Review of glucagon‐like peptide‐1 receptor agonists for the treatment of type 2 diabetes mellitus in patients with chronic kidney disease and their renal effects

Abstract

Type 2 diabetes mellitus (T2DM) is the most common cause of chronic kidney disease (CKD), and when it causes CKD it is collectively referred to as diabetic kidney disease. One of the newer therapies for managing hyperglycemia is the glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) drug class. This review summarizes the effects of GLP‐1RAs in patients with T2DM with CKD and evidence for renoprotection with GLP‐1RAs using data from observational studies, prospective clinical trials, post hoc analyses, and meta‐analyses. Evidence from some preclinical studies was also reviewed. Taken together, subgroup analyses of patients with varying degrees of renal function demonstrated that glycemic control with GLP‐1RAs was not markedly less effective in patients with mild or moderate renal impairment vs that in patients with normal function. GLP‐1RAs were associated with improvements in some cardiorenal risk factors, including systolic blood pressure and body weight. Furthermore, several large cardiovascular outcome studies showed reduced risks of composite renal outcomes, mostly driven by a reduction in macroalbuminuria, suggesting potential renoprotective effects of GLP‐1RAs. In conclusion, GLP‐1RAs effectively reduced hyperglycemia in patients with mild or moderately impaired kidney function in the limited number of studies to date. GLP‐1RAs may be considered in combination with other glucose‐lowering medications because of their ability to lower glucose in a glucose‐dependent manner, lowering their risk for hypoglycemia, while improving some cardiorenal risk factors. Potential renoprotective effects of GLP‐1RAs, and their renal mechanisms of action, warrant further investigation.

GLP-1 Receptor Agonists and Diabetic Kidney Disease: A Call of Attention to Nephrologists

“…Turning next to the effect on natriuresis, GLP-1 has been demonstrated to induce natriuresis and diuresis, likely involving inhibition of sodium-hydrogen exchanger 3 (NHE3) localized at the brush border of the renal proximal tubular cells [66]. NHE3 activity in the proximal tubule increases distal tubular sodium transport in the kidney to the macula densa, resulting in restored tubular glomerular feedback with a reduction in intraglomerular pressure, hyperfiltration and renin-angiotensin system activation [67]. These findings imply that GLP-1RA are proximal diuretics and renal vasodilators that under healthy conditions only mildly influence tubuloglomerular feedback [68].…”

Management of post‐transplant diabetes: immunosuppression, early prevention, and novel antidiabetics

“…Several mechanisms have been proposed how GLP1‐RAs exert their cardio‐ but also nephroprotective effects (partly summarized in Table 2, illustrated in Fig. 2 and reviewed in [139] and [140]). Direct effects of GLP1‐RAs on the heart may to our knowledge not play a major role and include a small but significant rise in heart rate [141].…”

“…One hypothesis that may not be well known is that by reducing prandial intraglomerular pressure, macronutrient loss into the glomerular filtrate may be prohibited [140]. Reduction in intraglomerular pressure and a subsequent antiproteinuric affect in the diabetic kidney, however, are also a consequence of GLP1‐RA induced natriuresis and subsequent increase in tubuloglomerular feedback, which most likely originates from GLP1‐RA‐induced inhibition of the sodium hydrogen exchanger 3 [140]. Besides inhibition of reactive oxygen species, GLP1‐RAs have also been shown to exert immunomodulatory properties [142].…”

Effect of long-term treatment of Carvacrol on glucose metabolism in Streptozotocin-induced diabetic mice

“…GLP-1 decreases the plasma glucose level by enhancing release of glucose-dependent insulin, inhibiting gastric emptying and the level of postprandial glucagon, and reducing food intake. Thus, GLP-1 activators are used for T2DM treatment [42]. Therefore, the antihyperglycemic effects of carvacrol might be through TRPA1-mediated GLP-1 secretion.…”