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Pharmacologic Management of Type 2 Diabetes: 2016 Interim Update

      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 (
      • Booth G.
      • Cheng A.Y.Y.
      Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada: Methods.
      ). 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 (
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ), 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 (
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ).
      Since the last update (
      • Canadian Diabetes Association Clinical Practice Guidelines Expert Committee
      Pharmacologic management of type 2 diabetes: 2016 interim update.
      ), a second publication from the EMPA-REG OUTCOME trial has been published, reaffirming the clinical benefits of empagliflozin in patients with pre-existing cardiovascular disease (
      • Fitchett D.
      • Zinman B.
      • Wanner C.
      • et al.
      EMPA-REG OUTCOME trial investigators
      Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG OUTCOME trial.
      ). 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 (
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ). 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 (
      • Fitchett D.
      • Zinman B.
      • Wanner C.
      • et al.
      EMPA-REG OUTCOME trial investigators
      Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG OUTCOME trial.
      ). 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 (
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      ). 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% (
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      ).
      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 (
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ). 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 nonfatal myocardial 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 1.2 mm 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 duration was 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 (
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ).
      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 (
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ). 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 (
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ). Furthermore, only 8.9% of subjects had chronic kidney disease (glomerular filtration rate <60 mL/min/1.73 m2) 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 LEADER was a placebo-controlled trial and did not allow for head-to-head comparisons of various agents, no conclusions can be made about how the 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 (
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      ). 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 unknown whether 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 trial was of insufficient duration to detect longer-term adverse effects, and the inclusion of relatively healthier patients in clinical trials may 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.
      Figure 1
      Figure 1Revised algorithm for the management of hyperglycemia in type 2 diabetes.

      Recommendations (changes from earlier 2016 interim update are in bold)

      • 1.
        In people with a new diagnosis of type 2 diabetes:
        • i.
          Metformin may be used at the time of diagnosis, in conjunction with lifestyle management (Grade D, Consensus).
        • ii.
          If A1C <8.5% and glycemic targets are not achieved using lifestyle management within 2 to 3 months, antihyperglycemic agent therapy with metformin should be initiated (Grade A, Level 1A) (
          UK Prospective Diabetes Study (UKPDS) Group
          Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
          ).
        • iii.
          If A1C levels are ≥8.5%, antihyperglycemic agents should be initiated concomitantly with lifestyle management, and consideration should be given to initiating combination therapy with 2 agents, 1 of which may be insulin (Grade D, Consensus).
        • iv.
          Individuals with symptomatic hyperglycemia and metabolic decompensation should receive an initial antihyperglycemic regimen containing insulin with or without metformin (Grade D, Consensus).
      • 2.
        Metformin should be the initial drug used in monotherapy (Grade A, Level 1A) (
        UK Prospective Diabetes Study (UKPDS) Group
        Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
        ,
        • Holman R.R.
        • Paul S.K.
        • Bethel M.A.
        • et al.
        10-year follow-up of intensive glucose control in type 2 diabetes.
        ) for overweight patients (Grade D, Consensus for non-overweight patients).
      • 3.
        Other classes of antihyperglycemic agents, including insulin, should be added to metformin, or used in combination with each other, if glycemic targets are not met, taking into account the information in the figure and the table available at http://guidelines.diabetes.ca/update (Grade D, Consensus), and these adjustments to and/or additions of antihyperglycemic agents should be made in order to attain target A1C levels within 3 to 6 months (Grade D, Consensus).
      • 4.
        In adults with type 2 diabetes with clinical cardiovascular disease in whom glycemic targets are not met, an antihyperglycemic agent with demonstrated cardiovascular outcome benefit should be added to reduce the risk of major cardiovascular events (Grade 1, Level 1A for empagliflozin (
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        ); Grade 1, Level 1A for liraglutide if age ≥50 years (
        • Marso S.P.
        • Daniels G.H.
        • Brown-Frandsen K.
        • et al.
        Liraglutide and cardiovascular outcomes in type 2 diabetes.
        ); Grade D, Consensus for liraglutide if age <50 years).
      • 5.
        Choice of additional pharmacologic treatment agents should be individualized by patient's characteristics, taking into consideration (Grade D, Consensus):
        • Degree of hyperglycemia
        • Risk of hypoglycemia
        • Overweight or obesity
        • Cardiovascular disease or multiple risk factors
        • Comorbidities (renal, congestive heart failure, hepatic, etc.)
        • Preferences of the patient
        • Access to treatment
      • 6.
        When basal insulin is added to antihyperglycemic agents, long-acting analogues (detemir or glargine) may be used instead of intermediate-acting Neutral Protamine Hagedorn (NPH) to reduce the risk for nocturnal and symptomatic hypoglycemia (Grade A, Level 1A) (
        • Sumeet R.
        • Singh S.R.
        • Ahmad F.
        • et al.
        Efficacy and safety of insulin analogues for the management of diabetes mellitus: A meta-analysis.
        ,
        • Horvath K.
        • Jeitler K.
        • Berghold A.
        • et al.
        Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus (review).
        ,
        • Monami M.
        • Marchionni N.
        • Mannucci E.
        Long-acting insulin analogues versus NPH human insulin in type 2 diabetes: A meta-analysis.
        ).
      • 7.
        When bolus insulin is added to antihyperglycemic agents, rapid-acting analogues may be used instead of regular insulin to improve glycemic control (Grade B, Level 2) (
        • Manucci E.
        • Monami M.
        • Marchionni N.
        Short-acting insulin analogues vs. regular human insulin in type 2 diabetes: A meta-analysis.
        ) and to reduce the risk for hypoglycemia (Grade D, Consensus).
      • 8.
        All individuals with type 2 diabetes currently using or starting therapy with insulin or insulin secretagogues should be counselled about the prevention, recognition and treatment of drug-induced hypoglycemia (Grade D, Consensus).

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