The kidney and cardiovascular outcome trials.

Chronic kidney disease (CKD) affects a substantial minority of people with type 2 diabetes (T2D). Analysis of US National Health and Nutrition Examination Survey (NHANES) datasets from 2007 through 2012 showed Stage 3 or worse disease (estimated glomerular filtration rate [eGFR] <60 mL/min per 1.73 m2 ) in nearly one in five patients, with increasing age, blood pressure, obesity, and levels of glycemia all associated with higher likelihood of Stage 3 or worse CKD, comparable to findings from surveys from many other areas, which also show micro- or macroalbuminuria to be present in one-sixth to one-third of diabetic people. Improvement in albuminuria has been shown in clinical trials of glycemic interventions, including the Action to Control Cardiovascular Disease in Diabetes (ACCORD) trial, the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, in which the nephroprotective effect of blood pressure lowering was also demonstrated, and the UK Prospective Diabetes Study (UKPDS). However, over the past decade a host of cardiovascular outcome trials (CVOTs) have been performed with newer T2D therapeutic agents, and many of these have included intriguing information pertaining to renal disease and renal outcomes not necessarily related to changes in glycemia. It is of interest to review some of these findings. Glucagon-like peptide-1 (GLP-1) has been reported to increase glomerular filtration rate (GFR), renal blood flow, and the fractional excretion both of sodium and potassium, with renal GLP-1 receptors present in afferent arteriolar vascular smooth muscle cells, glomerular endothelial cells and macrophages, juxtaglomerular cells, and the proximal tubule, perhaps mediating the greater natriuresis seen after oral than intravenous sodium. In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, the significant 13% reduction in the primary composite outcome of cardiovascular death, myocardial infarction, and stroke was found on subgroup analysis to particularly occur among participants with Stage 3 CKD, having eGFR 30-59 mL/min per 1.73 m2 . No significant effect on eGFR was found with liraglutide, although both those receiving and not receiving the drug showed a decline in eGFR from approximately 75 to 65 mL/min per 1.73 m2 over the 48-month period of observation. Liraglutide administration was associated with a significant reduction in albuminuria, with nearly a 25% lower likelihood of development of macroalbuminuria, and with the albumin:  creatinine ratio (ACR) approximately 20% lower among treated people, regardless of the baseline level of eGFR. Similarly, in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, a 34% increase in the urine ACR was reported among people receiving placebo, but the increase was 24% among those receiving lixisenatide, and in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6), persistent macroalbuminuria developed among 2.7% of those receiving semaglutide, but among 4.9% of those receiving placebo. The enzyme dipeptidyl peptidase (DPP)-4 is, like the GLP-1 receptor, present in multiple renal membrane-bound locations, including afferent arteriolar vascular smooth muscle cells, mesangial cells, podocytes, and proximal tubular cells, and DPP-4 inhibitors appear to have salutary effects on albuminuria similar to those of the GLP-1 agents. In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial, saxagliptin was associated with significantly less worsening and more improvement in microalbumin levels at 1 year, at 2 years, and by end-of-treatment. The reduction in microalbumin levels was similar in patients with and without renal impairment. Interestingly, there was no relationship between improvement in albuminuria and improvement in HbA1c. The other DPP4i CVOTs have not reported effects of these agents on renal function or albuminuria, but studies of sitagliptin and linagliptin suggest that these agents may also reduce albuminuria. Sodium-glucose cotransporter (SGLT) 2 inhibitors affect multiple sites, with the potential to affect renal function. The Canagliflozin Cardiovascular Assessment Study (CANVAS) showed a 27% reduction in progression of albuminuria, with a 40% reduction in eGFR, need for renal-replacement therapy, or death from renal causes associated with the use of canagliflozin. After a fall in mean eGFR with canagliflozin from 76 to 73 mL/min per 1.73 m2 at 3 months, eGFR remained stable through 6 years while gradually declining during the period of observation with placebo. Evidence of dual effects of SGLT2 inhibition on both albuminuria and GFR was even more strongly shown in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME); in that CVOT, although there was an initial decline in eGFR with empagliflozin, from 94 mL/min per 1.73 m2 through 192 weeks, eGFR was consistently higher with empagliflozin, although this was less clear in trial participants with baseline eGFR <60 mL/min per 1.73 m2 . Empagliflozin also reduced the development of acute renal failure. Further analysis showed empagliflozin to be associated with a reduction in albuminuria, regardless of the baseline urine albumin level. The CVOTs have offered the possibility that diabetes treatment may move beyond surrogate endpoints to actual cardiovascular outcome benefits. It appears that these drugs will also lead to a reduction in adverse renal outcomes. We should look with optimism at this potential approach to a major complication of diabetes.