Key messages
- Treatment with sodium-glucose co-transporter protein 2 (SGLT2) inhibitors decreases the risk of death and kidney problems for people with chronic kidney disease and diabetes.
- We are not sure whether SGLT2 inhibitors are better than other diabetes drugs as not enough clinical research has been done directly comparing them in clinical studies.
Chronic kidney disease and diabetes
Diabetes is a common disease caused by reduced insulin activity (the hormone that controls glucose levels in the blood) and increased insulin resistance. Diabetes decreases health-related quality of life and leads to heart attacks, stroke, limb amputation, death and depression at an early age, especially in people with chronic kidney disease. SGLT2 inhibitor drugs are now used to treat people with chronic kidney disease and diabetes. New studies are emerging, and combining the results of these trials together is essential to have the most up-to-date understanding of whether these drugs are safe and beneficial when compared with other treatments.
What did we want to find out?
We wanted to find out whether SGLT2 inhibitor drugs prevent diabetes problems in adults and children who have both chronic kidney disease (reduced kidney function) and diabetes.
What did we do?
We searched for all trials that assessed the benefits and harms of randomly allocating SGLT2 inhibitors to people with chronic kidney disease and diabetes. We compared and summarised the trials' results and rated our confidence in the information based on factors such as trial methods and sizes.
What did we find?
We included 53 clinical studies involving 65,241 adults with chronic kidney disease and diabetes. People in the studies were given an SGLT2 inhibitor, a sugar pill (placebo), standard care alone, or a different diabetes medication (e.g. metformin or insulin). The treatment allocation was decided by random chance (like tossing a coin). No studies were done on children.
Combining all the studies, we found that treatment with SGLT2 inhibitors decreases the chance of death, including death directly due to a heart problem or stroke. We also found that SGLT2 inhibitors prevent kidney failure, meaning that fewer people on this treatment needed dialysis or a kidney transplant. The effects of preventing a heart attack or a stroke are unclear. We also could not be sure whether SGLT2 inhibitor treatment was better or worse than other treatments because few data are available comparing it to other diabetic medications in clinical studies.
What are the limitations of the evidence?
Some of the studies did not clearly report how many people had chronic kidney disease, so some data could not be included. Adverse events were rarely and inconsistently reported, so we are uncertain about these outcomes. While we included studies in people with type 1 diabetes, not enough data was available to explore the effects of SGLT2 inhibitors in these people properly.
How up-to-date is the evidence?
The evidence is current to November 2023.
SGLT2 inhibitors alone or added to standard care decrease all-cause death, cardiovascular death, and kidney failure and probably decrease major cardiovascular events while incurring less hypoglycaemia compared to placebo in people with CKD and diabetes.
Diabetes is associated with high risks of premature chronic kidney disease (CKD), cardiovascular diseases, cardiovascular death and impaired quality of life. People with diabetes are more likely to develop kidney impairment, and approximately one in three adults with diabetes have CKD. People with CKD and diabetes experience a substantially higher risk of cardiovascular outcomes. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors have shown potential effects in preventing kidney and cardiovascular outcomes in people with CKD and diabetes. However, new trials are emerging rapidly, and evidence synthesis is essential to summarising cumulative evidence.
This review aimed to assess the benefits and harms of SGLT2 inhibitors for people with CKD and diabetes.
We searched the Cochrane Kidney and Transplant Register of Studies up to 17 November 2023 using a search strategy designed by an Information Specialist. Studies in the Register are continually identified through regular searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.
Randomised controlled studies were eligible if they evaluated SGLT2 inhibitors versus placebo, standard care or other glucose-lowering agents in people with CKD and diabetes. CKD includes all stages (from 1 to 5), including dialysis patients.
Two authors independently extracted data and assessed the study risk of bias. Treatment estimates were summarised using random effects meta-analysis and expressed as a risk ratio (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The primary review outcomes 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 kidney failure.
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 the majority of domains, the risks of bias in the included studies were low or unclear. No studies evaluated the treatment in children or in people treated with dialysis. No studies compared SGLT2 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; I2 = 0%; high certainty) and cardiovascular death (16 studies, 43,792 participants: RR 0.83, 95% CI 0.74 to 0.93; I2 = 29%; high certainty).
Compared to placebo, SGLT2 inhibitors probably make little or no difference to the risk of fatal or nonfatal MI (2 studies, 13,726 participants: RR 0.95, 95% CI 0.80 to 1.14; I2 = 24%; moderate certainty), and fatal or nonfatal stroke (2 studies, 13,726 participants: RR 1.07, 95% CI 0.88 to 1.30; I2 = 0%; moderate certainty). Compared to placebo, SGLT2 inhibitors probably decrease 3-point MACE (7 studies, 38,320 participants: RR 0.89, 95% CI 0.81 to 0.98; I2 = 46%; moderate certainty), and 4-point MACE (4 studies, 23,539 participants: RR 0.82, 95% CI 0.70 to 0.96; I2 = 77%; moderate certainty), and decrease hospital admission due to heart failure (6 studies, 28,339 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 17%; high certainty).
Compared to placebo, SGLT2 inhibitors may decrease creatinine clearance (1 study, 132 participants: MD -2.63 mL/min, 95% CI -5.19 to -0.07; low certainty) and probably decrease the doubling of serum creatinine (2 studies, 12,647 participants: RR 0.70, 95% CI 0.56 to 0.89; I2 = 53%; moderate certainty). SGLT2 inhibitors decrease the risk of kidney failure (6 studies, 11,232 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 0%; high certainty), and kidney composite outcomes (generally reported as kidney failure, kidney death with or without ≥ 40% decrease in estimated glomerular filtration rate (eGFR)) (7 studies, 36,380 participants: RR 0.68, 95% CI 0.59 to 0.78; I2 = 25%; high certainty) compared to placebo.
Compared to placebo, SGLT2 inhibitors incur less hypoglycaemia (16 studies, 28,322 participants: RR 0.93, 95% CI 0.89 to 0.98; I2 = 0%; high certainty), and hypoglycaemia requiring third-party assistance (14 studies, 26,478 participants: RR 0.75, 95% CI 0.65 to 0.88; I2 = 0%; high certainty), and probably decrease the withdrawal from treatment due to adverse events (15 studies, 16,622 participants: RR 0.94, 95% CI 0.82 to 1.08; I2 = 16%; moderate certainty).
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.
The effects of SGLT2 inhibitors compared to standard care alone, sulfonylurea, DPP-4 inhibitors, or insulin were uncertain.