North York General Hospital
LMC Diabetes & Endocrinology Centre
The clinical practice guidelines published by the Canadian Diabetes Association (CDA)1 provide clear recommendations regarding not only the glycemic targets that should be set for patients with type 2 diabetes, but also the timeframe in which therapy should be initiated and in which glycemic targets should be reached.
The guidelines specify that therapy should be targeted to achieve A1C goal in order to reduce the risk of microvascular complications and, if started early in the course of disease, macrovascular complications. They further specify that timely adjustments to therapy should be made in order to attain target A1C within 3 to 6 months.
Unfortunately, the Diabetes Mellitus Status in Canada (DM-SCAN) survey2 demonstrated that A1C targets remain elusive for many patients.
In the DM-SCAN survey, which included 5,123 patients with type 2 diabetes seen in primary care only about 50% of subjects were observed to achieve an A1C goal of 7% or less (Figure 1). This result is even more striking when one considers that the median duration of diabetes among DM-SCAN subjects overall was 8.5 years.
Primary-care physicians can take an active role on the front lines of diabetes care in Canada, and can help to close this care gap by setting A1C goals for their patients and guiding therapy in a timely fashion towards these goals. As mentioned, the goal is to attain A1C target within 3 to 6 months.
Motivating patients to be actively involved in their own diabetes management can be a major challenge. Primary-care physicians should read the chapters from the CDA guidelines (available at ) on “Organization of Diabetes Care” and on “Self-management Education” to learn more about effective strategies such as motivational interviewing and the types of training that can be most effective in helping patients manage their diabetes.
According to the CDA guidelines,1 optimal glycemic control is a cornerstone of diabetes management, and in epidemiological studies A1C levels greater than 7% are associated with significantly increased risk of microvascular and macrovascular complications, regardless of underlying treatment.
As detailed in the guidelines, glycemic targets should be individualized based on a patient’s age, duration of diabetes, risk of severe hypoglycemia, risk of coronary ischemic events, and life expectancy.
As shown in Figure 2, for most patients, an A1C target of ≤ 7% is suitable in order to reduce the risk of microvascular complications and, if implemented early in the course of disease, macrovascular complications.
A target of ≤ 6.5% may be considered in some patients in order to further lower the risk of nephropathy and retinopathy, but this must be balanced against the risk of hypoglycemia. This more intensive target may be suitable for patients with shorter duration of diabetes, no evidence of significant cardiovascular disease (CVD), and longer life expectancy.
Finally, a less stringent A1C target of 7.1% to 8.5% could be appropriate in patients fitting any of the characteristics or scenarios listed in Figure 2, such as those with limited life expectancy, higher level of functional dependency, extensive CAD at high risk of ischemic events, multiple comorbidities, history of recurrent severe hypoglycemia, hypoglycemia unawareness, and longstanding diabetes in which it is difficult to achieve an A1C ≤ 7% despite effective doses of multiple antihyperglycemic agents, including intensified basal-bolus insulin therapy.
In 2016, the CDA published two interim updates to their recommendations regarding pharmacologic management of type 2 diabetes.3,4.
The initial choice of pharmacotherapy—started at diagnosis along with lifestyle interventions or at 2-3 months if glycemic targets are not met with lifestyle changes alone—remains metformin.
Pharmacotherapy should then be adjusted with the goal of attaining target A1C within 3 to 6 months.
Choice of additional pharmacotherapy is to be individualized based on patient characteristics, with priority given to the presence of clinical CVD, with other considerations including the degree of hyperglycemia; risk of hypoglycemia; overweight or obesity; CVD or multiple risk factors; comorbidities such as renal disease, congestive heart failure or hepatic disease; and patient preferences regarding, and/or access to, treatment.
The authors of the 2016 updates point out that several trials examining cardiovascular outcomes in type 2 diabetes have now demonstrated the overall CV safety of three DPP-4 inhibitors (alogliptin, saxagliptin and sitagliptin). In respective trials of these agents, noninferiority of the primary CV composite endpoints was achieved, while saxagliptin demonstrated an unexpected increase in heart-failure hospitalization that led the CDA authors to recommend caution with this specific agent in patients with heart failure.
