Sodium-glucose co-transporter protein 2(SGLT2) inhibitors for people with chronic kidney disease and diabetes

Background Diabetes is associated with high risks of premature chronic kidney disease (CKD),cardiovascular diseases, cardiovascular death and impaired quality of life. People withdiabetes are more likely to develop kidney impairment, and approximately one in threeadults with diabetes have CKD. People with CKD and diabetes experience a substantiallyhigher risk of cardiovascular outcomes. Sodium-glucose co-transporter protein 2 (SGLT2)inhibitors have shown potential effects in preventing kidney and cardiovascular outcomes inpeople with CKD and diabetes. However, new trials are emerging rapidly, and evidencesynthesis is essential to summarising cumulative evidence. Objectives This review aimed to assess the benefits and harms of SGLT2 inhibitors for people withCKD and diabetes. Search methods We searched the Cochrane Kidney and Transplant Register of Studies up to 17 November2023 using a search strategy designed by an Information Specialist. Studies in the Registerare continually identified through regular searches of CENTRAL, MEDLINE, and EMBASE,conference proceedings, the International Clinical Trials Registry Platform (ICTRP) SearchPortal and ClinicalTrials.gov. Selection criteria Randomised controlled studies were eligible if they evaluated SGLT2 inhibitors versusplacebo, standard care or other glucose-lowering agents in people with CKD and diabetes.CKD includes all stages (from 1 to 5), including dialysis patients. 22/05/2024, 13:53 RevMan Web - Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabe… https://revman.cochrane.org/282122052223512205/dashboard/htmlView/current 3/252 Data collection and analysis Two authors independently extracted data and assessed the study risk of bias. Treatmentestimates were summarised using random effects meta-analysis and expressed as a riskratio (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI).Confidence in the evidence was assessed using the Grading of RecommendationsAssessment, Development and Evaluation (GRADE) approach. The primary reviewoutcomes were all-cause death, 3-point and 4-point major adverse cardiovascular events(MACE), fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, and kidneyfailure. Main results Fifty-three studies randomising 65,241 people with CKD and diabetes were included.SGLT2 inhibitors with or without other background treatments were compared to placebo,standard care, sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, or insulin. In themajority of domains, the risks of bias in the included studies were low or unclear. No studiesevaluated the treatment in children or in people treated with dialysis. No studies comparedSGLT2 inhibitors with glucagon-like peptide-1 receptor agonists or tirzepatide. Compared to placebo, SGLT2 inhibitors decreased the risk of all-cause death (20 studies,44,397 participants: RR 0.85, 95% CI 0.78 to 0.94; I = 0%; high certainty) andcardiovascular death (16 studies, 43,792 participants: RR 0.83, 95% CI 0.74 to 0.93; I =29%; high certainty). 2 2 Compared to placebo, SGLT2 inhibitors probably make little or no difference to the risk offatal or nonfatal MI (2 studies, 13,726 participants: RR 0.95, 95% CI 0.80 to 1.14; I = 24%;moderate certainty), and fatal or nonfatal stroke (2 studies, 13,726 participants: RR 1.07,95% CI 0.88 to 1.30; I = 0%; moderate certainty). Compared to placebo, SGLT2 inhibitorsprobably decrease 3-point MACE (7 studies, 38,320 participants: RR 0.89, 95% CI 0.81 to0.98; I = 46%; moderate certainty), and 4-point MACE (4 studies, 23,539 participants: RR0.82, 95% CI 0.70 to 0.96; I = 77%; moderate certainty), and decrease hospital admissiondue to heart failure (6 studies, 28,339 participants: RR 0.70, 95% CI 0.62 to 0.79; I = 17%;high certainty). 2 2 2 2 2 Compared to placebo, SGLT2 inhibitors may decrease creatinine clearance (1 study, 132participants: MD -2.63 mL/min, 95% CI -5.19 to -0.07; low certainty) and probably decreasethe doubling of serum creatinine (2 studies, 12,647 participants: RR 0.70, 95% CI 0.56 to0.89; I = 53%; moderate certainty). SGLT2 inhibitors decrease the risk of kidney failure (6studies, 11,232 participants: RR 0.70, 95% CI 0.62 to 0.79; I = 0%; high certainty), andkidney composite outcomes (generally reported as kidney failure, kidney death with orwithout ≥ 40% decrease in estimated glomerular filtration rate (eGFR)) (7 studies, 36,380participants: RR 0.68, 95% CI 0.59 to 0.78; I = 25%; high certainty) compared to placebo. 2 2 2 Compared to placebo, SGLT2 inhibitors incur less hypoglycaemia (16 studies, 28,322participants: RR 0.93, 95% CI 0.89 to 0.98; I = 0%; high certainty), and hypoglycaemiarequiring third-party assistance (14 studies, 26,478 participants: RR 0.75, 95% CI 0.65 to0.88; I = 0%; high certainty), and probably decrease the withdrawal from treatment due toadverse events (15 studies, 16,622 participants: RR 0.94, 95% CI 0.82 to 1.08; I = 16%;moderate certainty). 2 2 2 The effects of SGLT2 inhibitors on eGFR, amputation and fracture were uncertain. No studies evaluated the effects of treatment on fatigue, life participation, or lactic acidosis. 22/05/2024, 13:53 RevMan Web - Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabe… https://revman.cochrane.org/282122052223512205/dashboard/htmlView/current 4/252 The effects of SGLT2 inhibitors compared to standard care alone, sulfonylurea, DPP-4inhibitors, or insulin were uncertain. Authors' conclusions SGLT2 inhibitors alone or added to standard care decrease all-cause death, cardiovasculardeath, and kidney failure and probably decrease major cardiovascular events while incurringless hypoglycaemia compared to placebo in people with CKD and diabetes.