Type 2 diabetes mellitus (T2DM) significantly increases the risk of cardiovascular and renal diseases [1, 2]. However, SGLT-2 inhibitors not only lower blood glucose levels but also have cardio- and nephroprotective effects [3]. Recent data now show that SGLT-2 inhibitors also protect patients’ renal function under real-world conditions [4, 5].
Diabetes mellitus (DM) is one of the most common chronic diseases and the number of people affected is increasing worldwide [2, 6]. In Switzerland, approximately 500 000 people suffer from DM, 460 000 of whom have T2DM [6]. The increasing prevalence of T2DM is one of the primary causes for the worldwide increase in kidney disease within the last decades [7]. Thus, approximately 40% of all patients with T2DM develop diabetic kidney disease, which in turn contributes to increased cardiovascular and mortality risk [8, 9]. Therefore, prevention and therapy of cardiovascular as well as renal complications of T2DM are of central importance in addition to the reduction of blood glucose levels. SGLT-2 inhibitors have been developed to lower blood glucose levels in T2DM patients [10]. The glucose transporter SGLT-2 is responsible for the majority of glucose reabsorption in the proximal renal tubules. Inhibition of this transporter by SGLT-2 inhibitors consequently leads to glucose excretion via urine, thereby lowering blood glucose levels via an insulin-independent mechanism [11].
Canagliflozin has cardio- and nephroprotective effects
Beyond the blood glucose-lowering effect, SGLT-2 inhibitors have already been shown to have cardioprotective effects [3]. Canagliflozin (Invokana®) is now the first SGLT-2 inhibitor available to T2DM patients in Switzerland that is additionally approved to reduce the risk of progression to diabetic kidney disease in adult T2DM patients with albuminuria (ACR>300 mg/g) [11, 12]. The positive results of the renal endpoint study CREDENCE, in which T2DM patients with albuminuric chronic kidney disease benefited from canagliflozin treatment with regard to renal outcomes, were decisive for this indication expansion [10].
Kidney-protective effect confirmed in real-world setting
At this year’s American Diabetes Association (ADA) Congress, the results of two retrospective, multicenter studies (Renal-WECAN and Real-WECAN) in the real-world setting were now presented for the first time [4, 5]. These confirm that treatment with canagliflozin in T2DM patients leads to significant improvement in cardiometabolic parameters as well as renal function. The studies evaluated 583 male T2DM patients who received 100 mg canagliflozin (CANA100) or 300 mg canagliflozin (CANA300) daily in addition to antihyperglycemic therapy. The primary outcomes were changes in estimated glomerular filtration rate (eGFR), median albuminuria, systolic blood pressure, and median change in HbA1c over the median follow-up periods of 9.1 and 15.4 months. The CANA100 group showed a significant reduction in eGFR and systolic blood pressure (Table) [5]. Although no significant effect on median albuminuria was observed in the overall population, it could be significantly reduced in patients with a particularly high baseline albumin excretion [5]. In addition, the CANA100 group showed a significant reduction in HbA1c, body weight, serum uric acid concentration, and liver enzymes (Table) [4].
Dose increase or therapy change leads to significant benefit
Patients in the CANA300 group received prior treatment with an SGLT-2 inhibitor (dapagliflozin 10 mg, CANA100, or empagliflozin 10 or 25 mg) and were now newly switched to 300 mg canagliflozin. In this group of patients, an increase in dose or a change in therapy again resulted in a significant reduction in eGFR, systolic blood pressure, and albuminuria (Table) [5]. In addition, significant reductions in HbA1c, body weight, and liver enzymes were observed (Table) [4]. Only moderate side effects due to volume depletion were observed in the CANA300 group.
Conclusion
The increasing prevalence of T2DM in recent decades is among the main causes of the worldwide increase in kidney disease [7]. Switzerland is the first country to approve the SGLT-2 inhibitor canagliflozin to reduce the risk of progression to diabetic kidney disease in adult patients with T2DM and albuminuria (ACR > 300 mg/g) [11]. The Renal-WECAN and Real-WECAN studies presented at ADA 2020 confirm the cardioprotective and renal effects in T2DM patients and also demonstrate that patients already receiving therapy with SGLT-2 inhibitors may also benefit from a switch or dose increase to 300mg canagliflozin [4, 5].
| Outcome (change) | CANA100
(100 mg/d canagliflozin) 279 patients |
CANA300
(Dose increase/change from existing therapy to 300 mg/d canagliflozin). 304 patients |
| Mean HbA1c | -0.9% | -0.35%* |
| Body weight | -4.1 kg | -2.1 kg* |
| Systolic blood pressure | -4.8 mmHg | -3.2 mmHg* |
| Liver enzymes | significantly reduced | significantly reduced |
| Uric acid in serum | significantly reduced | not specified |
| eGFR | -2 ml/min | -1.8 ml/min* |
| Median albuminuria | no significant influence | -2.3 mg/g |
Table 1: Effects of canagliflozin on cardiometabolic parameters and renal function values (adapted from [4, 5]).
* additive effect related to prior treatment (dapagliflozin 10 mg, CANA100, or empagliflozin 10 or 25 mg).
Literature
CH-DIAB-2100001
This article was written with financial support from Mundipharma Medical Company, Basel Branch.
