SGLT2 inhibitors in T2D and associated comorbidities — differentiating within the class

Schernthaner, Guntram; Drexel, Heinz; Moshkovich, Evgeny; Žilaitienė, Birutė; Martinka, Emil; Czupryniak, Leszek; Várkonyi, Tamás; Ducena, Kristine; Lalić, Katarina; Tankova, Tsvetalina; Prázný, Martin; Duvnjak, Lea; Sukhareva, Olga Yur'evna; Sourij, Harald

doi:10.1186/s12902-019-0387-y

Cited by 11 publications

(15 citation statements)

References 67 publications

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“…Other secondary and exploratory outcomes in CVOTs have also suggested additional benefits of SGLT2i and GLP-1 RA that may be of particular relevance to patients with CVD, including slowed progression of albuminuria [ 39 , 40 ], and reductions in blood pressure and body weight [ 13 , 32 ]. For SGLT2i, CVOTs and other studies have consistently pointed to strong protection from renal function decline compared with placebo [ 10 , 12 , 38 ].…”

Section: Out Of Step With the Evidence: The Cvot-shaped Hole In Diabementioning

confidence: 99%

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

Schernthaner

Shehadeh

Аметов

et al. 2020

Cardiovasc Diabetol

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109

108

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The disclosure of proven cardiorenal benefits with certain antidiabetic agents was supposed to herald a new era in the management of type 2 diabetes (T2D), especially for the many patients with T2D who are at high risk for cardiovascular and renal events. However, as the evidence in favour of various sodium–glucose transporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) accumulates, prescriptions of these agents continue to stagnate, even among eligible, at-risk patients. By contrast, dipeptidyl peptidase-4 inhibitors (DPP-4i) DPP-4i remain more widely used than SGLT2i and GLP-1 RA in these patients, despite a similar cost to SGLT2i and a large body of evidence showing no clear benefit on cardiorenal outcomes. We are a group of diabetologists united by a shared concern that clinical inertia is preventing these patients from receiving life-saving treatments, as well as placing them at greater risk of hospitalisation for heart failure and progression of renal disease. We propose a manifesto for change, in order to increase uptake of SGLT2i and GLP-1 RA in appropriate patients as a matter of urgency, especially those who could be readily switched from an agent without proven cardiorenal benefit. Central to our manifesto is a shift from linear treatment algorithms based on HbA1c target setting to parallel, independent considerations of atherosclerotic cardiovascular disease, heart failure and renal risks, in accordance with newly updated guidelines. Finally, we call upon all colleagues to play their part in implementing our manifesto at a local level, ensuring that patients do not pay a heavy price for continued clinical inertia in T2D.

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Section: Out Of Step With the Evidence: The Cvot-shaped Hole In Diabementioning

confidence: 99%

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

Schernthaner

Shehadeh

Аметов

et al. 2020

Cardiovasc Diabetol

Self Cite

109

108

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“…This comprehensive safety analysis of a large pool of patients with advanced CKD who received empagliflozin in clinical trials found no overall differences in rates of SAEs, AEs leading to discontinuation, or events of special interest with empagliflozin treatment versus placebo, irrespective of baseline eGFR. An exception was genital infections, a well-recognized adverse effect of the SGLT2 inhibitor class ( 16 – 18 ), which occurred more frequently in the empagliflozin group versus the placebo group but with lower incidence rates in advanced CKD categories. This could be due to, at least in part, lesser urinary glucose excretion at lower levels of eGFR ( 19 ).…”

Section: Discussionmentioning

confidence: 99%

Safety of Empagliflozin in Patients With Type 2 Diabetes and Chronic Kidney Disease: Pooled Analysis of Placebo-Controlled Clinical Trials

