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Questions and Answers
What percentage of dietary fat absorption does orlistat reduce?
What is the most common adverse effect associated with orlistat?
Which condition is a contraindication for the use of orlistat?
How does GLP-1 affect food intake and appetite?
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What should patients taking orlistat do to mitigate the decreased absorption of fat-soluble vitamins?
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Which hormone is primarily responsible for the glucose-induced insulin secretory response during glucose ingestion?
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In what way does liraglutide primarily induce weight loss?
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What is a caution for patients taking incretin mimetics like liraglutide?
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What is the primary goal of anti-obesity therapy?
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Which medication is specifically indicated for weight management and is a sympathomimetic?
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What adverse effects are commonly associated with bupropion?
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For which BMI is bupropion/naltrexone indicated for weight management?
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Which class of drugs is NOT associated with weight gain as an adverse effect?
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What is the average weight gain associated with corticosteroid therapy after 6 months?
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What is one of the common side effects experienced with the combination of bupropion and naltrexone?
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What crucial caution must be taken before initiating treatment with bupropion/naltrexone?
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What is the role of lifestyle modifications in anti-obesity therapy compared to medications?
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Which of the following medications is associated with the highest average weight gain during therapy?
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What is the primary mechanism of action of metformin in diabetes management?
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Which adverse effect is most commonly associated with insulin therapy?
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Which class of medications is primarily known to delay the digestion of carbohydrates?
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What is the significant risk associated with long-term use of metformin?
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Acarbose requires dosing at which frequency for optimal effectiveness?
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Which medication class is contraindicated in patients with existing hepatic or renal disease due to the risk of lactic acidosis?
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What is a characteristic of Dipeptidyl Peptidase-4 inhibitors like sitagliptin?
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Which medication can cause dysglycemia as a side effect, particularly the ones ending in -olol?
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Which of the following medications is primarily indicated for improving postprandial glucose control?
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Which adverse effect is commonly associated with glucagon-like peptide-1 receptor agonists?
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What is a notable difference between the effects of thiazolidinediones and biguanides?
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What best describes the mechanism of sulfonylureas?
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What is the primary goal of pharmacotherapy in the management of type 2 diabetes?
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Which of the following medications is contraindicated in individuals with a history of medullary thyroid carcinoma?
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How much can glucagon-like peptide-1 receptor agonists decrease HbA1c?
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Which statement is true regarding the use of metformin in patients with irritable bowel syndrome?
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What is a noted conclusion regarding the effectiveness of sulfonylureas?
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Which of the following statements about the potential drug interactions of sitagliptin is accurate?
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Which of the following statements about meglitinides is accurate?
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What effect do sodium-glucose cotransporter 2 inhibitors have on body weight?
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Which of the following adverse effects is specifically increased by thiazolidinediones such as pioglitazone?
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For which patients is the risk of hypoglycemia greater when using gliclazide or glimepiride?
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What is a key outcome of sodium-glucose cotransporter 2 inhibitors besides enhanced glucose excretion?
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What is the primary mechanism of action for thiazolidinediones?
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Which adverse effect is associated with the use of sodium-glucose cotransporter 2 inhibitors?
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What outcome is likely when using thiazolidinediones for patients with existing heart failure conditions?
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Which statement accurately describes the effect of Dipeptidyl Peptidase-4 inhibitors like sitagliptin on cardiovascular risk?
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What is a common gastrointestinal adverse effect associated with glucagon-like peptide-1 receptor agonists?
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What is a key characteristic of sulfonylureas like Glyburide in diabetes management?
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Which of the following is a notable risk associated with the use of Glyburide?
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What is the likely impact of glucagon-like peptide-1 receptor agonists on body weight?
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Which condition is a contraindication for the use of glucagon-like peptide-1 receptor agonists?
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How do Dipeptidyl Peptidase-4 inhibitors like sitagliptin affect HbA1c levels?
