Pharmacology: Diabetes Lecture - PDF

PHARMACOLOGY: DIABETES Dr. Adam NMT200 Gratton MSc ND September 25, 2023 LECTURE COMPETENCIES 1. Compare and contrast the mechanisms of action, indications, and adverse effects of drugs to improve glycemic control A. Insulin B. Alpha-glucosidase inhibitors - acarbose...

PHARMACOLOGY: DIABETES Dr. Adam NMT200 Gratton MSc ND September 25, 2023 LECTURE COMPETENCIES 1. Compare and contrast the mechanisms of action, indications, and adverse effects of drugs to improve glycemic control A. Insulin B. Alpha-glucosidase inhibitors - acarbose C. Biguanides - metformin D. DPP4 inhibitors - sitagliptin E. GLP-1 receptor agonists – semaglutide, liraglutide F. Sulfonylureas - glyburide G. Meglitinides - repaglinide H. Thiazolidinediones - pioglitazone I. Sodium-Glucose Cotransporter 2 Inhibitors - canagliflozin 2. Recall commonly used medications that are known to cause dysglycemia INTRODUCTION Focus will be on type 2 diabetes (T2D) Key elements – insulin resistance resulting in insulin deficiency over time and hyperglycemia DRUGS THAT CAN CAUSE DYSGLYCEMIA Beta-blockers (drugs ending in –olol) Corticosteroids (prednisone) HMG-CoA Reductase Inhibitors (drugs ending in statin) Thiazide or loop diuretics (hydrochlorothiazide, furosemide) Protease antiviral medications Second-generation antipsychotics (olanzapine, quetiapine) GOALS OF THERAPY Control symptoms Establish and maintain glycemic control while avoiding hypoglycemia Prevent or minimize the risk of acute and chronic complications Achieve optimal control of associated risk factors such as hypertension, obesity, and dyslipidemia PHARMACOLOGIC CHOICES Important to emphasize that nonpharmacologic interventions (diet, exercise) and the role of self-monitoring are vital INSULIN Most available are human insulin and insulin analogues since they cause less antibody generation and adverse effects Generally classified by their onset of action and duration of action Rapid onset insulin preparation are useful for postprandial insulin injections or use with an insulin pump (continuous infusion) Long-acting insulin preparations are useful for basal insulin infusion ADVERSE EFFECTS Hypoglycemia is the most common and is usually the result of a missed meal or an increase in exercise Localized fat hypertrophy Allergic reactions BIGUANIDES Metformin Generally considered the first choice for patients with new and uncomplicated diagnosis of T2D Decreases hepatic glucose production Not associated with weight gain Lowers HbA1c by 1 – 1.5% ADVERSE EFFECTS Nausea, diarrhea, abdominal discomfort, anorexia, metallic taste May cause lactic acidosis in patients with existing hepatic or renal disease - contraindicated Vitamin B12 deficiency with long-term use Risk of hypoglycemia is low when used as monotherapy ALPHA-GLUCO SID ASE INHIB IT O R S Acarbose Inhibits intestinal alpha-glucosidases resulting in delayed digestion of starches and disaccharides which reduces postprandial glucose levels Does not significantly inhibit intestinal lactase ACARBOSE Requires TID dosing Only effective if taken with a meal Lowers HbA1c by 1% or less Hypoglycemic patients taking acarbose should be treated with glucose rather than sucrose Does not cause weight gain ADVERSE EFFECTS Flatulence, diarrhea, abdominal pain, cramps, nausea. May reduce metformin bioavailability Contraindicated in irritable bowel syndrome, inflammatory bowel disease D IPEPTIDYL PEPT ID ASE- 4 INHIB IT O R S Generic naming: -gliptin Sitagliptin Inhibit the enzyme responsible for the degradation of GLP-1 and other active peptides involved in glucose homeostasis Indirectly acts as an incretin mimetic D IPEPTIDYL PEPT ID ASE- 4 INHIB IT O R S Do not seem to alter cardiovascular risk Lower HbA1c by 1% or less Do not cause weight gain (considered weight neutral) ADVERSE EFFECTS Nasopharyngitis, hypersensitivity reactions Rare events of pancreatitis and severe joint pain Sitagliptin does not inhibit cytochrome P450 isozymes resulting in a low potential for drug interactions Low risk of hypoglycemia G LU C A G O N - L I K E P E P T I