SGLT-2 inhibitors are recommended as first-line and GLP-1 agonists as second-line drugs if SGLT-2 inhibitors cause adverse effects for persons with type 2 diabetes and chronic kidney disease.
The recommendation is strong, because the effect size is large for patient important outcomes (progression of renal disease and cardiovascular events) and benefits clearly outweigh harms. The recommendation attaches a relatively low value on cost for patient which may prevent use of these drugs if reimbursement is insufficient.
A systematic review and network-meta-analysis 7 included 816 RCTs with a total of 471 038 patients. SGLT-2 inhibitors (SGLT-2i) (odds ratio 0.88, 95% Cl 0.83 to 0.94; high certainty) and GLP-1 receptor agonists (GLP-1a) (OR 0.88, 95% CI 0.82 to 0.93; high certainty) reduced all cause death; non-steroidal mineralocorticoid receptor antagonists, so far tested only with finerenone in patients with chronic kidney disease, probably reduced mortality (OR 0.89, 95% CI 0.79 to 1.00; moderate certainty); other drugs did not. The study confirmed the benefits of SGLT-2i and GLP-1a in reducing cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease. Only GLP-1a reduced non-fatal stroke; SGLT-2i were superior to other drugs in reducing end stage kidney disease. GLP-1a and SGLT-2i and tirzepatide improved quality of life. Reported harms were largely specific to drug class (eg, genital infections with SGLT-2i, severe gastrointestinal adverse events with tirzepatide and GLP-1a, hyperkalaemia leading to admission to hospital with finerenone).
A meta-analysis 2 for prevention of cardiovascular and renal outcomes included 3 trials with a total of 34 322 patients (60.2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation for heart failure events, and 766 renal composite outcomes. SGLT-2 inhibitors (SGLT-2i) reduced major adverse cardiovascular events by 11% (HR 0.89, 95% CI 0.83 to 0.96, p=0.0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0.86, 95% CI 0.80 to 0.93) and not in those without (1.00, 95% CI 0.87 to 1.16). SGLT-2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0.77, 95% CI 0.71 to 0.84, p<0.0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT-2i reduced the risk of progression of renal disease by 45% (0.55, 95% CI 0.48 to 0.64], p<0.0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease.
A network-meta-analysis 3 including 764 RCTs with a total of 421 346 patients assessed addition of SGLT-2i or GLP-1 receptor agonists (GLP-1a) to existing type 2 diabetes treatment. Results included estimated absolute effects of treatment per 1000 patients treated for 5 years for patients at very low risk (no cardiovascular risk factors), low risk (3 or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular and kidney disease). Both SGLT-2i and GLP-1a lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). SGLT-2i reduced mortality and admission to hospital for heart failure. GLP-1a reduced non-fatal stroke. Main side-effects with SGLT-2i were genital infections and with GLP-1a severe gastrointestinal events. SGLT-2i and GLP-1a lowered body weight. The absolute benefits were seen in all patient groups, greatly more in the higher risk groups.
A randomized controlled trial 4 6609 patients with chronic kidney disease. Progression of kidney disease or death from cardiovascular causes occurred in 13.1% in the empagliflozin group and in 16.9% in the placebo group (hazard ratio, 0.72; 95% CI 0.64 to 0.82; P<0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. Hospitalization from any cause was lower in the empagliflozin group than in the placebo group (HR 0.86; 95% CI 0.78 to 0.95), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardio
A RCT 5 analyzed the long-term renal effects of empagliflozin in with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml/min. Incident or worsening nephropathy occurred in 12.7% of patients in the empagliflozin group (n=4124, 10mg or 25 mg empagliflozin) and in 18.8% in the placebo group (n=2061), hazard ratio (HR) 0.61; 95% CI 0.53 to 0.70; P<0.001). vascular causes or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Another RCT 6 investigated the effects of empagliflotsin in chronic kidney disease patients (n=2250), of whom 67% had type 2 diabetes. Compared with placebo, empagliflozin reduced the risk of cardiovascular death (HR 0.71, 95% CI 0.52 to 0.98), the risk of all-cause mortality (HR 0.76, 95% CI 0.59 to 0.99), the risk of hospitalization for heart failure (HR 0.61, 95% CI 0.42 to 0.87), and the risk of all-cause hospitalization by (HR 0.81, 95% CI 0.7 to 0.92).