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What mechanism of action do glucagon-like peptide-1 receptor agonists employ to manage diabetes?
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Which medication class is primarily associated with an increased risk of lactic acidosis?
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What is the mechanism by which acarbose lowers postprandial glucose levels?
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Which of the following is a common adverse effect of metformin?
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What is a key consideration when managing dysglycemia caused by acarbose?
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Which medication class has a risk of causing hypoglycemia primarily when combined with certain other medications?
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Which of the following medications is least likely to cause weight gain?
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What is an important goal of treatment in diabetes management beyond glycemic control?
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Which class of drugs is known to potentially contribute to insulin resistance as a side effect?
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Which statement best describes the role of insulin in diabetes management?
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What is a common characteristic of drugs that end with -olol?
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What is a unique characteristic of meglitinides compared to sulfonylureas?
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Which of the following best describes the mechanism of action of thiazolidinediones?
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What is a significant adverse effect associated with sodium-glucose cotransporter 2 inhibitors?
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How do beta-blockers affect hypoglycemia symptoms in patients using insulin secretagogues?
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Which outcome is most likely affected negatively by the use of thiazolidinediones?
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To what extent do sodium-glucose cotransporter 2 inhibitors lower HbA1c?
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In patients with renal impairment, which of the following medications would likely be less effective?
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What is the mechanism through which pioglitazone primarily influences glucose metabolism?
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What is the appropriate initial dose of levothyroxine for a patient weighing 102 kg with a TSH level of 21.3 U/mL?
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How should the dose of desiccated thyroid be calculated based on a patient's levothyroxine dosage?
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What BMI category does a patient with a weight of 102 kg and a height of 172 cm fall into?
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Which of the following factors must be considered when determining the levothyroxine dose for patients?
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What should be the primary consideration when prescribing levothyroxine for a patient with mild TSH elevation and mild symptoms?
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What is the average replacement dose of levothyroxine for an adult based on body weight?
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Which initial dosage of levothyroxine may be appropriate for patients with mild or subclinical hypothyroidism?
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What effect can levothyroxine have if it is overtaken in dosages?
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Which of the following medications should be taken at least 6 hours apart from levothyroxine to ensure proper absorption?
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In patients with negligible thyroid function, which dose of levothyroxine may be necessary?
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What factors can influence the adjustment of levothyroxine dosing?
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What potential adverse effect may arise from using desiccated thyroid therapy?
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Which administration timing is recommended for levothyroxine to optimize its effects?
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What is the primary action of methimazole in the treatment of hyperthyroidism?
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In which situation is propylthiouracil preferred over methimazole?
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Which of the following is a common adverse effect associated with antithyroid agents like methimazole?
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What is a potential adverse effect of using radioactive iodine treatment?
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What distinguishes propylthiouracil from methimazole regarding thyroid hormone action?
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Which of the following statements about beta blockers in hyperthyroid treatment is correct?
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Which factor is crucial when prescribing levothyroxine?
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What is the mechanism of action of radioactive iodine in treating thyroid conditions?
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Which adverse effect is NOT commonly associated with propylthiouracil?
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What condition can develop as a result of poorly managed hyperthyroidism leading to thyrotoxicosis?
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Study Notes
Introduction
- Obesity is a complex chronic condition with no single solution.
- Psychosocial, emotional, and physical barriers can hinder patients from engaging in obesity management strategies.
- Currently, no cure exists for obesity.
Goals of Therapy
- Aim is to reduce excess body fat for health and not for cosmetic reasons.
- Reducing weight by 5-10% yields significant health benefits.
- Stabilize and prevent further weight gain.
- Prevent weight regain.
- Prevent and treat obesity-related comorbidities and complications.
Treatment Phases
- Induction of weight loss through caloric restriction.
- Prevention of weight regain by countering neurobehavioural changes that attempt to restore original body weight.
Drugs Associated with Weight Gain
-
Antidepressants:
- Tricyclic antidepressants, particularly amitriptyline, associated with approximately 1.8 kg weight gain in the first 3 months of therapy, with slower increases thereafter.
