Emergence of GLP-1 Receptor Agonists as a Therapy for Diabetic Kidney Disease

A multitude of clinical effects beyond glycemic control have placed glucagon-like peptide-1 (GLP-1) receptor agonists front and center in the fields of diabetology, cardiology, and nephrology. These incretin-based antihyperglycemic agents reduce the risk of new or worsening kidney disease and decrease the risk of cardiovascular death and atherosclerotic events (15). In the wake of these findings, the American Diabetes Association Standards of Care for treatment of hyperglycemia in type 2 diabetes now state that GLP-1 receptor agonists with proven cardiovascular benefits (liraglutide > semaglutide > exenatide extended release) should be added to the therapeutic regimen if glycemic targets are not achieved with metformin, particularly in patients with atherosclerotic cardiovascular disease (6). GLP-1 receptor agonists currently approved by the United States Food and Drug Administration are liraglutide (Victoza, Saxenda), semaglutide (Ozempic), lixisenatide (Adlyxin), exenatide (Byetta) and exenatide extended-release (Bydureon, Bydureon, BCise), and dulaglutide (Trulicity). Approved combination therapies are insulin glargine/exanitide (Soliqua 100/33) and insulin degludec/liraglutide (Xultophy 100/3.6).

Evidence supporting the kidney and cardiovascular benefits of the GLP-1 receptor agonists comes from large clinical trials enrolling patients with type 2 diabetes, cardiovascular disease, chronic kidney disease (CKD), or a combination of these conditions (Figure 1).

Figure 1.

Kidney outcomes in four major clinical trials evaluating glucagon-like peptide-1 receptor agonist medications in patients with type 2 diabetes.

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The dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate to severe CKD (AWARD-7) clinical trial was the first to be conducted in patients with moderate to severe CKD; nearly a third of enrolled patients had stage 4 CKD (4). Dulaglutide outperformed insulin glargine, the active comparator, in achieving glycemic control in patients with type 2 diabetes and a mean estimated GFR (eGFR) of 38 ± 13 mL/min per 1.73 m2. Over 1 year, the average eGFR decline was −3.3 mL/min per 1.73 m2 in the insulin-treated group and −0.7 mL/min per 1.73 m2 in both the higher-dose (1.5 mg weekly) and lower-dose (0.75 mg weekly) dulaglutide-treated groups (4). Among AWARD-7 patients with macroalbuminuria (urine-to-albumin creatinine ratio >300 mg/g) at high risk for progression of kidney disease, attenuation of mean eGFR decline was maintained (−5.5 mL/min per 1.73 m2 in the insulin glargine group compared with −0.7 mL/min per 1.73 m2 and 0.5 mL/min per 1.73 m2 in the dulaglutide 0.75-mg and 1.5-mg groups, respectively). Notably, fewer patients in the higher-dose dulaglutide group reached the composite endpoint of ESRD or >40% eGFR decline in comparison with the insulin glargine group (5.2% vs. 10.8%, p = 0.038) (7).

In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) clinical trial and the Semaglutide and Cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6) clinical trial, treatment with liraglutide or semaglutide compared with placebo resulted in fewer patients experiencing a composite cardiovascular outcome and decreased risk of CKD development and progression—benefits mainly driven by the reduction in new-onset macroalbuminuria (2, 3, 5). Similarly to AWARD-7, in patients with albuminuria as well as those with eGFR <60 mL/min per 1.73 m2, the LEADER trial demonstrated reduction of a composite of new-onset macroalbuminuria, doubling of serum creatinine, requirement for kidney replacement therapy, and death due to kidney causes (2). Importantly, the reduction of cardiovascular events and all-cause mortality was greater in LEADER participants with eGFR <60 mL/min per 1.73 m2 than in those with eGFR ≥60 (8). In patients with type 2 diabetes and a recent acute coronary syndrome, the addition of lixisenatide to usual care moderately reduced albuminuria, even though the rates of cardiovascular events were unaffected (1).

The mechanism by which GLP-1 receptor agonists reduce the risk of macroalbuminuria and slow eGFR decline in patients with type 2 diabetes remains to be fully elucidated. These agents favorably affect major CKD risk factors by improving control of hyperglycemia, hypertension, and excess body weight (911). In addition to modifying CKD risk factors, GLP-1 signaling directly promotes antioxidant, anti-inflammatory, and antifibrotic effects in the diabetic kidney (12, 13).

GLP-1 receptor agonists fill longstanding unmet needs: antihyperglycemic agents that can be used safely and effectively in patients with moderate to severe CKD, and agents that will slow eGFR decline in patients with eGFR <30 mL/min per 1.73 m2. The encouraging results from the AWARD-7 and cardiovascular outcome trials provide hope that the GLP-1 receptor agonists will join a growing menu of agents available to tackle the burgeoning problem of CKD in type 2 diabetes.

August 2019 (Vol. 11, Number 8)

References

1. Pfeffer MA, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015; 373:2247–2257.

2. Mann JFE, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017; 377:839–848.

3. Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375:311–322.

4. Tuttle KR, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol 2018; 6:605–617.

5. Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375:1834–1844.

6. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes–2019. Diabetes Care 2019; 42:S90–S102.

7. Tuttle KR, et al. CKD outcomes in type 2 diabetes and moderate-to-severe CKD treated with dulaglutide versus insulin glargine: AWARD-7 [Poster]. JASN Kidney Week Edition Abstract Supplement 2018. 2018; Poster TH-OR033.

8. Mann JFE, et al. Effects of liraglutide versus placebo on cardiovascular events in patients with type 2 diabetes mellitus and chronic kidney disease. Circulation 2018; 138:2908–2918.

9. Sun F, et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Res Clin Pract 2015; 110:26–37.

10. Potts JE, et al. The effect of glucagon-like peptide 1 receptor agonists on weight loss in type 2 diabetes: a systematic review and mixed treatment comparison meta-analysis. PLoS One 2015; 10:e0126769.

11. Vilsboll T, et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ 2012; 344:d7771.

12. Dieter BP, Alicic RZ, Tuttle KR. GLP-1 receptor agonists in diabetic kidney disease: from the patient-side to the bench-side. Am J Physiol Renal Physiol 2018; 315:F1519–F1525.

13. Tanaka T, et al. The potential for renoprotection with incretin-based drugs. Kidney Int 2014; 86:701–711.