Novo Nordisk's LEADER Trial’s Effect in the Diabetes Market

Diabetes should be thought of as systemic disease whose microvascular and macrovascular complications affect

many areas of the body, ranging from the eyes down to the feet. The most noteworthy macrovascular complication

of diabetes is the significantly increased risk for cardiovascular disease (CVD) and the consequent cardiovascular

adverse events, including coronary heart disease, stroke, and cardiovascular death. The risk of cardiovascular

adverse events in diabetics over the age of 40 with CVD risk factors has prompted current diabetes guidelines and

treatment algorithms to recommend the addition of lipid-lowering agents, primarily HMG-CoA reductase inhibitors, to

patients’ current treatment regimen to reduce 10-year coronary heart disease risk and CVD morbidity and mortality.

Novo Nordisk’s recent LEADER study aims to push its once daily, subcutaneous GLP-1 agonist, Victoza (liraglutide),

into the cardiovascular risk reduction ring. GLP-1 agonists are analogs of human GLP-1, a hormone that is produced

in response to food consumption and allows for the production of insulin, suppression of glucagon, and regulation of

satiety. Victoza’s efficacy in reducing glucose, hemoglobin A1c, and body weight have been established; however,

the cardiovascular safety has not been formally assessed. The LEADER study was conducted as a FDA guidance

issued late in 2008 recommended sponsors of antidiabetic therapies to demonstrate their therapy, “will not result in

an unacceptable increase in cardiovascular risk” (Guidance for Industry Diabetes Mellitus — Evaluating

Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes).

The LEADER study is a phase 3B, multicenter, international, randomized, double-blind, placebo-controlled clinical

trial that followed over 9000 type 2 diabetics, who had prior CVD or were at a high risk, for up to 5 years. The trial’s

objective was to compare the incidence of cardiovascular events between once daily Victoza and placebo when used

as add-on therapy. This was achieved with a primary endpoint of time from randomization to a composite outcome

of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. While the results

of the LEADER study will not be disclosed until the annual American Diabetes Association meeting in June 2016,

Novo Nordisk reports once-daily Victoza reduces the cardiovascular event rate in diabetics relative to their current

standard of care while still maintaining a safety profile consistent with its previous clinical trials. The mechanism of

action behind Victoza’s cardiovascular risk reduction seems to involve several direct and indirect effects but has not

yet been clearly defined; decreases in systolic blood pressure, triglycerides, cardiovascular risk biomarkers, and

weight as well as effects on cardiac myocytes are thought to be implicated.

The results of the LEADER study bode well for Novo Nordisk’s Victoza as the company has not provided significant

rebates for their product to payers and also faces losses in market share. However, given that the competing GLP-1

agonists have not yet released any cardiovascular safety data or have only shown a neutral effect, Victoza is primed

to differentiate itself from its competitors if and when the product receives an approved labeling claim for its

cardiovascular benefit. Once the full data is released, Victoza may solidify its position in healthcare providers’ minds

as a potential option as add-on therapy to metformin over the second-line oral antidiabetic agents. Still, Novo

Nordisk faces several hurdles if they aim to raise Victoza’s use within the diabetic population. For instance,

Jardiance (empagliflozin), an oral SGLT-2 inhibitor, has already demonstrated a statistically significant reduction in

major adverse cardiovascular events, though the data is not very robust, and is currently seeking a mortality

reduction claim. Endocrinology specialists also believe GLP-1 agonists may be used as an earlier second-line agent,

however the reality is very few patients’ diabetes is managed mainly by endocrinologists as opposed to primary care

physicians. For Victoza to become the first choice after metformin monotherapy, the LEADER study data must

demonstrate both statistically and clinically significant cardiovascular risk reductions. The magnitude of the

cardiovascular benefit of using Victoza must be able to overcome patients’ discomfort with injectable therapy, defeat

the stigma of its increased cost, and even spur changes in the way diabetes is managed in the primary care setting.

More information can be found here:

https://www.pharmamedtechbi.com/Publications/The-Pink-Sheet-Daily/2016/3/4/Will-Novos-LEADER-Trial-Move-

GLP1-To-The-Front-Line-In-HighRisk-Diabetes

http://www.ahjonline.com/article/S0002-8703(13)00450-X/fulltext#s0090