Disease Prevalence and Incidence
Diabetes mellitus is a metabolic disease that is characterized by persistent elevations in blood glucose or hyperglycemia. There are two main subtypes of diabetes mellitus: type 1 diabetes mellitus, which is caused by inadequate secretion of insulin from pancreatic beta cells, and type 2 diabetes mellitus (T2DM), which results from cells that are unresponsive to the insulin that is produced. T2DM is more common than type 1, accounting for approximately 90% of cases of diabetes mellitus.1
The etiology of diabetes mellitus is associated with genetic factors and environmental triggers are believed to play a role in the development of disease.17 Onset of T2DM typically occurs around 40 years of age or older,18 although this is changing with the increase in obesity and sedentary behaviours leading to more frequent diagnosis of T2DM in children and younger people.19 Poor diet, minimal exercise, and associated weight gain are considered major risk factors for T2DM.20 Patients with T2DM who in the initial stages of their disease are able to secrete insulin but who are hyperinsulinemic, may progress to a stage where insulin secretion is reduced, similar to type 1 diabetes mellitus. As described by the patient input received for this report (Appendix 1), common symptoms of diabetes include extreme fatigue, unusual thirst, frequent urination, and weight change. More serious complications may present for patients with poor blood glucose control. For example, low blood glucose may cause confusion, coma, or seizures. High levels of glucose may lead to more long-term issues such as damage to the nerves and blood vessels, which increases the risk of blindness, heart disease, kidney disease, and damage to the extremities. Patients also report that diabetes has a great impact on patients’ emotional, social, and economic status.
Diabetes has a significant impact on both individuals and societies. The prevalence of diabetes is increasing at a dramatic rate around the world. In a report produced by the World Health Organization, there was an estimated 422 million adults living with diabetes globally in 2014, up from 108 million in 1980.19 Further, this number is projected to increase to 693 million by 2045 if the current trends continue.17 Diabetes is also a significant problem in Canada, as one of the most common chronic diseases in the country. Diabetes Canada estimated that 3.5 million people (9% of the population) were living with diabetes in 2018, and that this number will increase to 4.7 million people (11%) by 2028.2 People with diabetes are more likely to be hospitalized and to experience complications requiring care by a specialist. It is estimated that, by 2020, the direct and indirect costs of diabetes for the Canadian health care system will increase to C$16.9 billion per year.18
Standards of Therapy
Treatment regimens and therapeutic targets should be individualized in patients with T2DM due to the heterogeneous nature of the disease. Initial treatment often consists of lifestyle modifications through diet and exercise. When blood glucose levels are not adequately controlled by lifestyle modifications alone, pharmacological treatment becomes necessary.3 There are many classes of antihyperglycemic agents used to treat T2DM, which include both insulin and noninsulin therapies.3 Metformin (MET) is considered first-line therapy and is indicated for most patients. If treatment through lifestyle modifications and MET monotherapy fail to achieve adequate glycemic control, a second or third agent may be added in addition to MET.
There are several oral antidiabetic drugs (OADs) that may be used with MET, such as sulfonylureas (SU), meglitinides, thiazolidinediones (TZD), alpha-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose cotransporter-2 (SGLT2) inhibitors. Injectable agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists, and insulin and insulin analogues (rapid-acting, intermediate, or long-acting forms), may also be considered as an add-on to MET, or patients can be switched to insulin.4 However, according to the 2018 Diabetes Canada Clinical Practice Guidelines (DCCPG), it is recommended that DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors be considered first as hypoglycemia and weight gain are less of an issue with these agents, provided contraindications, accessibility, and affordability are considered.3
Although there are currently numerous therapeutic options and combination therapy strategies available, none of the available therapies are curative and many patients still have difficulty achieving adequate glycemic control.21 Further, there are certain disadvantages to consider with some of the options, such as weight gain or hypoglycemia associated with the use of TZDs, SUs, and insulin.3,22 In contrast, some agents, such as SGLT2 inhibitors and GLP-1 receptor agonists, may be advantageous in terms of cardiovascular (CV) effects, which is a particular concern as CV effects are common and a leading cause of death among those with diabetes.4,23,24
It is recommended that the selection of a second agent is patient specific, and based on the efficacy and safety profile of available agents.3 This includes various factors, such as the effectiveness of an agent at lowering blood glucose and glycated hemoglobin (A1C), concerns regarding hypoglycemia, effects on body weight, and the ability to reduce the risk of diabetic microvascular and/or CV complications.3 Additional considerations include patient’s renal function, other comorbidities, planning pregnancy, cost and coverage, ease of administration, and patient preference.3
Drug
Semaglutide (SEM) is a selective long-acting GLP-1 receptor agonist that mimics or acts on the same receptor as endogenous hormone incretin.5 In doing so, SEM increases glucose-dependent insulin secretion and decreases glucagon secretion, while also slowing gastric emptying. Overall, this increases first- and second-phase insulin secretion with the expectation of improved glycemic control.5,6,25 SEM received Health Canada Notice of Compliance (NOC) in January 4, 2018. As per the Health Canada–approved product monograph, SEM is indicated for the improvement of glycemic control in adult patients with T2DM via once-weekly treatment, in combination with diet and exercise when MET is inappropriate due to contraindications or intolerance, or when adequate glycemic control has not been achieved with diet and exercise plus: the maximum tolerated dose of MET, dual therapy with MET and a sulfonylurea (SU), or dual therapy with basal insulin and MET.6
The recommended route of administration for SEM is subcutaneously in the abdomen, thigh, or upper arm.6,25 It is available as a pre-filled multi-dose pen delivering doses of 0.25 mg or 0.5 mg, as well as a pre-filled pen that delivers a dose of 1 mg.6 It is recommended that a patient begins with a once-weekly sub-therapeutic dose of 0.25 mg, followed by an increase to 0.5 mg per week after four weeks. For patients that require additional glycemic control after four weeks, the dose may be increased to 1 mg once weekly, which is the maximum recommended dose.6,25
Other GLP-1 receptor agonists currently approved in Canada are dulaglutide, exenatide, liraglutide, and lixisenatide.
Key characteristics of currently available antihyperglycemic therapies are presented in .
Key Characteristics of Available Antihyperglycemic Agents.
