and death. It also leads to disability, high rates of lower-limb adverse events and non-traumatic amputation. In patients with diabetes, PAD is particularly frequent and has a worse prognosis than in patients without diabetes. The risk factors of PAD are comparable to those for cardiovascular disease. The ankle-brachial index is usually recommended to screen PAD despite its limited performance in patients with diabetes, affected by the presence of peripheral neuropathy, medial arterial calcification, incompressible arteries and infection. Toe brachial index and toe pressure emerge as alternative screening tools. The management of PAD requires strict control of cardiovascular risk factors including diabetes, hypertension and dyslipidaemia, the use of antiplatelet agents and lifestyle management, to reduce cardiovascular adverse events, but few randomized controlled trials have evaluated the benefits of these treatments in PAD. Several advances have been achieved in endovascular and surgical revascularization procedures, with obvious improvement in PAD prognosis. Further studies are required to increase our understanding of the pathophysiology of PAD and to evaluate the interest of different therapeutic strategies in the occurrence and progression of PAD in patients with diabetes. Here, we present a narrative and contemporary review to synthesize the key epidemiology findings, screening and diagnosis methods, and major therapeutic advances regarding PAD in patients with diabetes.
Medical optimization of the peripheral artery disease patient
2022, Seminars in Vascular SurgeryPeripheral artery disease (PAD) impacts an estimated 230 million adults worldwide, including more than 9.5 million adults older than 40 years in the United States. PAD remains more underdiagnosed and undertreated than manifestations of atherosclerosis elsewhere in the body, such as coronary artery disease and cerebrovascular disease. Medical therapies benefit all patients with PAD, including those who are asymptomatic, as well as those with symptoms and advanced disease requiring intervention. Comprehensive medical management of PAD is based on tempering atherosclerotic disease processes and should include smoking cessation, exercise therapy, cholesterol reduction, antiplatelet, and/or anticoagulation therapy, as well as the application of peripheral vasodilators and blood pressure control, when indicated. For patients with intermittent claudication, supervised exercise therapy has been shown to provide similar or superior benefit compared with intervention and is recommended by major society guidelines as first-line therapy. In patients with advanced PAD requiring endovascular or surgical intervention, continued adherence to optimal medical therapy has been found to improve functional outcomes and decrease post-interventional mortality. Optimal medical management provides crucial benefits to patients with early, moderate, and advanced PAD and, once started, should be continued for life.
SGLT2 inhibitors and risk of lower-limb amputations: More fear than harm?
2022, Medecine des Maladies MetaboliquesAu cours des cinq dernières années, l’éventualité d’une augmentation du risque d’amputations des membres inférieurs (AMI) chez les patients diabétiques de type 2 traités par des inhibiteurs des cotransporteurs sodium-glucose de type 2 (iSGLT2) a fait l’objet d’un débat passionné. Cet article retrace l’historique de cette problématique depuis la publication princeps de CANVAS jusqu’aux dernières grandes études observationnelles en vie réelle. En dépit des alertes émises par des rapports de pharmacovigilance, ni les essais contrôlés prospectifs versus placebo, ni les études observationnelles rétrospectives de cohorte versus inhibiteurs de la dipeptidyl peptidase-4 (iDPP-4), ne montrent de risque accru pour les AMI chez les patients nouvellement traités par iSGLT2. L’augmentation rapportée par rapport aux agonistes des récepteurs du glucagon-like peptide-1 (AR GLP-1), communément interprétée comme un risque accru avec les iSGLT2, pourrait plutôt correspondre à une réduction du risque avec les AR GLP-1. Les données disponibles en ce qui concerne le risque d’AMI avec les iSGLT2 devraient rassurer les cliniciens, même si certaines circonstances doivent sans doute inciter à la prudence.