-
Antipsychotics:
- First and second-generation antipsychotics can lead to weight gain between 9 and 12 kg.
-
Corticosteroids:
- Prednisone, for instance, can cause an average of 2 kg weight gain during a 6-month daily course of therapy.
-
Antihyperglycemic drugs:
- Sulfonylureas, meglitinides, and thiazolidinediones can cause up to 5 kg weight gain over 3-12 months of treatment.
- Insulin can lead to up to 8 kg weight gain during an intensive 3-month course of therapy.
-
Lithium:
- Used for mania treatment, can lead to 10 kg or more weight gain within 6-10 years of therapy.
Pharmacologic Choices
- Lifestyle modification combined with anti-obesity therapy is superior to lifestyle modification alone in achieving a 5-10% weight loss target over the long term.
- Discontinuing anti-obesity medication generally results in weight regain.
Appetite Suppressants
-
Bupropion: Sympathomimetic drug, available in sustained-release formula.
- Used as an antidepressant and smoking cessation aid.
- 300 mg for 24 weeks associated with a net weight loss of 2.2%.
- 400 mg associated with 5.1% weight loss.
- Weight loss maintained for 48 weeks.
-
Bupropion/Naltrexone: Indicated for weight management alongside diet and exercise for individuals with a BMI of 30 or higher (or 27 with weight-related comorbidity).
- Mediates hormones involved in appetite and reward.
- Net weight loss of 4.2% over 48 weeks.
Adverse Effects - Bupropion
- Dry mouth, constipation, agitation, insomnia, and anxiety.
- Can cause seizures in rare instances with higher doses.
- Caution in patients with hepatic impairment.
Adverse Effects - Bupropion/Naltrexone
- Nausea, vomiting, constipation, headache, dizziness, insomnia, and dry mouth.
- Contraindicated with concurrent opioid therapy due to the risk of precipitating opioid withdrawal.
- Patients must be opioid-free for 7 days before initiating treatment.
Cautions - Bupropion/Naltrexone
- Avoid concurrent use of drugs that lower the seizure threshold.
- Minimize or avoid alcohol consumption.
- Avoid consuming a high-fat meal while taking the medication.
- Avoid in patients with uncontrolled hypertension, seizure disorder, severe hepatic impairment, or end-stage renal failure.
Lipase Inhibitors
-
Orlistat: Pancreatic and gastric lipase inhibitor that reduces dietary fat absorption by 30%.
- For a typical diet of 60g of fat per day, it reduces fat absorption by 180 kcal/d.
- Compared to placebo, orlistat leads to an additional 2.9% weight loss over a year.
Orlistat - Adverse Effects
- Oily spotting, flatus with discharge, and fecal urgency.
- Decreased absorption of fat-soluble vitamins.
Orlistat - Cautions
- Contraindicated in patients with chronic malabsorption syndrome or cholestasis.
- Advise patients to take a daily multivitamin at least 2 hours before or after orlistat, or before bedtime.
- A high-fat intake is poorly tolerated.
- Less effective in individuals on low-fat diets and difficult to take for those with irregular eating patterns.
Incretin Mimetics
- The two major incretin hormones in humans are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).
- They are responsible for most of the glucose-induced insulin secretory response following glucose ingestion.
- Both are metabolized by the enzyme dipeptidyl peptidase 4 (DPP4).
GLP-1
- Responsible for reducing food intake and appetite, increasing satiety, and decreasing gastric emptying.
- Affects reward-related systems in the brain.
GIP
- Has less effect on other organs.
- Delays gastric emptying and may play a role in fat deposition.
Liraglutide
- GLP-1 agonist administered via subcutaneous injection.
- Originally approved for type 2 diabetes but rebranded for obesity.
- 3 mg subcutaneously can induce 8 kg weight loss over 2 years of therapy in conjunction with lifestyle measures.
