To my mind, at least, I have only identified three agents that can reduce progression to end-stage renal failure in patients with diabetes: captopril, losartan andcanagliflozin.
The first agent to demonstrate benefit was captopril. Lewis et al (1993) compared captopril 25 mg three times a day with placebo in 409 patients with type 1 diabetes of at least 7 years duration who were diagnosed before the age of 30. Participants were aged 18–49 years with diabetic retinopathy, protein excretion ≥500 mg/day and creatinine ≤220 μmol/L. With captopril, at a median follow-up of 3 years, the primary outcome of doubling creatinine was reduced by 48% (from 21.3% to 12.1%) and the risk of death was reduced by 43% (from 6.9% to 3.9%). Progression to end-stage renal disease (ESRD) was reduced by 37% (from 15.3% to 9.7%).
There have been trials with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and diabetic nephropathy, but only losartan showed a distinct significant reduction in progression to ESRD (Brenner et al, 2001). Several other agents showed a significant reduction in doubling of creatinine or other surrogate markers. These include ramipril in the MICRO-HOPE study (Heart Outcomes Prevention Evaluation (HOPE) Study Investigators, 2000) and irbesartan in the Irbesartan Diabetic Nephropathy Trial (IDNT). The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study randomised 1,513 patients aged 31–70 years with type 2 diabetes and diabetic nephropathy (urine albumin:creatinine ratio ≥ 300 and creatinine 115–265 μmol/L) to 50–100 mg losartan once daily or placebo (Brenner et al, 2001). At a median follow-up of 3.4 years, the primary outcome of doubling of creatinine was reduced by 25% (from 26.0% to 21.6%) with losartan and the death rate was similar in both groups, at around 21%. Progression to ESRD was reduced by 28% (from 25.5% to 19.6%).
Finally, and most recently, the Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE) randomised controlled trial recruited 4,401 type 2 diabetes patients with albuminuric chronic kidney disease (defined as an estimated glomerular filtration rate of 30–<60 ml/min/1.73m2) and albuminuria (urine albumin:creatinine ratio >300 to 5000 mg/g) to receive canagliflozin or placebo (Perkovic et al, 2019). The participants, who had an average duration of diabetes of 15.8 years and an average age of 63, were followed up for just 2.62 years as the trial was stopped early on the recommendation of the Data and Safety Monitoring Committee. With canagliflozin 100 mg daily, the primary outcome of doubling of creatinine, ESRD or death from renal or cardiovascular cause was reduced by 30% (from 15.5% to 11.1%). The renal-specific composite endpoint of ESRD, doubling of creatinine or death from renal causes was lowered by 34% (from 10.2% to 6.9%) and progression to ESRD by 32% (from 7.5% to 5.3%).
It is important to remember that CREDENCE was conducted with current standards of care, with 99.9% of the trial population being on ACE inhibitors or angiotensin II receptor blockers. Statin usage was 69% overall. There was evidence of benefit across all age groups, different ethnicities, for microalbuminuria, proteinuria, prior cardiovascular disease and heart failure. The combined major adverse cardiovascular event endpoint of cardiovascular disease death, myocardial infarction or stroke was significantly reduced in favour of canagliflozin. There were no differences in amputation between the canagliflozin and placebo group in this particularly high-risk population. To achieve the primary outcome, only 22 patients need to be treated for just over 2.5 years.
A further analysis of the CREDENCE trial, see the Digest here, showed that the risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalisation for heart failure were also consistently reduced in both the primary and secondary prevention groups (Mahaffey et al, 2019).
A new approach
Diabetic kidney disease is probably the most common cause of ESRD in the UK as it is in the United States, where it accounts for 44% of all cases (U.S. Renal Data System, 2012). It is clearly a complication that causes severe distress to the patient, adding to their morbidity and reducing life expectancy. We now have a new approach to managing diabetic kidney disease, at least delaying progression to ESRD. The latter is an outcome our patients must avoid because of its associated increased risk of mortality and devastating effect on quality of life. It is also extremely expensive burden on healthcare resources.
Click the links below to access the latest Diabetes Digests related to cardiovascular disease:
- Canagliflozin is cardioprotective in diabetic kidney disease
- Semaglutide reduces cardiovascular risk in type 2 diabetes
- Lowering LDL-cholesterol reduces CV event risk in diabetic dyslipidaemia
Brenner BM, Cooper ME, de Zeeuw D et al (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345: 861–9
Heart Outcomes Prevention Evaluation (HOPE) Study Investigators (2000) Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 355: 253–9
Lewis EJ, Hunsicker LG, Bain RP, Rhode RD (1993) The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329: 1456–62
Lewis EJ, Hunsicker LG, Clarke WR et al (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345: 851–60
Mahaffey KW, Jardine MJ, Bompoint S et al (2019) Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups: Results from the Randomized CREDENCE Trial. Circulation 140: 739–50
Perkovic V, Jardine MJ, Neal B et al (2019) Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 380: 2295–306
U.S. Renal Data System (2012). Incidence, prevalence, patient characteristics, & modality. In: USRDS Annual Data Report 2012: Epidemiology of Kidney Disease in the United States. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases: 216–28. https://www.usrds.org/2012/pdf/v2_ch1_12.pdf (accessed 30 September 2019)