From Pages to Practice
You are seeing Ms. Peters today in clinic. She says to you, “I am so happy to hear that my heart disease is under better control, but I am worried about my type 2 diabetes and the damage it could cause in the long-run. Aside from checking my finger-stick glucose levels and adjusting my regimen to improve my HbA1c, is there anything I can do now to prevent diabetes-related problems in the future?”
In addition to facing the challenge of day-to-day glucose control, patients with diabetes — even those who meet their glycated hemoglobin (HbA1c) goal — remain at risk for developing diabetes-related cardiovascular disease, eye disease, and kidney disease. Like Ms. Peters, many patients have wondered whether any breakthroughs have been developed to reduce the long-term risk. This week’s issue of NEJM presents the prespecified secondary renal outcomes from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial in patients with type 2 diabetes and high cardiovascular risk who were treated with liraglutide or placebo in addition to usual care. Liraglutide is a long-acting human glucagon-like peptide-1 analog approved for treatment of type 2 diabetes. It is administered as a daily subcutaneous injection and acts by mimicking the incretin hormones normally produced by the body to stimulate postprandial insulin release.
Between 2010 and 2012, the LEADER trial enrolled patients with adult-onset type 2 diabetes and HbA1c levels ≥7.0% who were at high risk for cardiac complications, defined as the presence of at least one coexisting cardiovascular condition (coronary heart disease, cerebrovascular disease, peripheral vascular disease, chronic kidney disease stage 3 or greater, or chronic heart failure [New York Heart Association class II or III]) in a patient aged 50 years or more, or at least one cardiovascular risk factor (microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or an ankle-brachial index of less than 0.9) in a patient aged 60 years or more.
All 4668 patients randomized to liraglutide and 4672 randomized to placebo were monitored for renal outcomes, specifically a composite of persistent macroalbuminuria, doubling of serum creatinine, development of end stage renal disease, or death due to renal disease. During a median follow-up of 3.84 years, significantly fewer patients treated with liraglutide than with placebo experienced the composite renal outcome (5.7% vs. 7.2%, p<.01). This difference was primarily driven by a reduction in new onset macroalbuminuria in the liraglutide group.
These results leave providers and patients with several questions. First, what is the clinical significance of this apparent decreased risk for macroalbuminuria? New-onset macroalbuminuria is considered an early indicator of diabetic nephropathy, and therefore is a surrogate outcome. The authors argue that a reduced risk for persistent macroalbuminuria could translate to reduced rates of chronic kidney disease over time among patients treated with liraglutide.
Next, how might the addition of liraglutide to usual care for type 2 diabetes reduce the risk of developing macroalbuminuria? While differences in HbA1c, body weight, and systolic blood pressure were identified between the groups (favoring liraglutide), subsequent analyses considering these factors did not significantly alter the composite renal outcome. The authors posit that liraglutide has a multifactorial mechanism of action, including a possible direct protective effect on the kidney.
Finally, can we apply this new information to our current practice for patients with type 2 diabetes? The LEADER study population consisted of patients with type 2 diabetes who were also at high risk for cardiac complications. Therefore, these results do not apply to patients without cardiac risk factors. The participants were followed for a maximum of 5 years, so long-term chronic kidney disease outcomes remain uncertain. As liraglutide will remain under exclusive patent in the United States for some years, cost may also pose an important barrier to widespread use.
You explain to Ms. Peters that several new medications, including liraglutide, appear to show promise in preventing certain heart and kidney complications of diabetes, but more research is needed to determine their long-term effects. You review Ms. Peters’ HbA1c results and her log of finger-stick glucose testing and decide to make some dose modifications in her current diabetes regimen. She leaves with a plan to return in 3 months to reassess her status and to consider whether starting a new medication such as liraglutide might be beneficial.