Liraglutide: The New LEADER for Second Line Therapy in Diabetes Management?

Cardiovascular disease is the leading cause of morbidity and mortality in patients with type 2 diabetes.¹ While many medications effectively treat the hyperglycemia and microvascular complications associated with diabetes, there has been a recent focus on medications that not only lower blood glucose but mitigate the risk of cardiovascular events.¹  The need for more data regarding the macrovascular safety of antidiabetic drugs entered the spotlight in 2008 when the FDA recommended that all antihyperglycemic agents be evaluated after concerns over cardiovascular harm observed with rosiglitazone.^1,2

According to the current (2016) ADA guidelines, no agent is “the preferred” second line therapy after metformin monotherapy — instead the benefits, risks, cost, and convenience of each option should be considered and treatment should be individualized.³ In contrast, the 2015 AACE/ACE Comprehensive Diabetes Management Algorithm recommends glucagon-like peptide-1 (GLP-1) receptor agonists and sodium glucose co-transporter-2 inhibitors (SGLT-2i) as second and third line options, respectively.⁴ The liraglutide and cardiovascular outcomes in type 2 diabetes (LEADER) trial, which assessed the long-term cardiovascular effects of liraglutide, a GLP-1 receptor agonist, comes at an interesting time shortly after the publication of the empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes (EMPA-REG OUTCOME) trial.^5,6  Both studies found a cardiovascular benefit. How, then, will the results of these trials affect the algorithm for type 2 diabetes management and more importantly, clinical practice?

The LEADER trial was a multicenter, double-blind, placebo-controlled trial initiated in September 2010 that enrolled 9,340 patients from 32 countries who were followed for 3.8 years (mean duration). Patients with type 2 diabetes who were at high risk for cardiovascular disease received either liraglutide 1.8mg subcutaneously daily (or the maximum tolerated dose) (N = 4,668) or placebo (N = 4,672).  Participants in both arms were also treated according to the standards of care for the management of diabetes, hypertension, and dyslipidemia. Inclusion criteria included: A1c ≥ 7%, age ≥ 50 years with at least one cardiovascular condition (CHD, CVD, PVD, CKD stage 3 or greater, or heart failure with NYHA class II or III symptoms), or age > 60 years with at least one cardiovascular risk factor (microalbuminuria/proteinuria, HTN and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or ankle-brachial index < 0.9). Major exclusion criteria were type 1 diabetes; use of GLP-1 receptor agonists, dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), pramlintide, or rapid-acting insulin; history of multiple endocrine neoplasia type 2 or medullary thyroid cancer; or an acute coronary/cerebrovascular event within 14 days.

The primary composite endpoint was the time to first occurrence of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. Secondary end points included the first occurrence of an expanded composite cardiovascular outcome, including cardiovascular death, nonfatal MI, nonfatal stroke, revascularization, hospitalization for unstable angina, or hospitalization for chronic heart failure. Exploratory outcomes included a composite of renal and retinal microvascular outcomes, neoplasms, and pancreatitis. Baseline characteristics were similar between groups. The typical patient in the LEADER trial was a 64-year-old Caucasian male with type 2 diabetes for 12.8 years, an A1c of 8.7%, and a BMI of 32.5 kg/m². Approximately 81% of enrolled patients had established CVD.  Only 19% of participants were older than 60 years with 1 or more CVD risk factors. Approximately 35% of enrolled patients had normal renal function (eGFR ≥ 90 mL/min/1.73 m²) and 42% had mild renal impairment (eGFR 60 – 89 mL/min/1.73 m²).⁵

The composite primary outcome occurred in fewer patients in the liraglutide group than in the placebo group (P < 0.001 for noninferiority; P = 0.01 for superiority). See Table 1.  This result was primarily driven by a reduction in death from cardiovascular causes (P = 0.007) rather than reductions in nonfatal MI or nonfatal stroke. Of note, death from any cause was also significantly lower in the liraglutide group (P = 0.02).  Overall rates of MI were lower in the liraglutide group as well (P = 0.046).⁵

Table 1. LEADER Primary Results⁵

^{*Reported 3-year NNT by LEADER study authors}

Liraglutide was also associated with a lower incidence of microvascular events, although this difference was driven by lower rates of nephropathy in the liraglutide group.⁵ See Table 2.

