The Canadian Diabetes Association Clinical Practice Guidelines (CPGs) for the Prevention and Management of Diabetes in Canada are formally updated in a 5-year cycle in order to provide comprehensive, evidence-based recommendations for healthcare professionals (1). However, interim updates are published in light of new evidence that is considered to be practice changing, as was the case following the publication of the Empagliflozin Cardiovascular Outcome Event (EMPA-REG OUTCOME) trial (2), which demonstrated the cardioprotective effect of empagliflozin in patients with type 2 diabetes and clinical cardiovascular disease. This interim update provides a revised recommendation based on the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (3).
Since the last update (4), a second publication from the EMPAREG OUTCOME trial has been published, reaffirming the clinical benefits of empagliflozin in patients with pre-existing cardiovascular disease (5). The first publication, in 2015, reported significantly fewer major adverse cardiovascular events in those taking empagliflozin compared to placebo, including lower rates of hospitalizations due to heart failure as well as to cardiovascular death and death from any cause (2). In a secondary analysis, empagliflozin was also associated with a significant reduction in hospitalizations for congestive heart failure (4.1% vs. 2.7%) (HR 0.65; 95% CI 0.50 to 0.85; p<0.002), corresponding to a number-needed-to-treat of 71 over 3 years or 213 per year (5). Although this finding is compelling, we await results from further trials of sodium/glucose co-transporter 2 (SGLT2) inhibitors to confirm this benefit.
Further analyses published in June 2016 now show a significantly lower risk for major adverse renal outcomes in those who received empagliflozin (6). After a median observation period of 3.1 years, participants in the pooled empagliflozin group had significantly fewer microvascular outcomes than those allocated to placebo, driven primarily by a reduction in progression to macroalbuminuria, a doubling of serum creatinine and initiation of renal replacement therapy, with relative risk reductions ranging from 38% to 55% (6).
The LEADER trial, published in June 2016, also demonstrated the benefits of the glucagon-like peptide 1 receptor agonist (GLP1 receptor agonist) liraglutide in a high-risk population of patients with type 2 diabetes similar to that of the EMPA-REG OUTCOME trial (3). The LEADER trial enrolled 9340 patients with long-standing type 2 diabetes (median duration 12.8 years) and glycated hemoglobin (A1C) levels ≥7%. The majority of participants (81%) were at least 50 years of age or older and had at least 1 co-existing cardiovascular condition (coronary heart disease, cerebrovascular disease, peripheral arterial disease, chronic heart failure or stage 3 or higher chronic kidney disease). The remaining participants were 60 years of age or older and had at least 1 co-existing cardiovascular risk factor. Participants were randomized to receive liraglutide 1.8 mg (or the maximally tolerated dose) or a matched placebo administered subcutaneously once daily in addition to standard care. Over a median follow up of 3.8 years, fewer patients in the liraglutide arm compared to placebo had the primary endpoint of nonfatalmyocardial infarction, nonfatal stroke or cardiovascular death (14.9% vs. 13%, respectively; HR 0.87, 95% CI 0.78 to 0.97), fulfilling both the statistical criteria for noninferiority (p<0.001) and for superiority (p=0.01). This finding corresponds to a number-needed-to-treat of 66 over 3 years or 198 per year. The rate of cardiovascular death and death from any cause was also significantly lower in the group receiving liraglutide compared with the group receiving placebo (4.7% vs. 6%; HR 0.78, 95% CI 0.66 to 0.93; and 8.2% vs. 9.6%; HR 0.85, 95% CI 0.74 to 0.97, respectively) as was the rate of microvascular endpoints, primarily because of fewer nephropathy events. Unlike the EMPA-REG OUTCOME trial, there was no significant reduction in hospitalizations for heart failure for people taking liraglutide.
Intermediary endpoints were also more favourable in the group receiving liraglutide; compared to placebo, the treatment group had a 0.4% lower mean A1C level, a 2.3 kg greater weight loss and a 1.2mm Hg lower systolic blood pressure. A greater number of participants in the liraglutide than the placebo group discontinued their medication due to adverse side effects (largely gastrointestinal). Acute gallstone disease was also more common in patients receiving liraglutide, whereas severe hypoglycemia was more common in the placebo group, likely due to greater use of insulin and sulfonylureas in this group.