Liraglutide - Adverse Effects
- Nausea, vomiting, constipation, and diarrhea are most common.
- Gastrointestinal side effects can be minimized by slow titration.
- Can cause pancreatitis in rare instances.
- Severe hypoglycemia may be observed in patients with type 2 diabetes; adjustments to diabetes medications may be required.
Liraglutide - Cautions
- Caution in patients with heart rhythm disturbances, hepatic insufficiency, and severe renal impairment.
- Should not be used in patients with inflammatory bowel disease.
- Contraindicated in pregnancy, breastfeeding, and individuals with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN 2).
- Discontinuation after 12 weeks if no body weight loss is observed.
Drugs Causing 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 diabetes symptoms
- Establish and maintain glycemic control, avoiding hypoglycemia
- Prevent or minimize long-term complications of diabetes
- Achieve good control of associated risk factors like hypertension, obesity, and dyslipidemia
Pharmacologic Choices
- Nonpharmacologic interventions (diet, exercise) and self-monitoring are essential
Insulin
- Human insulin and insulin analogues cause fewer antibodies and side effects.
- Different types are categorized by onset of action and duration of action.
- Rapid-acting insulin preparations are useful for postprandial injections or use with an insulin pump.
- Long-acting insulin preparations are useful for basal insulin infusion.
Insulin Adverse Effects
- Hypoglycemia (most common) due to missed meals or increased exercise.
- Localized fat hypertrophy.
- Allergic reactions.
Biguanides - Metformin
- Usually the first-line therapy for newly diagnosed, uncomplicated T2D.
- Decreases hepatic glucose production
- Lowers HbA1c by 1 – 1.5%
- Not associated with weight gain.
Biguanides - Metformin Adverse Effects
- Nausea, diarrhea, abdominal discomfort, anorexia, metallic taste.
- Contraindicated in patients with existing hepatic or renal disease (may cause lactic acidosis).
- Vitamin B12 deficiency with long-term use.
- Low risk of hypoglycemia when used alone.
Alpha-Glucosidase Inhibitors - Acarbose
- Inhibits intestinal alpha-glucosidases, delaying starch and disaccharide digestion.
- Reduces postprandial glucose levels.
- Does not significantly inhibit intestinal lactase.
- Requires TID dosing with meals to be effective.
- Lowers HbA1c by 1% or less.
- Does not cause weight gain.
- Hypoglycemic patients taking acarbose should be treated with glucose (not sucrose).
Alpha-Glucosidase Inhibitors - Acarbose Adverse Effects
- Flatulence, diarrhea, abdominal pain, cramps, nausea.
- May reduce metformin bioavailability.
- Contraindicated in irritable bowel syndrome, inflammatory bowel disease.
Dipeptidyl Peptidase-4 Inhibitors
- Generic naming: -gliptin. (e.g. Sitagliptin)
- Inhibit the enzyme degrading GLP-1 and other active peptides involved in glucose homeostasis.
- Indirect incretin mimetic action.
Dipeptidyl Peptidase-4 Inhibitors Advantages
- No apparent impact on cardiovascular risk.
- Lower HbA1c by 1% or less.
- Do not cause weight gain (considered weight neutral).
Dipeptidyl Peptidase-4 Inhibitors Adverse Effects
- Nasopharyngitis, hypersensitivity reactions.
- Rare events of pancreatitis and severe joint pain.
- Sitagliptin does not inhibit cytochrome P450, making it unlikely to cause drug interactions.
- Low risk of hypoglycemia.
Glucagon-Like Peptide-1 Receptor Agonists
- Semaglutide and liraglutide (direct incretin mimetics).
- Act on GLP-1 receptors, increasing insulin secretion and suppressing postprandial glucagon secretion.
- Slow gastric emptying, increasing satiety.
Glucagon-Like Peptide-1 Receptor Agonists
- Usually given as subcutaneous injections, but semaglutide is available orally.