A Cochrane review [Abstract] 1 included 44 studies with a total of 13 036 subjects. Compared to placebo, SGLT-2 inhibitors reduced HbA1c (table T1), fasting blood glucose (FBG), weight, heart failure (RR 0.59, 95% CI 0.41 to 0.87; 3 studies, n=2519), and hyperkalaemia (RR 0.58, 0.42 to 0.81; 4 studies, n=2788); but increased genital infections (RR 2.50, 1.52 to 4.11; 7 studies, n=3086). Compared to placebo, GLP-1 agonists reduced HbA1c (table T2) and weight but have little or no effect on eGFR. There was insufficient evidence whether glitazones have any effect on HbA1c (table T3).
| Outcome | Effect estimate (95% CI) | Control - Risk with placebo | Risk with intervention - SGLT-2 inhibitors | No. of participants (studies) |
|---|---|---|---|---|
| Mean difference in HbA1c %and [HbA1c mmol/mol] | -- | - | 0.29% lower (0.19 to 0.38 lower) and [3.2 mmol/mol lower (2.2 to 4.2 lower)] | 1092 (7) |
| FBG (mmol/L) | -- | 0.48 mmol/L lower (0.19 to 0.78 lower) | 855 (5) | |
| Death (all causes) | RR 0.78 (0.60 to 1.02) | 78 per 1000 | 61 per 1000 (47 to 79) | 2933 (5) |
| All cardiovascular death | RR 0.78 (0.56 to 1.10) | 52 per 1000 | 40 per 1000 (29 to 57) | 2788 (4) |
| Weight (kg) | MD -1.41(-1.8 to -1.02) | 1.41 kg lower (1.02 to 1.8 lower) | 1029 (5) | |
| eGFR (mL/min/1.73 m2) | MD -1.85(-2.76 to -0.94) | 1.85 mL/min/1.73 m2 lower (0.94 to 2.76 lower) | 848 (4) | |
| Hypoglycaemia | RR 0.88 (0.73 to 1.07) | 118 per 1000 | 104 per 1000 (86 to 126) | 3086 (7) |
| Outcome | Effect estimate (95% CI) | Control - Risk with placebo | Risk with intervention - GLP-1 agonists | No. of participants (studies) |
|---|---|---|---|---|
| Mean difference in HbA1c %and [HbA1c mmol/mol] | -- | 0.53% lower (0.06 to 1.01 lower) and [5.8 mmol/mol lower (0.7 to 11.0 lower)] | 283 (2) | |
| FBG (mmol/L) | -- | 1.08 mmol/L lower (0.45 to 1.71 lower) | 231 (1) | |
| Death (all causes) | RR 3.91 (0.44 to 34.58) | 7 per 1000 | 27 per 1000 (3 to 235) | 301 (2) |
| Outcome | Effect estimate (95% CI) | Control - Risk with placebo | Risk with intervention - Glitazone | No. of participants (studies) |
|---|---|---|---|---|
| Mean difference in HbA1c %and [HbA1c mmol/mol] | -- | 0.41% lower (1.15 lower to 0.32 higher) and [4.5 mmol/mol lower (12.6 lower to 3.5 higher)] | 88 (2) | |
| Death (all causes) | RR 0.50 (0.05 to 5.18) | 77 per 1000 | 38 per 1000 (4 to 398) | 52 (1) |
| Hypoglycaemia | RR 0.95 (0.15 to 6.08) | 59 per 1000 | 56 per 1000 (9 to 358) | 70 (2) |
Choose a SGLT-2i or GLP-1a with a proven beneficial effect for cardiovascular events (all agents do not have the body of evidence for a beneficial effect).
Date of latest search: 2024-01-03
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