More recently, the SGLT2 inhibitor, empagliflozin, demonstrated CV superiority in the first CV-outcome trial of this class of agents. It is important to note that these results were observed among patients with clinical CVD, A1C 7-10%, and eGFR > 30 mL/min, and therefore should not be extrapolated to patients without established CVD. In the EMPA-REG OUTCOME trial,5 patients with clinical CVD included those with prior myocardial infarction, CAD, unstable angina, stroke or occlusive peripheral arterial disease. Although the first CV outcome trial with a GLP-1R agonist was neutral (lixisenatide in ELIXA6), the results of the recent LEADER trial with liraglutide (a GLP-1R agonist)7 showed that this agent was associated with lower risk of CV outcomes than placebo. Patients included in LEADER had to be aged 50 years or older with known CVD, or aged 60 years or older with at least one CV risk factor, but the CV benefit was mainly confined to the patients in the established CVD cohort.
The recent CV outcome trials have been reflected in the guidelines, and antihyperglycemic agents with demonstrated CV outcome benefit (empagliflozin, liraglutide) are now the agents of choice for adding to the treatment regimen in patients with clinical CVD who are not at glycemic target. Furthermore, CV outcome trial results are now reflected in a new column in the CDA treatment algorithm, labelled “Effect in CV outcome trial” (Figure 3).
In the DM-SCAN survey,2 patients with known CAD represented only 22.5% of the type 2 diabetes population; and in a large U.S. database,8 only 16% of patients with type 2 diabetes met EMPA-REG OUTCOME eligibility criteria.
The authors of the CDA guidelines employ the principles of evidence-based medicine, and these principles dictate that the results of clinical studies should be applied only to relevant patient populations.
As shown in Figure 3, the treatment approach is to be individualized following a simple algorithm.4
Lifestyle intervention is the cornerstone of therapy and should continue at each stage of treatment.
Metformin is the initial drug of choice, and may be started at diagnosis or added if lifestyle interventions do not achieve glycemic targets. Thereafter, if patients are not at glycemic targets and do not have clinical CVD, choice of additional pharmacotherapy is to be individualized based on patient characteristics, including the degree of hyperglycemia; risk of hypoglycemia; overweight or obesity; CVD or multiple risk factors; comorbidities such as renal disease, congestive heart failure or hepatic disease; and patient preferences regarding, and/or access to, treatment.
Before initiating any antihyperglycemic therapy, clinicians should take into account the patient’s individual needs and the therapeutic considerations listed by the guideline authors in this table.
The guidelines indicate that timely adjustments should be made, with the goal of attaining A1C target within 3 to 6 months.
1. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013; 37(Suppl 1): S1-S212
2. Grenier J, Leiter LA, Langer A, et al. Glycaemic control and cardiovascular risk factor management in patients with diabetes with and without coronary artery disease: insights from the Diabetes Mellitus Status in Canada survey. Eur Heart J 2016; [epub ahead of print].
3. Goldenberg R, Clement M, Hanna A, et al, for the Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Pharmacologic management of type 2 diabetes: 2016 interim update. Can J Diabetes 2016; [epub ahead of print.
4. Booth G, Lipscombe L, Butalia S, et al, for the Steering Committee for the Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Pharmacologic management of type 2 diabetes: 2016 interim update. Can J Diabetes 2016; 40:484-6.
5. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373:2117-28.
6. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015; 373(23):2247-57.
7. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375(4):311-22.
8. Arnold SV, et al. Presented at EASD 2016. Poster 729.
Development of this article was made possible through the financial support of Merck Canada Inc. The opinions expressed herein are those of the author and do not necessarily reflect the views and opinions of Merck Canada Inc. The author had complete editorial independence in the development of this article and is responsible for its accuracy. The sponsor exerted no influence in the selection of content or material published.