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.