Key points
- The FLOW trial showed semaglutide 1 mg reduced the risk of kidney disease progression by 24 per cent in patients with type 2 diabetes and CKD
- The trial was stopped early due to clear evidence of benefit — a strong indicator of efficacy
- Semaglutide slowed eGFR decline by approximately 1.16 ml per minute per year compared with placebo
- Kidney benefits appeared to be partly independent of blood glucose and weight reduction
- Semaglutide does not require dose adjustment for kidney impairment and can be used with eGFR as low as 15
- Chronic kidney disease affects approximately 1 in 10 adults in the UK and is a leading cause of premature death
Understanding chronic kidney disease
Chronic kidney disease (CKD) is a progressive condition in which the kidneys gradually lose their ability to filter waste products, regulate fluid balance and maintain electrolyte homeostasis. It is classified into five stages based on the estimated glomerular filtration rate (eGFR), which measures how well the kidneys filter blood.
| CKD Stage | eGFR (ml/min/1.73m²) | Description |
|---|---|---|
| Stage 1 | 90 or above | Normal or high eGFR with other evidence of kidney damage |
| Stage 2 | 60 to 89 | Mildly reduced |
| Stage 3a | 45 to 59 | Mildly to moderately reduced |
| Stage 3b | 30 to 44 | Moderately to severely reduced |
| Stage 4 | 15 to 29 | Severely reduced |
| Stage 5 | Below 15 | Kidney failure (may require dialysis or transplant) |
The UK burden
CKD affects approximately 1 in 10 adults in the United Kingdom, with prevalence rising sharply with age. Diabetes is the leading cause of CKD in the UK, accounting for approximately 25 to 30 per cent of cases of kidney failure requiring dialysis or transplantation. The NHS spends an estimated 1.5 to 2 billion pounds annually on treating CKD and its complications.
Diabetic kidney disease (DKD) is characterised by progressive albuminuria (protein leaking into the urine), declining eGFR and increased cardiovascular risk. Historically, treatment has focused on blood pressure control with ACE inhibitors or ARBs, glucose management, and SGLT2 inhibitors. The FLOW trial has now added semaglutide to this treatment armoury.
The FLOW trial: landmark kidney evidence
FLOW (Evaluate Renal Function with Semaglutide Once Weekly) was a randomised, double-blind, placebo-controlled trial designed specifically to evaluate the kidney effects of semaglutide in patients with type 2 diabetes and chronic kidney disease. It was published in the New England Journal of Medicine and represents the first dedicated kidney outcomes trial for a GLP-1 receptor agonist.
Trial design
- Participants: 3,533 adults with type 2 diabetes and CKD (eGFR 25 to 75 ml/min/1.73m² with albuminuria)
- Treatment: Semaglutide 1 mg weekly injection (the Ozempic dose) versus placebo
- Duration: Median follow-up approximately 3.4 years (stopped early for efficacy)
- Background therapy: Standard of care including ACE inhibitors/ARBs and, in many patients, SGLT2 inhibitors
- Primary endpoint: Composite of onset of kidney failure, sustained 50 per cent or more eGFR decline, or kidney-related or cardiovascular death
Key results
| Outcome | Semaglutide | Placebo | Risk reduction |
|---|---|---|---|
| Primary composite kidney outcome | 5.8% | 7.5% | 24% reduction (HR 0.76) |
| Kidney-specific composite (excluding CV death) | 3.4% | 5.2% | 34% reduction |
| Cardiovascular death | Reduced | Higher | 29% reduction |
| All-cause death | Reduced | Higher | 20% reduction |
| Annual eGFR decline | Slower | Faster | 1.16 ml/min/year preserved |
| UACR (albuminuria) reduction | Significant reduction | Stable | Approximately 24% reduction |
Why early stopping matters: The FLOW trial was stopped early by the independent data monitoring committee because the benefits of semaglutide were so clear that it was considered unethical to continue giving some participants a placebo. Early stopping for efficacy is a strong signal that the treatment works.
How semaglutide protects the kidneys
The nephroprotective effects of semaglutide appear to result from multiple interconnected mechanisms. Importantly, mediation analyses from the FLOW trial suggest that the kidney benefits are only partially explained by improvements in blood glucose and body weight, indicating direct renal protective effects.
Metabolic mechanisms
- Improved glycaemic control: Semaglutide reduces HbA1c by approximately 1 to 1.5 percentage points, which reduces the glucose-mediated damage to kidney glomeruli and tubules
- Weight loss: Reduces visceral and ectopic fat, including renal sinus fat, which has been linked to kidney damage
- Blood pressure reduction: Semaglutide lowers systolic blood pressure by approximately 4 to 6 mmHg, reducing the haemodynamic stress on damaged kidneys
- Improved lipid profile: Reduced triglycerides and improved cholesterol ratios may contribute to reduced renal inflammation
Direct kidney effects
- Reduced albuminuria: The FLOW trial showed significant reduction in urinary albumin-to-creatinine ratio (UACR), indicating less protein leaking through damaged glomeruli
- Anti-inflammatory effects: GLP-1 receptors are expressed in the kidney, and activation appears to reduce local inflammation, oxidative stress and fibrosis
- Natriuretic effect: Semaglutide promotes sodium excretion, which may reduce glomerular hyperfiltration — a key driver of CKD progression in diabetes
- Reduced tubular injury: Preclinical studies suggest GLP-1 agonists reduce proximal tubule stress markers
Implications for UK clinical practice
The FLOW trial results have significant implications for how CKD is managed in patients with type 2 diabetes in the United Kingdom.
