July 26, 2018
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Dulaglutide improves glycemic profile in type 2 diabetes, CKD

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Katherine Tuttle
Katherine R. Tuttle

Adults with type 2 diabetes and mild to moderate chronic kidney disease assigned the once-weekly GLP-1 receptor agonist dulaglutide experienced a similar reduction in HbA1c vs. those assigned insulin glargine, along with a lower rate of hypoglycemia and a slower decline in renal function, according to findings from the AWARD-7 clinical trial.

“AWARD-7 shows that once-weekly dulaglutide, compared with titrated daily insulin glargine, both combined with insulin lispro, attenuated the decline in estimated glomerular filtration rate [eGFR] in patients with type 2 diabetes and moderate-to-severe chronic kidney disease,” Katherine R. Tuttle, MD, FASN, FACP, executive director for research at Providence Health Care in Spokane, Washington, and a clinical professor of medicine in the nephrology division at the University of Washington School of Medicine, told Endocrine Today. “These benefits were achieved while lowering HbA1c to a similar extent to insulin glargine, but with weight loss and a substantially lower rate of hypoglycemia. To our knowledge, this is the first clinical trial in patients with type 2 diabetes and moderate to severe chronic kidney disease that has shown clear effects of a GLP-1 receptor agonist to preserve eGFR.”

In moderate to severe chronic kidney disease, treatment options for hyperglycemia are limited, and many antihyperglycemic drugs, including insulin, are primarily cleared by the kidneys and therefore require dose adjustments or are considered contraindicated for patients with chronic kidney disease, Tuttle and colleagues wrote in the study background. As a result, adults with type 2 diabetes and CKD are at increased risk for hypoglycemia because of reduced drug clearance and impaired gluconeogenesis by the kidney.

Tuttle and colleagues analyzed data from 577 patients with type 2 diabetes and moderate to severe CKD (stages 3 or 4) prescribed insulin with or without an oral antihyperglycemic agent as well as a maximum-tolerated dose of a renin-angiotensin system inhibitor. Between August 2012 and November 2015, researchers randomly assigned patients to either 1.5 mg dulaglutide (Trulicity, Eli Lilly; n = 193), 0.75 mg dulaglutide (n = 190) or daily insulin glargine (n = 194) as basal therapy, all in combination with insulin lispro (Humalog, Lilly) for 52 weeks. Insulin glargine and lispro doses were titrated per an adjustment algorithm. Primary outcome was HbA1c at 26 weeks, with a 0.4% noninferiority margin. Secondary outcomes included estimated glomerular filtration rate and urinary albumin to creatinine ratio.

At 26 weeks, all treatment groups experienced similar least squares mean reductions in HbA1c from baseline, demonstrating both dulaglutide doses were noninferior to insulin glargine (P .001 for both comparisons). Proportions of patients achieving an HbA1c of less than 8% and less than 7% were similar between groups at both 26 and 52 weeks, according to researchers. Across all groups, daily insulin lispro doses increased progressively from baseline to 26 weeks and were generally stable from 26 to 52 weeks.

The researchers found that eGFR did not change for either dulaglutide group at 26 or 52 weeks; however, eGFR declined during the study in the insulin glargine group.

Among patients with baseline macroalbuminuria, the observed decline in eGFR was smaller with both doses of dulaglutide vs. insulin glargine at 26 and 52 weeks. Additionally, decreases from baseline in urinary albumin to creatinine ratio were observed at 26 and 52 weeks for patients in the dulaglutide 1.5-mg group vs. the insulin glargine group; however, decreases in urinary albumin to creatinine ratio for patients in the dulaglutide 0.75-mg group vs. insulin glargine did not rise to significance, according to the researchers.

Reported serious adverse events did not differ between groups. The most commonly reported adverse events were hypoglycemia (4%), acute myocardial infarction (2%), acute kidney injury (2%) and increase in blood creatinine concentrations (1%). Most adverse events leading to treatment discontinuation with dulaglutide were gastrointestinal. The proportion of patients with severe hypoglycemia was lower with dulaglutide 1.5 mg (none) and dulaglutide 0.75 mg (3%) vs. insulin glargine (7%). Adverse events for kidney disease did not differ by group.

“Dulaglutide treatment showed an overall favorable safety profile along with possible therapeutic benefits, including lower rates of hypoglycemia, weight loss, reduced decline in eGFR and increased reduction in albuminuria,” the researchers wrote.

The study findings led drugmaker Eli Lilly to recently update the label for dulaglutide to reflect new safety and efficacy data. As Endocrine Today previously reported, the label now includes data that demonstrated that people treated with dulaglutide 1.5 mg or 0.75 mg combined with mealtime insulin lispro achieved similar glycemic control with weight loss vs. those treated with a traditional basal-bolus insulin regimen.

“Dulaglutide can be used to safely and effectively to treat type 2 diabetes in patients with moderate-to-severe chronic kidney disease,” Tuttle told Endocrine Today. “This is a major advance since many other anti-hyperglycemic medicines cannot be given in this population due to safety concerns, ineffectiveness, or both. As a result, the FDA label for dulaglutide was recently updated to include the AWARD-7 data. The approved doses of dulaglutide are 0.75 mg once-weekly and 1.5 mg once-weekly by subcutaneous injection. No dose adjustment is needed for patients with CKD.” – by Regina Schaffer

For more information:

Katherine R. Tuttle, MD, FASN, FACP, can be reached at the University of Washington School of Medicine, 1959 NE Pacific St, Seattle, WA 98195; email: Katherine.Tuttle@providence.org.

Disclosures: Eli Lilly funded this study. Tuttle reports she is a consultant for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Gilead Sciences. Please see the study for the other authors’ relevant financial disclosures.