Chronic kidney disease (CKD) affects 10% of the population worldwide, but many people do not have access to affordable treatment.1,2 All stages of CKD are associated with increased risks of cardiovascular disease, premature death, and/or decreased quality of life.3 Diabetes is the leading cause of CKD, and it develops in around 40% of people with diabetes.4 The incidence of CKD is increasing in parallel with the incidence of diabetes, representing a global health crisis.5 However, the only treatment approved for CKD in patients with type 2 diabetes (T2D) is renin-angiotensin system (RAS) blockade, and, despite treatment, many patients continue to lose kidney function and ultimately need dialysis.6 The high cost of dialysis is a challenge to health service budgets in both developing and developed countries. There is, therefore, an urgent need for treatments that can prevent or delay progression of CKD in patients with T2D.
Sodium–glucose cotransporter-2 (SGLT2) inhibitors have become widely used glucose-lowering drugs in patients with T2D.7 SGLT2 inhibitors exert their glucose-lowering effect by blocking the reabsorption of glucose in the kidney and increasing glucose excretion.8 In recent years, these drugs have attracted considerable attention after achieving stunning results in cardiovascular outcome trials.9–11 Results from the CANVAS (CANagliflozin cardioVascular Assessment Study) Program were published in 2017, and, in addition to showing cardiovascular benefits, found that canagliflozin (InvokanaÒ, Janssen, Beerse, Belgium) had favourable effects on renal outcomes including albuminuria.10 Secondary analyses of other cardiovascular outcome trials have suggested renal benefits for SGLT2 inhibitors.11,12 This has prompted a new wave of outcome trials for SGLT2 inhibitors to investigate potential benefits for patients with T2D and CKD.
One of the highlights of the 28th Annual Congress of the American Association of Clinical Endocrinologists (AACE), which was held from 24–28 April 2019, in Los Angeles, California, USA, was the encore presentation of data from the CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) trial (ClinicalTrials.gov Identifier: NCT02065791). These data had been announced for the first time on 14 April at the International Society of Nephrology 2019 World Congress in Melbourne, Australia, and simultaneously published in the New England Journal of Medicine,13 but this was the first presentation of these eagerly awaited data in the USA.
A total of 4,401 people with T2D and CKD (defined as an estimated glomerular filtration rate [eGFR] of 30–90 mL/min/1.73 m2 and a urinary albumin: creatinine ratio of >34 mg/mmol) were randomly assigned 1:1 to either canagliflozin 100 mg once daily or placebo, together with their ongoing RAS blockade therapy. The trial was halted early because the strength of the efficacy data: after a median 2.62 years, the primary composite outcome of end-stage kidney disease, doubling of serum creatinine, or renal or cardiovascular death was 30% lower in the canagliflozin group than in the placebo group (43.2 versus 61.2 events per 1,000 person-years; hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.59–0.82). The relative risk of the renal-specific composite endpoint (end-stage kidney disease, a doubling of the creatinine level, or death from renal causes) was 34% lower (HR, 0.66; 95% CI, 0.53–0.81; p<0.001), and the relative risk of end-stage kidney disease was 32% lower (HR, 0.68; 95% CI, 0.54–0.86; p=0.002). Subgroup analysis found that the reduction in the primary endpoint was at least as robust, if not more, in the 60% of trial participants who had an eGFR between 30–60 mL/min/1.73 m2.13
The risk of cardiovascular events, including cardiovascular death or hospitalisation for heart failure (HR, 0.69; 95% CI, 0.57–0.83); cardiovascular death, myocardial infarction or stroke (HR, 0.80; 95% CI, 0.67–0.95); and hospitalisation for heart failure (HR, 0.61; 95% CI, 0.47–0.80), was also lower in the canagliflozin group compared with placebo, suggesting that canagliflozin has multiple benefits in patients with T2D and CKD.
The safety of canagliflozin has been called into question in the last year following reports of increased risks of for lower-limb amputations and diabetic ketoacidosis in the CANVAS study, causing the US Food and Drug Administration (FDA) to issue a boxed warning.10,14 However, data from the CREDENCE study showed that there was no significant difference in the risk of lower-limb amputation (HR, 1.11; 95% CI, 0.79–1.56) or fracture (HR, 0.98; 95% CI, 0.70–1.37) between the groups. Diabetic ketoacidosis was more frequent in the canagliflozin group, but these events were rare (2.2 versus 0.2 events per 1,000 person-years). This discrepancy was a relief to investigators but prompts questions as to the reasons for the difference. CREDENCE used only the lower of the two canagliflozin doses used in CANVAS and had a different study population, but the potential risk should not be forgotten.
The CREDENCE trial has been described as a ‘landmark’ and ‘practice changing’. The results of this high-quality study are certainly impressive, but it has limitations. All patients were taking adequate RAS blockade therapy and loss of kidney function was still observed among participants taking canagliflozin, so other treatments will be needed. Certain patients cannot tolerate SGLT2 inhibitors. In addition, patients with advanced CKD (eGFR <30 mL/min/1.73 m2), CKD without albuminuria or microalbuminuria, and kidney disease believed to have been caused by conditions other than T2D were excluded from the study, so it is not known whether these findings can be applied to a broader population of patients with T2D and CKD.
Renal outcome trials for the other most widely used SGLT2 inhibitors, dapagliflozin (Farxiga®, AstraZeneca, Cambridge, UK), and empagliflozin (Jardiance®, Eli Lilly, Indianapolis, Indiana, USA and Boehringer Ingelheim, Ingelheim am Rhein, Germany), are underway. The DAPA-CKD (ClinicalTrials.gov Identifier: NCT03036150) dapagliflozin study is due to complete in November 2020, and data from EMPA-KIDNEY (ClinicalTrials.gov Identifier: NCT03594110) for empagliflozin, are due in June 2022. These studies also contain a proportion of participants without T2D, which will potentially broaden the indications for SGLT2 inhibitors.
The next step for canagliflozin will be its widespread introduction into clinical practice. At the moment SGLT2 inhibitors are considered solely as a means of managing blood glucose and renal specialists tend not to use them. However, it is worth noting that, in the CREDENCE study, differences in blood glucose, weight and blood pressure, were only modest between the two groups, continuing the uncertainty around the precise mechanism of action of SGLT2 inhibitors.13 It is, therefore, important to raise awareness of the use of canagliflozin in the patient populations most likely to benefit from it. The findings of this pivotal study offer the promise to reduce the number of people requiring treatment for kidney failure in the future.
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