et al. 2022

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OBJECTIVE To assess the safety of empagliflozin in patients with type 2 diabetes and moderate to severe chronic kidney disease (CKD) (category G3–4) enrolled in clinical trials. RESEARCH DESIGN AND METHODS This analysis pooled data from 19 randomized, placebo-controlled, phase 1–4 clinical trials and 1 randomized, placebo-controlled extension study in which patients received empagliflozin 10 mg or 25 mg daily. Time to first occurrence of adverse events (AEs) was evaluated using Kaplan-Meier analysis and multivariable Cox regression models. RESULTS Among a total of 15,081 patients who received at least one study drug dose, 1,522, 722, and 123 were classified as having G3A, G3B, and G4 CKD, respectively, at baseline. Demographic and clinical characteristics were similar between treatment groups across CKD categories. Rates of serious AEs, AEs leading to discontinuation, and events of special interest (including lower limb amputations and acute renal failure [ARF]) were also similar between empagliflozin and placebo across CKD subgroups. In adjusted Cox regression analyses, risks for volume depletion and ARF were similar for empagliflozin and placebo in the combined group with CKD categories G3B and G4 and the G3A group. Notably lower risks were observed in both groups for hyperkalemia (hazard ratio 0.59 [95% CI 0.37–0.96, P = 0.0323] and 0.48 [0.26–0.91, P = 0.0243], respectively) and edema (0.47 [0.33–0.68, P < 0.0001] and 0.44 [0.28–0.68, P = 0.0002], respectively). CONCLUSIONS Use of empagliflozin in patients with type 2 diabetes and advanced CKD raised no new safety concerns and may have beneficial effects on the development of hyperkalemia and edema.

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“…On the other hand, the applicability of SGLT2i is certainly much wider than the strict entry criteria of CVOTs, as shown in several of studies and subanalyses reporting the additional benefits of SGLT2i, particularly in chronic kidney disease and heart failure [40]. For instance, real-world evidence (RWE) studies have also confirmed reductions in mortality (43% to 49%) and hospitalization for heart failure (40% to 51%) in hundreds of thousands of patients [40]. So far, the main RWE studies published are CVD-Real, CVD-Real 2, EASEL, and EMPRISE; these studies compared SGLT2i with other antidiabetic drugs, especially against DPP-4 inhibitors (CVD-Real 2 and EMPRISE).…”

Section: Discussionmentioning

confidence: 99%

How Many Patients with Type 2 Diabetes Meet the Inclusion Criteria of the Cardiovascular Outcome Trials with SGLT2 Inhibitors? Estimations from a Population Database in a Mediterranean Area

Canivell

Mata-Cases

Vlacho

et al. 2019

Journal of Diabetes Research

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Objective Regulatory agencies require the assessment of cardiovascular (CV) safety for new type 2 diabetes (T2D) therapies through CV outcome trials (CVOTs). However, patients included in CVOTs assessing sodium-glucose cotransporter-2 inhibitors (SGLT2i) might not be representative of those seen in clinical practice. This study examined the proportion of patients that would have been enrolled into three main SGLT2i CVOTs to determine whether these trials' eligibility criteria can be applied to a real-world Mediterranean T2D population. Methods Cross-sectional, retrospective, cohort study of T2D patients registered in primary care centres of the Catalan Institute of Health using medical records from a population database (SIDIAP) that includes approximately 74% of the population in Catalonia (Spain). Eligibility criteria were according to those of three SGLT2i CVOTs: EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), and DECLARE-TIMI 58 (dapagliflozin). Results By the end of 2016, the database included 373,185 patients with T2D with a mean age of 70 ± 12 years, 54.9% male, with a mean duration of T2D of 9 ± 6 years, and a mean glycated haemoglobin (HbA1c) of 7.12% ± 1.32 (59% with HbA1c < 7%). Of these, 86,534 (23%) had established CV disease and 28% chronic renal failure (estimated glomerular filtration < 60 ml/min/1.73m2). Among all included patients, only 8.2% would have qualified for enrolment into the EMPA-REG OUTCOME trial, 29.6% into the CANVAS program, and 38% into the DECLARE-TIMI 58 trial. The main limiting factors for inclusion would have been a previous history of CV disease and the baseline HbA1c value. Conclusion The external validity of the analysed CVOTs is clearly limited when applying the same eligibility criteria to a T2D Mediterranean population.

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SGLT2 inhibitors in T2D and associated comorbidities — differentiating within the class

Cited by 11 publications

References 67 publications

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

Safety of Empagliflozin in Patients With Type 2 Diabetes and Chronic Kidney Disease: Pooled Analysis of Placebo-Controlled Clinical Trials

How Many Patients with Type 2 Diabetes Meet the Inclusion Criteria of the Cardiovascular Outcome Trials with SGLT2 Inhibitors? Estimations from a Population Database in a Mediterranean Area

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