Net effects of sodium-glucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials

Abstract

Background: The net absolute effects of sodium-glucose co-transporter-2 (SGLT-2) inhibitors across different patient groups have not been quantified. Methods: We performed a meta-analysis of published large (>500 participants/arm) placebo-controlled SGLT-2 inhibitor trials after systematically searching MEDLINE and Embase databases from inception to 28th August 2021 (PROSPERO 2021 CRD42021240468). Findings: Four heart failure trials (n=15,684 participants), four trials in type 2 diabetes mellitus at high atherosclerotic cardiovascular risk (n=42,568), and three trials in chronic kidney disease (n=19,289) were included. Relative risks (RRs) for all cardiovascular, renal and safety outcomes were broadly similar across these three patient groups, and between people with or without diabetes. Overall, compared to placebo, allocation to SGLT-2 inhibition reduced risk of hospitalization for heart failure or cardiovascular death by 23% (RR=0.77, 95%CI 0.73-0.80; n=6658), cardiovascular death by 14% (0.86, 0.81-0.92; n=3962), major adverse cardiovascular events by 11% (0.89, 0.84-0.94; n=5703), kidney disease progression by 36% (0.64, 0.59-0.70; n=2275), acute kidney injury by 30% (0.70, 0.62-0.79; n=1013 events) and severe hypoglycaemia by 13% (0.87, 0.79-0.97; n=1484). There was no effect of SGLT-2 inhibition on risk of non-cardiovascular death (0.93, 0.86-1.01; n=2226), but a net 12% reduction in all-cause mortality remained evident (0.88, 0.84-0.93; n=6188). However, the risk of ketoacidosis was 2-times higher among those allocated SGLT-2 inhibitors compared to placebo (2.03, 1.41-2.93; n=159; absolute excess in people with diabetes »0.3/1000 patient years). A small increased risk of urinary tract infection was evident (1.07, 1.02-1.13; n=5384) alongside a known increased risk of mycotic genital infections. Overall, risk of lower limb amputations was increased by 16% (1.16, 1.02-1.31; n=1074), but this risk was largely driven by a single outlying trial (CANVAS). Interpretations: The relative effects of SGLT-2 inhibition on key safety and efficacy outcomes are consistent across the different studied groups of patient. Consequently, absolute benefits and harms are determined by the absolute baseline risk of particular outcomes, with absolute benefits on mortality and on non-fatal serious cardiac/renal outcomes substantially exceeding the risks of amputation and ketoacidosis in the main patient groups studied to date. Funding: MRC-UK & KRUK.

Effect of Empagliflozin on Kidney Biochemical and Imaging Outcomes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction (SUGAR-DM-HF)

“…Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of worsening kidney function in patients with heart failure and reduced ejection fraction (HFrEF). 1 Comparatively little is known about the effects of these drugs on kidney perfusion in the setting of randomized controlled trials. We studied effects of these drugs using kidney magnetic resonance imaging (MRI).…”

The kidney matrisome in health, aging, and disease

“…Recently SGLT2 inhibitors, targeting tubular glucose reabsorption, have shown to have enormous therapeutic potential with cardioand kidney protective effects in both diabetic and non-diabetic CKD. 156 Whilst SGLT2 inhibitors also lower the mechanical load to the kidney, the impact of these drugs on fibrotic molecular mechanisms have yet to be elucidated and warrant further investigation. Identification of the mode of action of those inhibitors and their effect on kidney cells using proteomics and scRNAseq might unravel new specific targets for therapy.…”

Practical aspects of initiation and use of SGLT2 inhibitors: inpatient and outpatient perspectives

“…По данным масштабного метаанализа, включавшего 11 состоявшихся РКИ, риск развития инфекций мочевыводящего тракта на фоне приема глифлозинов незначителен и составляет лишь 7% (ОР 1,07; 95% ДИ 1,02-1,13) [36]. Исключением является урогенитальный кандидоз -нередкое нежелательное явление, связанное с применением SGLT2 у пациентов с СД2 и без него, обусловленное глюкозурическим эффектом препаратов, протекающее в виде вульвовагинита/баланита (в гинекологической практике более принят термин вульвовагинальный кандидоз (ВВК)).…”

“…В уже упоминавшемся выше масштабном метаанализе N. Staplin и соавт. было показано, что влияние применения иSGLT2 на риск ампутации нижних конечностей после исключения результатов исследования CANVAS не имеет статистической значимости и составляет 6% (ОР 1,06; 95% ДИ 0,93-1,21) [36]. В обновленном консенсусе эксперты ADA и EASD дали пояснение, что пациентам с язвами на стопах или больным с высоким риском ампутаций лечение иSGLT2 следует назначать после коллегиального обсуждения с учетом всех рисков и преимуществ, а также при условии комплексного обучения пациента уходу за стопами и принятия соответствующих мер по профилактике ампутаций [42].…”