1.1. Disease Prevalence/Incidence

Diabetes is a chronic, metabolic disease with significant health impacts on individuals and societies. The incidence of diabetes is increasing at a dramatic rate around the world. The International Diabetes Federation estimated that 371 million people worldwide had diabetes in 2012, and projected that this number would increase to 552 million by 2030.¹ The prevalence of diabetes in Canada was 6.8% (2.4 million Canadians) in 2009 and is expected to rise to 3.7 million people by 2019.² People with diabetes are more likely to be hospitalized and to experience complications requiring specialist care. By 2020, diabetes-associated costs to the Canadian health care system will be an estimated $16.9 billion per year.³

Ninety per cent of people with diabetes have type 2 diabetes mellitus (T2DM).⁴ T2DM is characterized by increased hepatic glucose output, reduced insulin secretion, and insulin resistance. It is generally diagnosed in adults older than 40 years of age, although increasingly it is being detected in adolescents and children. Diagnosis is based on an FPG level of ≥ 7.0 mmol/L, a two-hour plasma glucose level with a 75 g oral glucose tolerance test of ≥ 11.1 mmol/L, or a glycated hemoglobin (A1C) of ≥ 6.5%.¹

The thresholds for diagnosis have been established because they predict the development of retinopathy, which is one of the common microvascular complications of diabetes.¹ Other microvascular complications are nephropathy (which may progress to end-stage renal disease) and neuropathy (which may cause pain, tingling, gastroparesis, erectile dysfunction, or lower extremity peripheral vascular disease, often resulting in the need for amputation). The primary cause of blindness, end-stage renal disease, and non-traumatic amputation in Canadian adults is diabetes.¹ Cardiovascular disease (i.e., heart disease, stroke, and peripheral vascular disease) is a major macrovascular complication and is the leading cause of death in people with type 2 diabetes.²

1.2. Standards of Therapy

The Canadian Diabetes Association (CDA) 2013 clinical practice guidelines recommend a target A1C of 7% for most patients with type 2 diabetes, and fasting plasma glucose (FPG) and two-hour post-prandial glucose targets of 4 to 7 mmol/L and 5 to 10 mmol/L, respectively.¹ There are currently 11 classes of anti-hyperglycemic drugs approved for use in Canada: biguanides (i.e., metformin), sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, sodium-glucose cotransporter-2 (SGLT2) inhibitors, basal insulins, bolus insulins, and biphasic insulins. Metformin is recommended as the first-line oral antidiabetes drug for most patients with type 2 diabetes when glycemic control cannot be achieved by dietary and lifestyle interventions alone.¹ Because of the progressive nature of type 2 diabetes, patients treated with metformin may require additional therapies over time to maintain glycemic control. Recommendations regarding which drugs should be added to metformin vary, with some guidelines providing considerations for choosing between the available drug classes based on patient factors rather than recommending one drug class over another.¹ In 2013, CADTH published an updated Therapeutic Review assessing the comparative safety, efficacy, and cost-effectiveness of all available classes of anti-hyperglycemic therapies in the following clinical situations: (1) patients with type 2 diabetes with inadequate glycemic control on metformin monotherapy;⁵ and (2) patients with type 2 diabetes with inadequate glycemic control on metformin and a sulfonylurea.⁶

Based on this evidence, the Canadian Drug Expert Committee (CDEC) recommended the following:⁷

• A sulfonylurea should be added to metformin for most adults with type 2 diabetes who are inadequately controlled on metformin alone.
• Insulin-neutral protamine Hagedorn (NPH) should be added for most adults with type 2 diabetes inadequately controlled on metformin and a sulfonylurea.
• A DPP-4 inhibitor may be added to metformin and sulfonylurea therapy in circumstances in which patients with type 2 diabetes are unable to use insulin as a third-line option.

CDEC recommendations for DPP-4 inhibitors submitted to date to the CADTH Common Drug Review (CDR) have aligned with the above recommendations.^8–10 In addition, CDEC recommendations for other DPP-4 inhibitor/metformin (MET) fixed-dose combinations (FDCs) have aligned with the above recommendations.^11–13

1.3. Drug

Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory peptide, GIP) belong to the incretin class of gastrointestinal hormones. Incretins stimulate a decrease in blood glucose levels by causing increased post-prandial insulin release from the beta cells of the pancreas. GLP-1 also suppresses glucagon secretion and exhibits other glucoregulatory actions after secretion in the gut.¹⁴ DPP-4 is an enzyme that rapidly degrades, and thereby inactivates, both GLP-1 and GIP. DPP-4 inhibitors prolong the endogenous plasma levels and hence the activity of both of these key hormones.¹⁵ Alogliptin (ALO), a potent and highly selective DPP-4 inhibitor, is the fourth DPP-4 inhibitor to be introduced in Canada after sitagliptin, saxagliptin, and linagliptin. Kazano (ALO/MET) is the fourth DPP-4 inhibitor/metformin (MET) FDC introduced in Canada after saxagliptin/MET, linagliptin/MET, and sitagliptin/MET.

ALO/MET FDC is indicated to improve glycemic control in adult patients with type 2 diabetes mellitus (T2DM) as follows:

• As an adjunct to diet and exercise in patients inadequately controlled on metformin or in patients already being treated with the combination of alogliptin and metformin.
• In combination with pioglitazone when diet and exercise plus dual therapy with metformin and pioglitazone do not provide adequate glycemic control.
• In combination with insulin, when insulin and metformin do not provide adequate glycemic control.

Of note, unlike other DPP-4 inhibitor/MET FDCs available in Canada, ALO/MET FDC is not approved for use in combination with a sulfonylurea.

Upon submission, the manufacturer requested listing of ALO/MET FDC in a similar manner as other DPP-4 inhibitor/MET FDCs in Canada. While listing criteria for DPP-4 inhibitors vary somewhat across Canada, the indication listed in the following table was determined, in consultation with the manufacturer, to be of greatest relevance for listing decisions and are the focus of this review. Upon review of the draft CDR clinical and pharmacoeconomic reports, the manufacturer asked that the requested listing criteria be modified to reflect the indication under review.