The incidence of end-stage renal disease due to diabetes is increasing, a phenomenon documented in multiple studies. Globally, that figure rose from 22.1% in 2000 to 31.3% in 2015.1 In the United States, 36.9% of patients with chronic kidney disease have diabetes.2 In the United Kingdom Prospective Diabetes Study (UKPDS), patients with newly diagnosed type 2 diabetes were found to progress from normoalbuminuria to microalbuminuria (urinary albumin concentration [UAC] > 50 mg/l) by 2% per annum and a further 2% from microalbuminuria to clinical grade proteinuria (UAC > 300 mg/l). Mortality rates are also higher among these individuals, ranging from 1.4% per annum (in those with normoalbuminuria) to 4.6% per annum (in those with clinical grade proteinuria), and to 19.2% per annum for those with renal impairment.3 Chronic kidney disease is diagnosed when there is persistent presence of elevated urinary albumin excretion (albuminuria) or low estimated glomerular filtration rate (eGFR); diabetic kidney disease is usually a clinical diagnosis in the absence of signs or symptoms of other primary causes of kidney damage in a person with diabetes.4,5 However in recent years, several studies have found that patients with diabetes can also have decline in eGFR despite being normoalbuminuric.6,7
As seen in the Diabetes Control and Complication Trial (DCCT) and the UKPDS 33, achieving glycemic control can delay the onset and reduce progression of microvascular complications including diabetes nephropathy. In the DCCT, after three months, patients in the intensive diabetes control arm (those using three or more daily insulin injections or an insulin pump) had a 2% lower mean HbA1c level than those receiving conventional treatment (1 to 2 daily insulin injections)—a difference of 7.2% versus 9.1%. Moreover, in those given intensive treatment, the risk of incident microalbuminuria was reduced by 39%, while a reduction of 54% in risk of macroalbuminaria was achieved. In UKPDS 33, patients in the intensive treatment arm had a significant 25% risk reduction in microvascular endpoints (P=0.0099) compared with those receiving conventional treatment.8,9
Cardiovascular outcome studies of newer antihyperglycemic agents, sodium glucose cotransporter 2 inhibitors, showed not only the cardiovascular benefit as summarized in my previous article but also secondary outcomes, which included favorable secondary renal indicators. Dedicated renal outcome studies, such as Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) and the Dapaglifozin in Patients with Chronic Kidney Disease (DAPA-CKD) trials, have since demonstrated the efficacy of these agents for the management of diabetic nephropathy. In the CREDENCE trial, a total of 4401 patients with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate 30-90 ml/min/1.73m2) and albuminuria (urine albumin:creatinine ratio >300-5000 mg/g) were recruited to receive either canagliflozin at dose of 100 mg daily or placebo, with a median follow up of 2.62 years. Patients were also treated with renin-angiotensin system blockade. The primary outcome measure of the study was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Investigators found a 30% relative risk reduction in primary outcome in patients receiving canagliflozin. The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was reduced by 34% (hazard ratio, 0.66; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; P=0.002).10
Renal benefits of SGLT-2 inhibitors were also demonstrated in the DAPA-CKD trial. The cohort of patients differed from those in CREDENCE, as patients without diabetes were included and the eGFR range was lower (25-75 ml/min/1.73m2). Primary composite outcome was the first occurrence of any of the following: a decline of at least 50% in the eGFR, the onset of end-stage kidney disease or death from renal or cardiovascular cause. The trial showed that treatment with dapagliflozin, compared to placebo, resulted in a 39% risk reduction of primary composite outcomes (hazard ratio, 0.61; P<0.001); this benefit was seen regardless of whether or not the participant had diabetes.11
Glucagon-like peptide-1 receptor agonists (GLP-1RA) are another class of anti-hyperglycemic agents which not only demonstrated cardiovascular protection benefit, but renal benefits as well. Liraglutide, semaglutide, and dulaglutide have been shown to reduce albuminuria thereby driving the reduction in combined secondary renal outcomes12. A dedicated renal outcome trial with GLP-1RA in patients with diabetes and chronic kidney disease is still in progress. Among other newer agents showing promising results in kidney disease risk reduction is finerenone, a non-steroidal highly selective mineralocorticoid receptor antagonist. The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial showed a 18% risk reduction (hazard ratio, 0.82; P=0.001) in composite outcome of kidney failure, sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes. It also demonstrated cardiovascular benefit with a 14% risk reduction (hazard ratio, 0.86; P=0.03) in secondary outcome, which was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.13
Patients with diabetes and chronic kidney disease are at increased cardiovascular risk. The development of medications with cardiorenal benefits have given healthcare providers more treatment options along with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers which have been the cornerstone treatment in these patients. In addition to glycemic control, other important modifiable risk factors such as high blood pressure, obesity and smoking need to be targeted. By taking a multipronged approach, prevention of complications of diabetes can be achieved.
- Cheng HT, Xu X, Lim PS, Hung KY. Worldwide epidemiology of diabetes-related end-stage renal disease, 2000–2015. Diabetes Care. 2021;44(1):89-97.
- CKD in the general population. US Renal Data System. http://adr.usrds.org/2020/chronic-kidney-disease/1-ckd-in-the-general-population. Published 2021. Accessed April 20, 2021.
- Bilous R. Microvascular disease: what does the UKPDS tell us about diabetic nephropathy? Diabet Med. 2008;25(Suppl 2):25-9.
- American Diabetes Association. 11. Microvascular complications and foot care: standards of medical care in diabetes—2021. Diabetes Care. 2021 Jan;44(Supplement 1):S151-S167.
- KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020:98(4):S1–115.
- Vistisen D, Andersen GS, Hulman A, et al. Progressive decline in estimated glomerular filtration rate in patients with diabetes after moderate loss in kidney function—even without albuminuria. Diabetes Care. 2019;42(10):1886–1894.
- Krolewski AS, Skupien J, Rossing P, Warram JH. Fast renal decline to end-stage renal disease: an unrecognized feature of nephropathy in diabetes. Kidney Int. 2017;91(6):1300–1311.
- Control TD, Group CD. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int. 1995;47(6):1703-20.
- UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-53.
- Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-306.
- Heerspink HJ, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-46.
- Górriz JL, Soler MJ, Navarro-González JF, et al. GLP-1 Receptor Agonists and Diabetic Kidney Disease: A Call of Attention to Nephrologists. J Clin Med. 2020;9(4):947.
- Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219-29.
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