Current treatment landscape
The standard of care for diabetic kidney disease in the UK currently includes:
- ACE inhibitor or ARB: First-line therapy for all patients with diabetic CKD and albuminuria (NICE CG182)
- SGLT2 inhibitor: Dapagliflozin or empagliflozin, based on the DAPA-CKD and EMPA-KIDNEY trials (NICE TA775)
- Blood glucose management: Target HbA1c agreed individually, with caution around hypoglycaemia risk in advanced CKD
- Blood pressure control: Target below 130/80 mmHg for patients with albuminuria
- Finerenone: Non-steroidal mineralocorticoid receptor antagonist for patients with persistent albuminuria despite ACE/ARB (NICE TA877)
Where semaglutide fits
Following the FLOW trial, updated guidelines from KDIGO (Kidney Disease: Improving Global Outcomes) recommend GLP-1 receptor agonists for patients with type 2 diabetes and CKD, particularly those who have not achieved adequate glucose control or who have additional cardiovascular risk factors. The NICE technology appraisal for this specific indication is anticipated.
In the interim, many UK nephrologists and diabetologists are already prescribing semaglutide for patients with type 2 diabetes and CKD, using its existing diabetes licence. The FLOW trial provides strong evidence to support this practice.
Practical point: Semaglutide does not require dose adjustment for kidney impairment. It is metabolised by peptide degradation rather than renal excretion. However, patients with advanced CKD (eGFR below 30) should be monitored more closely for dehydration, particularly during the dose titration phase when gastrointestinal side effects are most common.
Semaglutide and SGLT2 inhibitors: complementary or redundant?
Many patients with diabetic CKD are already taking an SGLT2 inhibitor (such as dapagliflozin or empagliflozin). The question of whether adding semaglutide provides additional kidney benefit was addressed in the FLOW trial, where approximately 25 per cent of participants were also taking an SGLT2 inhibitor.
Subgroup analyses suggest that semaglutide provided kidney benefit regardless of SGLT2 inhibitor use, supporting a complementary rather than redundant role. The two drug classes protect the kidney through different mechanisms:
- SGLT2 inhibitors: Reduce glomerular hyperfiltration through tubuloglomerular feedback, reduce glucose toxicity and have diuretic and natriuretic effects
- GLP-1 agonists: Reduce inflammation, improve metabolic parameters, reduce body weight and may have direct anti-fibrotic effects on kidney tissue
Current thinking supports a multi-pillar approach to diabetic CKD: ACE/ARB + SGLT2 inhibitor + GLP-1 agonist + finerenone, each addressing different pathways of kidney injury. Not all patients will need all four, but for those at highest risk, combination therapy may offer the best protection.
Monitoring kidney function on GLP-1 therapy
If you have CKD and are prescribed semaglutide, your doctor will monitor your kidney function through regular blood and urine tests.
Key monitoring parameters
- eGFR: Estimated glomerular filtration rate, measured from a blood creatinine test. Checked every 3 to 12 months depending on CKD stage.
- UACR: Urinary albumin-to-creatinine ratio, measuring protein in the urine. A falling UACR is a positive sign indicating less kidney damage.
- Potassium: Important to monitor, particularly if also taking ACE inhibitors, ARBs or finerenone.
- HbA1c: Glycated haemoglobin, reflecting average blood glucose over the preceding 2 to 3 months.
- Blood pressure: Regular monitoring to ensure target is maintained.
Dehydration risk: GLP-1 medications can cause nausea, vomiting and diarrhoea, particularly during dose titration. In patients with reduced kidney function, dehydration can worsen kidney injury. If you experience significant gastrointestinal symptoms, maintain adequate fluid intake and contact your GP or renal team. Temporary dose reduction may be appropriate.
Practical advice for CKD patients
If you have chronic kidney disease and type 2 diabetes, the following steps can help you make the most of GLP-1 therapy:
- Discuss semaglutide with your diabetologist or nephrologist — the FLOW trial evidence supports its use in CKD
- Stay well hydrated, especially during the first weeks of treatment when gastrointestinal side effects are most common
- Continue all other kidney-protective medications (ACE/ARB, SGLT2 inhibitor) unless advised otherwise
- Follow a kidney-friendly diet that manages sodium, potassium and protein intake as advised by your renal dietitian
- Attend all monitoring appointments and blood tests as scheduled
- Report any symptoms of dehydration (dizziness, dark urine, dry mouth) promptly to your healthcare team
- Maintain regular physical activity as tolerated — exercise benefits both kidney function and metabolic health