For the last five years, a potential increased risk of lower-limb amputation (LLA) among patients with type 2 diabetes treated with sodium-glucose cotransporter type 2 inhibitors (SGLT2is) has been a matter of debate. The present article traces the history of this controversy since the landmark publication of CANVAS until the last observational studies in real life. Despite the warnings that emerged from pharmacovigilance reports, neither prospective randomized placebo-controlled trials nor large cohort retrospective observational studies vs. dipeptidyl peptidase-4 inhibitors were able to demonstrate a significant increased risk of LLA among new SGLT2i users. The higher incidence of LLA when compared to glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which is commonly interpreted as an increased risk associated with SGLT2is, might rather reflect a reduction of the risk of LLA with GLP-1 ARs. Overall, available data regarding the risk of LLA with SGLT2is should reassure clinicians, even if some circumstances should call for caution.
Lower-limb amputations in patients treated with SGLT2 inhibitors versus DPP-4 inhibitors: A meta-analysis of observational studies
2022, Diabetes Epidemiology and ManagementAn increased risk of lower limb amputations (LLA) has been suspected with the use of sodium-glucose cotransporter type 2 inhibitors (SGLT2is) in the CANVAS programme with canagliflozin and in pharmacovigilance reports with all SGLT2is. Even if reassuring observations were reported in several large prospective placebo-controlled cardiovascular outcome trials, real-life conditions in more frailty patients might be associated with a higher risk.
This work analyses the incidence of LLA events in retrospective observational studies that compared SGLT2i users with patients treated with dipeptidyl peptidase-4 inhibitors (DPP-4is), a pharmacological class with an excellent safety profile. A meta-analysis of 12 comparative cohort studies (9 of them using a propensity score matching) worldwide has been performed.
The relative risk of LLA tended to be slightly lower in SGLT2i users (1228 LLA events/711159 patients) versus DPP-4i users: 2167 LLA events/1121914 patients, with a hazard ratio 0.91, 95% CI 0.85-0.98, p=0.01). However, a high between-study heterogeneity was observed (I² = 79%, P<0.00001), which could not be explained by differences across countries, between studies with/without propensity score matching, between cohorts treated with/without canagliflozin or between patients with/without peripheral artery disease. The incidence rate expressed as a number of LLA events per 1000 patient.years was almost similar among SGLT2i users and DPP-4i users (2.48±1.45 versus 2.67±3.09, p=0.849).
Physicians should not fear an increased risk of LLA with SGLT2is compared with DPP-4is in daily clinical practice, even if caution may be advised in some patients exposed to special conditions.
The association between GLP-1 receptor agonist and diabetic ketoacidosis in the FDA adverse event reporting system
2022, Nutrition, Metabolism and Cardiovascular DiseasesIn 2019, the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom (UK) and food and drug administration (FDA) of the United States of America (US) suggested that the relationship between glucagon-like peptide-1 receptor agonists (GLP-1RA) and diabetic ketoacidosis (DKA) deserved attention. This study is aiming to assess the association between GLP-1RA and DKA/ketosis in the FDA Adverse Event Reporting System (FAERS) database.
Using FAERS database, we firstly extract the number of DKA reports from the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2019 and calculate proportional reporting ratios (PRRs). We then mined each FAERS file from 2004 Q1 to 2020 Q4 and obtained detailed information on DKA reports. From the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2019, there are 1382 DKA cases (1491 ketosis cases) associated with GLP-1RA in the FAERS database. There was a slight disproportionate reporting of DKA associated with overall GLP-1RA (PRR 1.49, 95%CI 1.24–1.79, p < 0.001) after excluding the impact of SGLT2i, T1D and insulin. Any disproportionality disappeared after selecting the GLP-1RA combined with insulin for comparison.
When GLP-1RA not combined with insulin, the disproportionality of DKA reports associated with GLP-1RA was observed. Our analysis mined the FAERS database to provide evidence and highlight the potential association between DKA adverse events and GLP-1RA therapy that clinicians tend to overlook.