Renal outcomes with the newer antidiabetes drugs: the era before and after CREDENCE

Abstract

In 2008, the US Food and Drug Administration provided guidance for the evaluation of the cardiovascular safety of antidiabetes drugs. The newer antidiabetes drugs, approved after 2008, were therefore evaluated in long‐term cardiovascular outcome trials, designed and powered for the assessment of cardiovascular safety. Accordingly, the primary endpoint of these trials was a cardiac composite endpoint. Since 2008, the data from various cardiovascular outcome trials have been reported, including SAVOR‐TIMI 53 (saxagliptin), EXAMINE (alogliptin), TECOS (sitagliptin), CARMELINA (linagliptin), CAROLINA (linagliptin), ELIXA (lixisenatide), LEADER (liraglutide), EXSCEL (exenatide once‐weekly), SUSTAIN‐6 (injectable semaglutide), HARMONY Outcomes (albiglutide), REWIND (dulaglutide), PIONEER‐6 (oral semaglutide), EMPA‐REG OUTCOME (empagliflozin), the CANVAS Program (canagliflozin) and DECLARE‐TIMI 53 (dapagliflozin). Some of these trials subsequently also published data on renal outcomes, although these were secondary or exploratory analyses. Dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide‐1 receptor agonists had beneficial effects on albuminuria, while sodium‐glucose co‐transporter‐2 inhibitors additionally showed a positive effect on ‘hard’ renal outcomes. In contrast to the cardiovascular outcome trials, the renal outcome trial of canagliflozin, CREDENCE, assessed a hard renal endpoint as its primary endpoint and showed positive effects on these hard renal outcomes. In this review, we aim to highlight the renal outcome data from the cardiovascular outcome trials and the CREDENCE trial and understand the differences between their results. The post CREDENCE era would appear to reinforce the position of sodium‐glucose co‐transporter‐2 inhibitors as drugs providing cardiorenal protection, in addition to their anti‐glycaemic effects.

Effectiveness and Safety of SGLT2 Inhibitors in Clinical Routine Treatment of Patients with Diabetes Mellitus Type 2

“…Albuminuria was used as a second renal parameter. SGLT-2-inhibitors are known to be renoprotective [11] but lead to an initial decline of eGFR which stabilizes over time [4]. In our study eGFR decreased on average 7.0 mL/min.…”

“…Although the change was not statistically significant, a negative trend of albuminuria was observed. Regression of albuminuria is a known effect of SGLT-2-inhibitors and can be considered as a renal outcome [11]. Another well-known effect of SLGT-2-inhibition is an improvement in blood pressure control [12].…”

Harmful versus beneficial effects of using short-term combined oral antidiabetic therapy: ‎An open label comparative clinical trial ‎

“…Previous studies showed that glimepiride can impair renal function, while long term therapy with canagliflozin slowly reduced the renal function, which is dose-independent [28]. Thus, slow decline of the kidney function during canagliflozin therapy suggests that canagliflozin offered cardiorenal protection [29]. Short-term canagliflozin therapy that was applied in this study does not show the harmful effect of canagliflozin on the renal function, which is in agreement with a study by Takashima et al who reported a decline of eGFR by 0.7 mL/min/1.73 m 2 in T2D patients treated with canagliflozin for 52 weeks.…”

Obesity-Related Kidney Disease: Current Understanding and Future Perspectives

“…These pleiotropic agents were initially used for managing T2D, but emerging evidence has confirmed their beneficial effects on cardiovascular and kidney outcomes, even though the mechanistic basis for these benefits remains incompletely understood [ 94 , 95 ]. Studies have shown that SGLT-2 inhibitors reduce the risk of major adverse cardiovascular events, hospitalization for heart failure, and the progression of CKD [ 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ]. In CKD, they slow the decline in glomerular filtration rate, reduce albuminuria, and delay the onset of end-stage kidney disease [ 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ].…”

“…Studies have shown that SGLT-2 inhibitors reduce the risk of major adverse cardiovascular events, hospitalization for heart failure, and the progression of CKD [ 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ]. In CKD, they slow the decline in glomerular filtration rate, reduce albuminuria, and delay the onset of end-stage kidney disease [ 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ]. SGLT-2 inhibitors can promote weight loss in individuals with T2D via the increase in the amount of glucose excreted in the urine, which results in a loss of calories [ 112 ].…”