- Decrease HbA1c by 1 – 1.5%
- Do not cause weight gain (cause weight loss).
- Evidence suggests cardiovascular event prevention in primary and secondary prevention patients.
Glucagon-Like Peptide-1 Receptor Agonists Adverse Effects
- Common GI adverse effects (nausea is common initially.
- Injection site reactions.
- Rare cases of acute pancreatitis.
- Caution needed in patients with heart rhythm disturbances and severe renal impairment.
- Contraindicated in pregnancy and patients with personal or familial history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.
Sulfonylureas: Glyburide
- Generic names often begin with gly or gli.
- Insulin secretagogues that stimulate both basal and meal-stimulated insulin release.
- Usually considered add-on therapy to metformin, not monotherapy.
- Lower HbA1c by 1 – 1.5%
Sulfonylureas Advantages and Disadvantages
- Significant differences exist between sulfonylureas in effectiveness, hypoglycemia risk, and weight gain.
- Glyburide is associated with a greater risk of hypoglycemia and more weight gain.
- The effect on cardiovascular events is uncertain (lack of good evidence).
Sulfonylureas Adverse Effects
- Weight gain, prolonged hypoglycemia.
- Higher hypoglycemia risk compared to other sulfonylureas (especially in elderly and renal impairment patients).
- Beta-blockers may mask hypoglycemic symptoms.
Meglitinides: Repaglinide
- A different class of insulin secretagogues.
- Stimulates insulin release but has a much shorter effect than sulfonylureas.
- Similar effects and adverse effects to sulfonylureas.
- Lower hypoglycemia risk if meals are skipped.
- More extensive metabolic drug interactions.
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors - Canagliflozin
- Prevent glucose reabsorption in the kidneys, causing enhanced glucose excretion.
- Do not cause weight gain (cause weight loss).
- Lower HbA1c by 1% or less.
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors Advantages
- Shown to reduce the risk of cardiovascular mortality, major adverse cardiovascular events, and heart failure hospitalizations.
- Cause a small decrease in blood pressure.
- Require adequate kidney function (antihyperglycemic effect declines as kidney function deteriorates).
- Shown to slow nephropathy progression.
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors Adverse Effects
- Increased risk of genitourinary infections.
- Reduced intravascular volume leading to hypotension.
- Hyperkalemia.
- Risk of diabetic ketoacidosis.
- Loop diuretics increase hypotension risk when used together.
Thiazolidinediones - Pioglitazone
- Peroxisome proliferator-activated receptor gamma (PPARG) receptor agonists located on the cell nucleus (mainly in adipose tissue).
- Influence gene expression, including upregulation of GLUT4 transporters and lipoprotein lipase.
- Enhance glucose reabsorption and hydrolyze circulating triglycerides.
- Precise mechanism is still unclear.
Thiazolidinediones Benefits
- Increased peripheral glucose uptake.
- Enhanced fat cell sensitivity to insulin.
- Decreased hepatic glucose output.
- Reduce HbA1c by 1 – 1.5%
Thiazolidinediones Adverse Effects
- Increased heart failure incidence (fluid retention and edema).
- Increased risk of fractures (hip and wrist).
- Worsen macular edema.
Thiazolidinediones: Rosiglitazone
- Healthcare providers must counsel patients and obtain their written consent for new and renewed prescriptions due to the potential risks and benefits of this medication.
Sample Question
- Metformin is typically considered the first-line therapy for most patients with type 2 diabetes.
