Canadian Diabetes & Endocrinology Today

Addressing Inositol Use in PCOS Management

Alyse Goldberg — 2025-05-08

Polycystic ovary syndrome (PCOS) is a heterogeneous complex endocrine disorder characterized by oligo-ovulation, insulin resistance, and hyperandrogenism. Treatment should be individualized based on each patient’s symptoms and reproductive goals. Unfortunately, there is no pharmacologic medication that simultaneously promotes ovulation, improves metabolic health, and reduces clinical hyperandrogenism. Metformin is a well accepted, evidence-based pharmacologic therapy that targets the insulin resistance pathway and improves ovulatory frequency, but it has limited effects on clinical hyperandrogenism as well as poor tolerability for some patients. The growing interest in complementary therapies has highlighted the need for more tolerable and ‘non-pharmacologic’ treatment options. Inositol, a naturally occurring compound, has gained attention as a promising therapeutic agent for managing PCOS. This review aims to support shared decision-making between clinicians and patients by exploring the roll of inositol as a complementary therapy for PCOS management.

Diabetes Remission: Where are We Now?

Akshay Jain — 2025-05-08

Type 2 diabetes (T2D) poses a substantial global health burden. In 2023, we published an overview on the remission of T2D. Since then, additional long-term data has emerged regarding the outcomes associated with T2D remission, highlighting the importance of revisiting this topic. This article synthesizes findings from the landmark Diabetes Remission Clinical Trial (DiRECT), its 5-year follow-up, and recent studies exploring the enduring benefits of both short-term and sustained remission.

Glucagon-like Peptide-1 Receptor Agonists and Thyroid Cancer: Myth or Reality?

Ronald M. Goldenberg — 2025-05-08

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are being used increasingly for the management of type 2 diabetes mellitus (T2DM) or obesity because of their association with robust glucose lowering, weight loss, and cardiorenal benefits. The association between GLP-1RA treatments and thyroid cancer has been a topic of discussion since their early development with the understanding that GLP-1 receptors are present on rodent thyroid parafollicular cells (C-cells), and that GLP-1RAs can cause an increase in calcitonin, and both C-cell hyperplasia and medullary thyroid carcinoma (MTC). This data from rodent studies has led to GLP-1RAs being contraindicated in patients with a personal or family history of MTC or with multiple endocrine neoplasia syndrome type 2.

Despite this contraindication, the human relevance of GLP-1RA induced MTC in rodents has not been proven. Normal or hyperplastic C-cells in humans may not express the GLP-1 receptor, and studies of human MTCs have shown variable expression of the GLP-1 receptor. Studies have shown conflicting evidence regarding the expression of the GLP-1 receptor in human papillary thyroid cancer (PTC) cell lines: however, GLP-1RAs did not have significant effects on the proliferation of PTC cells.

Because of the data that potentially links GLP-1RAs to an increased risk of thyroid cancer, clinical studies in humans are important in addressing this issue. I will review the relevant data from human studies that have analyzed the potential link between GLP-1RA treatment and thyroid cancer, including pharmacovigilance and observational studies as well as randomized controlled trials (RCTs).

The Role of GLP-1R and GIPR Agonism in Heart Failure

Phelopater Sedrak — 2025-05-08

Heart failure (HF) is a clinical syndrome characterized by signs and symptoms of structural and functional cardiac abnormalities. It is corroborated by elevated N-terminal pro‑B‑type natriuretic peptide (NT-proBNP) levels and objective evidence of pulmonary or systemic congestion. More than 100,000 Canadians are diagnosed with HF annually. For years, HF has been classified based on left ventricular ejection fraction (LVEF). HF with reduced ejection fraction (HFrEF) refers to symptomatic HF with an LVEF <40%. However, if the LVEF is >50%, this is known as HF with preserved ejection fraction (HFpEF). In HFpEF, obesity is commonly implicated in the disease pathophysiology, and is present in up to 80% of people with this condition. Obesity contributes to concentric heart remodelling through mechanisms such as insulin resistance, diabetes, hyperlipidemia, visceral adipose tissue expansion, and myocardial steatosis. Additionally, obesity leads to a pro-inflammatory state which affects the vasculature and visceral organs.² Glucagon‑like peptide-1 receptor agonists (GLP‑1RAs), such as semaglutide, have shown promise in weight reduction across multiple Phase 3 clinical trials. Agents combining GLP-1RA and glucose-dependent insulinotropic peptide receptor (GIPR) agonism, such as tirzepatide, have also contributed to clinically significant weight loss. As such, their impact in addressing obesity‑related HFpEF is under investigation. This paper reviews the data on GLP-1RAs and tirzepatide in patients with HF across the LVEF spectrum, with a particular focus on those with HFpEF.

GLP-1 Receptor Agonist Use in Pregnancy

Irena Druce — 2025-05-08

As of 2018 data, 30–60% of reproductive‑aged women in Canada were affected by overweight (body mass index [BMI] 25.9–29.9) and obesity (BMI >30.0), and these rates are increasing. Obesity during pregnancy is associated with higher rates of preeclampsia, gestational diabetes, macrosomia, stillbirth, post‑term pregnancy, and increased caesarean delivery rates. Obesity is also associated with higher rates of diabetes, which has well‑known consequences for pregnancy, and ovulatory dysfunction, which impacts fertility, such as in polycystic ovarian syndrome (PCOS). Addressing obesity and its associated metabolic impacts could have a profound effect on reproductive and fetal health.

Since the 2000s, incretin-based therapies for diabetes and obesity have become the focus of research and clinical practice. Glucagon‑like‑peptide 1 (GLP-1), an endogenous incretin hormone secreted by intestinal L-cells in response to food intake, and its agonists, have been available for clinical use in Canada since the introduction of liraglutide in 2011. Recently, pharmacologic agonists of glucose-dependent insulinotropic polypeptide (GIP), an incretin synthesized in the K-cells of the duodenum and jejunum, have also become available. Dual agonism of these hormones is associated with more significant reductions in blood glucose and weight. The currently available incretin-based therapies are listed in Table 1, and their physiologic effects are summarized in Figure 1.

Active research is underway on new molecules, for example agonists of amylin and glucagon, in various combinations with GLP‑1 and GIP, to maximize clinical benefits. These combinations have shown weight loss effects rivalling those of metabolic surgery. Considering their potential, this medication class has taken the world by storm. Canada's Drug Agency (CDA) found that expenditure on injectable semaglutide, under the brand-name Ozempic™, increased from $13.5 million in 2019 to $227 million in 2021, with 20% of the claims being for non-type 2 diabetes use.

The metabolic improvements and weight loss achieved with incretin-based therapies are associated with improved fertility. While product monographs warn against use in pregnancy and lactation, conception while on these treatments is becoming more common. Considering this increasing reality, this review aims to summarize what is currently known about GLP-1 and GIP agonists and their effects during pregnancy.