Table 2. LEADER Exploratory Results⁵

Significant improvements were also observed from baseline to 36 months with liraglutide when compared to placebo for weight loss (2.3kg) and systolic blood pressure (1.2mm Hg) but heart rate was increased by 3 beats per minute. In terms of adverse effects, the overall rates of neoplasms were numerically higher in the liraglutide group but the difference did not reach statistical significance. Pancreatic cancer occurred in 13 patients in the liraglutide group compared to 5 in the placebo group. There were no reported cases of medullary thyroid carcinoma in the liraglutide group and 1 in the placebo group. It is important to note that while liraglutide carries a Black Box Warning for thyroid carcinoma, this has yet to be seen in humans. Liraglutide was discontinued more frequently than placebo due to adverse effects (9.5% vs. 7.3%; p<0.001), primarily and unsurprisingly driven by gastrointestinal effects.

Interestingly, in a sub-group analysis, patients enrolled in North American centers did not appear to benefit from liraglutide treatment when compared to placebo (primary composite outcome HR 1.01; 0.84 – 1.22). This differed from patients from all other continents, where primary event rates were consistently lower in the liraglutide group (HR ranging from 0.62 to 0.83). There is no clear explanation for this finding.

One limitation of the LEADER trial its relatively short duration (mean of 3.8 years, range: 3.5 to 5 years), limiting the safety and efficacy data to that time frame. Patients enrolled in the study also had a relatively high baseline A1c of 8.7%, and thus results should cautiously be extrapolated to patients with better controlled diabetes.

Other subgroup analyses suggest a greater benefit from liraglutide therapy in patients with moderate renal disease [eGFR 30 – 59 mL/min/1.73 m2] as well as in patients with established CVD. Conversely, patients older than 60 years of age who did not have established CVD and patients with eGFR less than 30 or greater than 60 mL/min/1.73m² may not derive a benefit with liraglutide.  Of course, subgroup analyses should be taken with a grain of salt and are merely hypothesis generating.

The positive results of the LEADER trial come less than a year after the publication of the EMPA-REG OUTCOME trial, where the SGLT-2 inhibitor empagliflozin reduced the composite outcome of death from CV causes, nonfatal MI, or nonfatal stroke in patients with type 2 diabetes. However, in EMPA-REG OUTCOME, only patients with type 2 diabetes and previously established cardiovascular disease were enrolled. The positive results in EMPA-REG OUTCOME were driven by a reduction in death due to cardiovascular causes.³ The LEADER trial shows a similar reduction in the same composite endpoint, similarly driven by a reduction in CVD death, and with a similar benefit observed in patients with established CVD. However, the benefits from empagliflozin were observed earlier, within approximately 3 months, compared to 15 months in LEADER.⁶ Empagliflozin also significantly reduced hospital admission rates for heart failure — a similar benefit was not observed with liraglutide.

Given that liraglutide and empagliflozin have both demonstrated reductions in cardiovascular event rates in patients with type 2 diabetes and CVD, their respective side effect profiles may help guide decision-making when selecting an agent to add-on to metformin. Patients prone to mycotic infections, hypotension, or with lower eGFRs may benefit from liraglutide; conversely, patients with needle phobia, gastrointestinal issues, or a history of pancreatitis or medullary thyroid carcinoma might be better served by empagliflozin. It is important to keep in mind that the positive cardiovascular benefits of each of these trials do not extend to all other agents in these same medication classes. In-class differences can be seen with the recent FDA warning for increased risk of acute kidney injury (AKI) with canagliflozin and dapagliflozin, while EMPA-REG OUTCOME showed a reduction in rates of AKI with empagliflozin.^6,7 Similarly, the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial evaluated lixisenatide, a GLP-1 receptor agonist, and failed to show a cardiovascular benefit in patients with type 2 diabetes and recent acute coronary syndrome.⁸ [See Lixisenatide and Cardiovascular Outcomes: The Burden of Proof]  In contrast, the not-yet-FDA approved GLP-1 receptor agonist semaglutide demonstrated a cardiovascular benefit in the SUSTAIN-6 trial.⁹

The LEADER trial provides valuable data that can guide treatment decisions and liraglutide is an attractive option for many patients with type 2 diabetes at high risk for cardiovascular events.  Treatment guidelines will most assuredly change in 2017.  After metformin for the treatment of type 2 diabetes, has liraglutide become the new LEADER? What do you think? Given that positive cardiovascular data cannot be extrapolated to other GLP-1 receptor agonists, will liraglutide become the workhorse GLP-1 receptor agonist despite competition from once weekly regimens?