Introduction
- Focus 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
- Nonpharmacologic interventions (diet, exercise) and 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 of Insulin
- 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 of Biguanides
- 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-Glucosidase Inhibitors
- 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 of Acarbose
- Flatulence, diarrhea, abdominal pain, cramps, nausea
- May reduce metformin bioavailability
- Contraindicated in irritable bowel syndrome, inflammatory bowel disease
Dipeptidyl Peptidase-4 Inhibitors
- 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
Dipeptidyl Peptidase-4 Inhibitors
- Do not seem to alter cardiovascular risk
- Lower HbA1c by 1% or less
- Do not cause weight gain (considered weight neutral)
Adverse Effects of Dipeptidyl Peptidase-4 Inhibitors
- 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
Glucagon-Like Peptide-1 Receptor 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
Glucagon-Like Peptide-1 Receptor 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 of Glucagon-Like Peptide-1 Receptor Agonists
- 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 of Sulfonylureas
- 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
Sodium-Glucose Cotransporter 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
Sodium-Glucose Cotransporter 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 of Sodium-Glucose Cotransporter 2 Inhibitors
- 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 of Thiazolidinediones
- 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 of Thiazolidinediones
- 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?
- Metformin
Thyroid Disorders: Goals of Therapy
- Achieve euthyroid state and manage symptoms in patients with hypothyroidism, thyrotoxicosis, or hyperthyroidism.
- Appropriately manage hypo & hyperthyroidism during pregnancy.
- Determine if patients require fine needle biopsy or observation of thyroid nodules.
Hyperthyroidism: Introduction
- Thyrotoxicosis: Any condition of excessive thyroid hormone and its effects.
- Hyperthyroidism: Specifically caused by excess thyroid hormone production.
- Thyroid storm: Life-threatening medical emergency due to severe thyrotoxicosis.
Hyperthyroidism: Causes
- Graves disease, toxic nodules, iodine excess, TSH-producing pituitary adenomas.
Hyperthyroidism: Nonpharmacologic Options
- Consider surgery as an option with limitations of medication and risk of goitre formation.
Hyperthyroidism: Radioactive Iodine
- Iodine 131 used to ablate thyroid tissue in patients with Graves disease and toxic nodules.
- Thyroid rapidly concentrates iodine, oral dose has minimal effect on the rest of the body.
- Beta wave emission destroys surrounding tissue within a range of 0.6-2 mm.
Hyperthyroidism: Radioactive Iodine - Adverse Effects
- High risk of hypothyroidism.
- Possible worsening of Graves orbitopathy.
- Risk of radiation thyroiditis.
Hyperthyroidism: Methimazole
- Decreases thyroid hormone production.
- Interferes with iodination of tyrosine and coupling.
- Does not affect stored thyroid hormone or circulating thyroid hormone.
Hyperthyroidism: Methimazole - Adverse Effects
- Risk of skin rash, allergic reaction, and agranulocytosis.
- Can cause hepatotoxicity in rare instances.
- Contraindicated during the first trimester of pregnancy due to causing aplasia cutis.
Hyperthyroidism: Propylthiouracil
- Similar mechanism of action to methimazole.
- Inhibits the conversion of T4 to T3 in the periphery.
- Affects production of thyroid hormone and existing thyroid hormone.
Hyperthyroidism: Propylthiouracil - Adverse Effects
- Similar adverse effects to methimazole.
- Risk of severe hepatotoxicity that can be fatal.
- Does not cause aplasia cutis.
Hyperthyroidism: Methimazole vs Propylthiouracil
- Methimazole is preferred due to lower risk of hepatotoxicity.
- Methimazole is preferred while breastfeeding and for children.
- Propylthiouracil is preferred in the first trimester of pregnancy.
- Propylthiouracil can be used to treat thyroid storm due to its peripheral thyroid conversion impact.
Hyperthyroidism: Beta Blockers
- Do not affect thyroid hormone production.
- Used to ameliorate adrenergic excess symptoms caused by excess thyroid hormone (elevated heart rate, hypertension).
- Propranolol can decrease conversion of T4 to T3 in the periphery.
Hyperthyroidism: Beta Blockers - Adverse Effects
- Bradycardia, dizziness, fatigue, headache, hypotension.
- Avoid in patients with asthma or conditions associated with bradycardia.
- Taper once thyrotoxicosis improves.
Hypothyroidism: Introduction
- Very common.