D E - 1 R E C E P T O R AGONISTS Semaglutide and liraglutide Direct incretin mimetics by acting on GLP-1 receptors Increases insulin secretion, suppresses postprandial glucagon secretion, slows gastric emptying, increases satiety G LU C A G O N - L I K E P E P T I D E - 1 R E C E P T O R AGONISTS Usually given by subcutaneous injection although there is an oral formulation of semaglutide Decrease HbA1c by 1 – 1.5% Do not cause weight gain (cause weight loss) Evidence suggesting prevention of cardiovascular events in both primary and secondary prevention patients ADVERSE EFFECTS GI adverse effects are common and nausea upon initiation is a common experience May also cause injection site reactions Rarely causes acute pancreatitis Caution in patients with heart rhythm disturbances and severe renal impairment Contraindicated in pregnancy and those with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 SULFONYLUREAS Glyburide Generic names often begin with gly or gli Considered an insulin secretagogue which stimulates both basal and meal-stimulated insulin release Generally considered add-on therapies to metformin rather than used as monotherapy SULFONYLUREAS Lower HbA1c by 1 – 1.5% Significant differences exist between the available drugs in this class in terms of effectiveness, risk of hypoglycemia, and weight gain Glyburide is associated with a higher risk of hypoglycemia and more weight gain Ability to reduce cardiovascular events is uncertain due to lack of evidence ADVERSE EFFECTS Weight gain; prolonged hypoglycemia. Risk of hypoglycemia may be greater compared with gliclazide and glimepiride, especially in elderly or patients with renal impairment beta-blockers may mask hypoglycemic symptoms MEGLITINIDES Repaglinide A different class of insulin secretagogues Stimulate insulin release but the activity is much shorter Effect and adverse effects are similar to those with sulfonylureas Lower risk of hypoglycemia in the context of skipped meals More extensive metabolic drug interactions S O D I U M - G LU C O S E C O T R A N S P O RT E R 2 INHIBITORS Canagliflozin Work by preventing glucose reabsorption in the kidneys which leads to enhanced glucose excretion Do not cause weight gain (causes weight loss) Lowers HbA1c by 1% or less S O D I U M - G LU C O S E C O T R A N S P O RT E R 2 INHIBITORS Shown to reduce the risk of cardiovascular mortality, major adverse cardiovascular events, and hospitalization due to heart failure Cause a small decrease in blood pressure Require sufficient kidney function to work; as kidney function declines so does the antihyperglycemic effect Shown to slow the progression of nephropathy ADVERSE EFFECTS Increased risk of genitourinary infections Reduced intravascular volume resulting in hypotension Hyperkalemia, Risk of diabetic ketoacidosis Use with loop diuretics increase risk of hypotension THIAZOLIDINEDIONES Pioglitazone This class acts as agonists at peroxisome proliferator-activated receptor gamma (PPARG) receptors located on the cell nucleus (particularly in adipose tissue) This influences gene expression including upregulation of GLUT4 transporters and lipoprotein lipase This enhances glucose reabsorption and hydrolysis of circulating triglycerides, respectively Precise mechanism is still unclear THIAZOLIDINEDIONES Increased peripheral glucose uptake Enhanced fat cell sensitivity to insulin Decreased hepatic glucose output Reduce HbA1c by 1 – 1.5% Associated with weight gain ADVERSE EFFECTS Increased incidence of heart failure likely because of their ability to cause increased fluid retention and edema Increase the risk of fractures (hip and wrist) Worsen macular edema ADVERSE EFFECTS To ensure that the risks and benefits of this medication have been clearly communicated, Health Canada requires that physicians counsel patients and obtain their written consent for all new and renewed rosiglitazone prescriptions SAMPLE QUESTION Which of the following medications is generally considered first-line therapy for most patients with type 2 diabetes? A. Glyburide B. Metformin C. Canagliflozin D. Semaglutide