Amel Arnaout

Immune Checkpoint Inhibitor Therapy Associated Hypophysitis

Ipilimumab is a monoclonal antibody directed against CTLA4 T-lymphocyte antigen used as cancer therapy. Immune-related adverse events are common side effects and may include hypophysitis-related hypopituitarism. The clinical features of six patients with ipilimumab-induced hypophysitis (IH) are described. The clinical features of IH reported in clinical trials, including the incidence of IH by gender and the likelihood of adrenal axis recovery, are summarized. Following the development of IH, most patients remain on glucocorticoid replacement despite efforts to withdraw therapy. Analysis of gender information in published clinical trials suggests that men are more prone to developing IH than women, and few patients fully recover the pituitary-adrenal axis function. Ipilimumab and other drugs within its class are likely to be used to treat many forms of cancer. Endocrinologists should anticipate a significant increase in the incidence of autoimmune hypophysitis. Strategies for early detection of IH and long-term management should be considered.

Insights Into the Recognition and Management of SGLT2-Inhibitor-Associated Ketoacidosis: It's Not Just Euglycemic Diabetic Ketoacidosis

Sodium glucose cotransporter 2 inhibitors (SGLT2i) are a new class of agents for treatment of type 2 diabetes. Their primary action is to promote glucosuria by blocking glucose reabsorption at the proximal tubule. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada recommend SGLT2i use in patients with clinical cardiovascular disease as add-on therapy if glycemic targets are not met (1). This recommendation is based largely on the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPAREG OUTCOME) trial, which showed cardiovascular benefit in the empagliflozin arm (2). This will likely lead to increased prescribing of SGLT2i. Ketoacidosis is an adverse effect of SGLT2i use in patients with both type 1 and type 2 diabetes. A meta-analysis of 10 randomized control trials found a low incidence (0.1%) of diabetic ketoacidosis (DKA) in SGLT2i groups versus controls (3); however, these study populations may not represent SGLT2i users in clinical practice and may underestimate actual risk. A recent case series, including data from 3 institutions, found an incidence rate of 0.003% (39 cases of 11,197 patients taking SGLT2i) (4). Case reports describing SGLT2i-associated ketoacidosis (SAK) report near-normal glucose values (euglycemic ketoacidosis) at presentation, leading to delays in diagnosis and management. SGLT2i use is thought to reduce the threshold for development of ketoacidosis in the presence of precipitant causes, such as infections, surgical stress, poor oral intake and insulin reduction or omission (5,6). Several pathophysiologic mechanisms may explain the development of ketoacidosis with SGLT2i use, including lower insulin:glucagon ratios, stimulation of glucagon release and decreased urinary ketone body excretion (6). Reductions in insulin levels can be attributed to less glucose-mediated insulin secretion because glucosuria lowers serum glucose concentrations (7). Elevated glucagon levels are related to decreased paracrine inhibition by insulin and decreased SGLT2-mediated glucose transport into alpha cells (7,8). A study examining effects of dapagliflozin on human islet cells found that expression of SLC5A2, which encodes SGLT2 on pancreatic alpha cells, is downregulated, which may account for increased glucagon secretion because less glucose is sensed by alpha cells (9). Furthermore, SGLT2i-induced diuresis may exacerbate hypovolemia, leading to elevations in counterregulatory hormones that further drive lipolysis, ketogenesis and insulin resistance (5). Understanding the features of SAK has implications for diagnosis and management because the approach may differ from standard DKA management.

Diabetes Canada Position Statement for People with Types 1 and 2 Diabetes Who Fast During Ramadan

OBJECTIVE Fasting from dawn to dusk during Ramadan, including abstaining from water and food, is 1 of the pillars of Islam and is observed by the majority of Muslims. Most research concerning diabetes and fasting during Ramadan originates from Middle Eastern or South Asian countries; however, differences exist in hours of work and fasting, pharmacotherapy and blood glucose monitoring between these countries and Canada. METHODS An expert forum of 7 Canadian experts and 1 international expert collaborated to develop Canadian guidelines using the same evidence-based principles, with the exception of an independent methods review used for the Diabetes Canada clinical practice guidelines. Diabetes Canada scientific leadership and Canadian health-care providers performed independent external reviews. Religious leaders endorsed the position statement and provided letters of support. An informed patient participated in the position-statement development. Each recommendation was approved with 100% consensus of the expert forum. RESULTS Recommendations for risk stratification, education, pharmacotherapy and blood glucose monitoring for adults with type 1 and type 2 diabetes who intend to fast during Ramadan have been developed. CONCLUSIONS This is the first Canadian position statement on the topic of Ramadan fasting and diabetes. It was developed by an expert faculty and endorsed by Diabetes Canada, and provides guidance about pharmacotherapy and glucose monitoring for health-care providers so that they can assist Canadian Muslims living with diabetes to observe fasting during Ramadan safely.