Does treatment with GLP-1 receptor agonists prevent complications for people with chronic kidney disease and diabetes?

Key messages

• For people with chronic kidney disease (CKD) (a long-term condition where the kidneys do not work effectively) also having diabetes (a lifelong condition that causes a person's blood sugar level to become too high) increases the chances of early death, heart attack, stroke and reduces a person's quality of life.

• Glucagon-like peptide 1 receptor agonists (GLP-1) (medicines used to lower blood glucose) probably reduce the risk of death due to any cause but may have little or no death due to a heart attack in people with CKD and diabetes.

• For combined major heart-related events (stroke, nonfatal heart attack and death due to a heart attack), GLP-1 probably lowers the risk of these events but probably has little or no effect on the risk of kidney failure or abnormally low blood sugar levels.

Why treat people with chronic kidney disease and diabetes with GLP-1 receptor agonists?

Chronic kidney disease (CKD) (a long-term condition where the kidneys do not work effectively) and diabetes (a lifelong condition that causes a person's blood sugar level to become too high) are chronic conditions that bring on many challenges for people, particularly when they have to manage both at the same time. Diabetes can accelerate the development of kidney disease and is the leading cause of kidney failure (a condition where the kidneys no longer function well enough to keep a person alive). GLP-1 receptor agonists (GLP-1) are medicines that lower blood glucose levels and may also have beneficial effects on high blood pressure and obesity, and decrease the chances of death, heart attack, stroke and kidney failure (a condition where the kidneys no longer function well enough to keep a person alive).

What did we want to find out?

We wanted to find out if GLP-1 improves diabetes control and kidney function, decreases heart-related complications such as heart attacks and stroke, and decreases the risk of kidney failure in people with both CKD and diabetes.

What did we do?

We searched for all trials that assessed the benefits and harms of GLP-1 for treating people with both CKD and diabetes. We compared GLP-1 with placebo (dummy medicine), usual care, and other glucose-lowering medicines (for example, insulin).

What did we find?

We included 42 studies that randomised 48,148 adults (18 years or older) with CKD and diabetes. None of the studies included children. The number of people ranged from 7 to 14,691, and the age ranged from 51 to 71 years. On average, the duration of the studies was six months. Twenty-one studies compared GLP-1 to placebo, 16 compared GLP-1 to a variety of glucose-lowering medicines, and five compared GLP-1 to standard care. Twenty-eight studies were multinational.

Compared to placebo, GLP-1 probably reduces the overall risk of dying due to any cause but may have little or no effect on the chances of dying from a heart-related problem. When major heart-related events were investigated together (death due to a heart attack, nonfatal heart attack and nonfatal stroke), GLP-1 probably reduces the risk of these combined events occurring. GLP-1 probably makes little or no difference to kidney failure and may make little or no difference to abnormally low blood glucose levels.

The effect of GLP-1 compared to usual care and other glucose-lowering medicines is unclear.

What are the limitations of the evidence?

We are moderately confident that GLP-1 reduces the risk of dying due to any cause, reduces major heart-related events, and makes little or no difference to kidney failure. We are less confident in its effect on death from a heart-related problem or abnormally low blood sugar levels.

How up to date is the evidence?

The evidence is current to September 2024.

Authors' conclusions: 

GLP-1 receptor agonists probably reduced all-cause death but may have little or no effect on cardiovascular death in people with CKD and diabetes. GLP-1 receptor agonists probably lower major cardiovascular events, probably have little or no effect on kidney failure and composite kidney outcomes, and may have little or no effect on the risk of severe hypoglycaemia in people with CKD and diabetes.

Read the full abstract...
Background: 

Approximately 40% of people with diabetes develop kidney failure and experience an accelerated risk of cardiovascular complications. Glucagon-like peptide 1 (GLP-1) receptor agonists are glucose-lowering agents that manage glucose and weight control.

Objectives: 

We assessed the benefits and harms of GLP-1 receptor agonists in people with chronic kidney disease (CKD) and diabetes.

Search strategy: 

The Cochrane Kidney and Transplant Register of Studies was searched to 10 September 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov.

Selection criteria: 

Randomised controlled studies were eligible if participants with diabetes and CKD were randomly allocated to a GLP-1 receptor agonist, placebo, standard care or a second glucose-lowering agent. CKD included all stages (from 1 to 5).