The many strengths of the LEADER trial include its randomized, double-blinded placebo-controlled study design and near complete assessment of participants for study outcomes. Vital status was known in virtually all (99.7%) participants, and 96.8% had a final visit or study outcome or died. One limitation is that the study’s durationwas insufficient to make conclusions about long-term safety. For example, the study was not powered to evaluate the effects of liraglutide on cancer risk. There was a nonsignificantly higher number of cases of pancreatic cancer in the liraglutide group, but higher numbers of several nonpancreatic cancers in the placebo group. Overall, a very low number of pancreatic cancer events were observed (0.3% and 0.1% for liraglutide and placebo, respectively). Another limitation is that the study recruited participants over 50 years of age only, with or at high risk for cardiovascular events. Therefore, the study’s findings may not be generalizable to younger individuals with type 2 diabetes or those at lower cardiovascular risk. It is important to acknowledge that although the EMPA-REG OUTCOME trial permitted recruitment of participants younger than 50 years of age, the age distributions of the 2 studies were similar; only a small percentage of subjects in the EMPA-REG OUTCOME trial were younger than 50 years of age (2).
The subgroup analyses in the LEADER trial should be interpreted with caution, given the small number of patients and the few events observed. For example, the subgroup analysis of primary prevention suggested that this group had less benefit than those with pre-existing cardiovascular disease (3). However, no conclusion can be made about the safety and efficacy of liraglutide in primary prevention because the subgroup of 1742 subjects without cardiovascular disease (18.7% of the total) accounted for only 137 of the 1302 (10.5%) primary outcome events in the trial (3). Furthermore, only 8.9% of subjects had chronic kidney disease (glomerular filtration rate <60 mL/min/1.73m2) without cardiovascular disease, and the rate of events in this small subgroup was not reported. Also, only 3.9% of the population were antihyperglycemic agent-naive, accounting for only 4% of primary events, suggesting that the LEADER trial results are applicable only to patients requiring add-on antihyperglycemic agent therapy.
Given that LEADERwas a placebo-controlled trial and did not allow for head-to-head comparisons of various agents, no conclusions can bemadeabout howthe cardioprotective properties of liraglutide compared to other agents from a different class, such as empagliflozin, or to agents from the same class. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial did not demonstrate any cardiovascular benefit of lixisenatide in high-risk patients with type 2 diabetes (7). There were some notable differences in eligibility criteria between the 2 studies, leading to some differences in population characteristics. For example, baseline A1C levels were higher in participants enrolled in the LEADER trial than in those in the ELIXA trial. It is unknownwhether the variation in outcomes across studies is due to differences in trial design or in the cardiovascular effects of different drugs within the class of GLP1 receptor agonists. Finally, as is the case with most CV outcome studies, the ELIXA trialwas of insufficient duration to detect longer-term adverse effects, and the inclusion of relatively healthier patients in clinical trialsmay underestimate potential real-world harms of therapies.
The revised algorithm for the management of hyperglycemia in type 2 diabetes is summarized in Figure 1, which integrates the updated findings from the LEADER and EMPA-REG OUTCOME trials. As highlighted in the previous update, the presence of clinical cardiovascular disease and the effect of antihyperglycemic agents on cardiovascular outcomes should be considered the top priority in choosing add-on treatment regimens for patients with type 2 diabetes. The algorithm for management, as illustrated in the figure, now recommends that an antihyperglycemic agent with demonstrated cardiovascular outcome benefits, such as empagliflozin or liraglutide, should be added if glycemic targets are not met in patients with clinical cardiovascular disease. The figure provides further information about the agents that have cardiovascular outcome trial data and the results of such trials (superiority, neutrality or inferiority). As future cardiovascular outcome trials of antihyperglycemic agents are published, the guidelines committee will continue to assess new evidence and update recommendations and the algorithm.