Data collection and analysis: 

Three authors independently extracted data and assessed the risk of bias using the risk of bias assessment tool 2. Pooled analyses using summary estimates of effects were obtained using a random-effects model, and results were expressed as risk ratios (RR) and/or hazard ratio (HR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. The primary outcomes included death (all-cause and cardiovascular), 3- and 4-point major adverse cardiovascular events (MACE), kidney failure, composite kidney outcome, and severe hypoglycaemia. The secondary outcomes included non-fatal or fatal myocardial infarction (MI) or stroke, non-fatal peripheral arterial events, heart failure, hospitalisation due to heart failure, estimated glomerular filtration rate or creatinine clearance, doubling of serum creatinine, urine albumin-to-creatinine ratio, albuminuria progression, vascular access outcomes, body weight, body mass index, fatigue, life participation, peritoneal dialysis infection, peritoneal dialysis failure, adverse events, serious adverse events, withdrawal due to adverse events, HbA1c, sudden death, acute MI, ischaemic stroke, and coronary revascularisation. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results: 

Forty-two studies involving 48,148 participants were included. All studies were conducted on people with type 2 diabetes, and no studies were carried out on children. The median study age was 66 years. The median study follow-up was 26 weeks. Six studies were conducted in people with CKD stages 1-2, 11 studies in people with CKD stages 3-5, one study in people on dialysis, and the remaining studies included people with both CKD stages 1-2 and 3-5. Risks of bias in the included studies for all the primary outcomes in studies that compared GLP-1 receptor agonists to placebo were low in most methodological domains, except one study that was assessed at high risk of bias due to missing outcome data for death (all-cause and cardiovascular). The overall risk of bias for all-cause and cardiovascular death in studies that reported the treatment effects of GLP-1 receptor agonists compared to standard care, dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT2) inhibitors were assessed as unclear or at high risk of bias due to deviations from intended interventions or missing data. For GLP-1 receptor agonists compared to insulin or another GLP-1 receptor agonist, the risk of bias for all-cause and cardiovascular death was low or unclear.

Compared to placebo, GLP-1 receptor agonists probably reduced the risk of all-cause death (RR 0.85, 95% CI 0.74 to 0.98; I2 = 23%; 8 studies, 17,861 participants; moderate-certainty evidence), but may have little or no effect on cardiovascular death (RR 0.84, 95% CI 0.68 to 1.05; I2 = 42%; 7 studies, 17,801 participants; low-certainty evidence).

Compared to placebo, GLP-1 receptor agonists probably decreased 3-point MACE (RR 0.84, 95% CI 0.73 to 0.98; I² = 65%; 4 studies, 19,825 participants; moderate-certainty evidence), and 4-point MACE compared to placebo (RR 0.77, 95% CI 0.67 to 0.89; 1 study, 2,158 participants; moderate-certainty evidence). Based on absolute risks of clinical outcomes, it is likely that GLP-1 receptor agonists prevent all-cause death in 52 people with CKD stages 1-2 and 116 in CKD stages 3-5, cardiovascular death in 34 people with CKD stages 1-2 and 71 in CKD stages 3-5, while 95 CKD stages 1-2 and 153 in CKD stages 3-5 might experience a major cardiovascular event for every 1000 people treated over 1 year.

Compared to placebo, GLP-1 receptor agonists probably had little or no effect on kidney failure, defined as starting dialysis or kidney transplant (RR 0.86, 95% CI 0.66 to 1.13; I2 = 0%; 3 studies, 4,134 participants; moderate-certainty evidence), or on composite kidney outcomes (RR 0.89, 95% CI 0.78 to 1.02; I2 = 0%; 2 studies, 16,849 participants; moderate-certainty evidence).

Compared to placebo, GLP-1 receptor agonists may have little or no effect on the risk of severe hypoglycaemia (RR 0.82, 95% CI 0.54 to 1.25; I2 = 44%; 4 studies, 6,292 participants; low-certainty evidence).

The effects of GLP-1 receptor agonists compared to standard care or other hypoglycaemic agents were uncertain.

No studies evaluated treatment on risks of fatigue, life participation, amputation or fracture.