- Rarely caused by iodine deficiency in North America.
- Most commonly caused by Hashimoto's thyroiditis.
Hypothyroidism: Levothyroxine
- The standard therapy for treating hypothyroidism.
- Oral T4 replacement therapy.
- Takes 6 weeks to reach a new steady state after dosage adjustments.
Hypothyroidism: Levothyroxine - Dosing
- Average adult replacement: 1.6 mcg/kg/day PO.
- Generally based on lean body mass.
- Elderly patients may need less.
- For those at risk of angina, start with 12.5 – 25 mcg/day PO.
Hypothyroidism: Levothyroxine - Dosing Variations
- Initial doses vary depending on endogenous thyroid function.
- Patients with intact thyroid or mild/subclinical disease may need smaller initial dosages (25 – 50 mcg).
- Patients with negligible thyroid function may need full replacement dosages.
Hypothyroidism: Levothyroxine - Dosing Adjustments
- Wait at least 6 weeks post initial dosing or last dose adjustment.
- TSH values slightly out of range can be adjusted by 12.5 – 25 mcg.
Hypothyroidism: Levothyroxine - Interactions
- Absorption may be reduced by antacids and mineral supplements.
- Proton pump inhibitors and estrogens may interfere with absorption.
- Variable effects with anticoagulant drugs.
- Separate administration by 6 hours.
- Levothyroxine is typically taken first thing in the morning before any other medications.
Hypothyroidism: Levothyroxine - Adverse Effects
- Symptoms of hyperthyroidism if overtreated.
- Possible exacerbation of angina.
- Glycemic control may decline with initiation of levothyroxine, potentially requiring antihyperglycemic agent dose adjustments.
Hypothyroidism: Desiccated Thyroid
- Used based on patient preference.
- Tablets contain T4 and T3 in fixed amounts.
- Available in 30 mg, 60 mg, or 125 mg tablets.
Hypothyroidism: Desiccated Thyroid - Dosing Comparison
- Levothyroxine Dose (mcg) || Desiccated Thyroid Dose (mg)
- 50 || 32
- 100 || 65
- 200 || 130
- 300 || 200
- 400 || 260
- 500 || 325
Hypothyroidism: Desiccated Thyroid - Adverse Effects
- Similar to levothyroxine.
- Risk of cardiovascular and neurological adverse effects increases with larger doses (due to T3).
- Palpitation, tachycardia, cardiac arrhythmias, angina pectoris.
- Nervousness, tremors, headache, insomnia.
- Sweating, heat intolerance, fever, weight loss.
Hypothyroidism: Dosing Case 1 - Considerations
- BMI is under 25.
- Symptoms are mild, and TSH is mildly elevated.
- Patient has an intact thyroid.
- Patient is not elderly.
Hypothyroidism: Dosing Case 1 - Initial Dose
- Full replacement dose based on weight: 1.6 * 62 kg = 99.2 mcg.
- Conservative initial dosing: 25 – 50 mcg.
- Desiccated thyroid dose is levothyroxine dose multiplied by 0.65.
Hypothyroidism: Dosing Case 2 - Considerations
- Significant symptoms present.
- Serum TSH level is high.
- Patient is not elderly.
- Intact thyroid.
- BMI is above 25.
Hypothyroidism: Dosing Case 2 - Initial Dose
- Unadjusted weight: 1.6 * 102 kg = 163.2 mcg.
- Ideal body weight for patient's height: 58.8 kg; 1.6 * 58.8 kg = 94 mcg.
- TSH-based dose: 107 + 0.69(21.3) = 121 mcg.
Hypothyroidism: Sample Question - Best Course of Action
-
Patient's TSH remains unchanged after 6 weeks of levothyroxine.
-
Patient reports taking levothyroxine every morning with their iron supplement.
-
Correct Answer: D. Change the time the patient takes their iron supplement.
-
Explanation: Iron supplementation can interfere with levothyroxine absorption. Adjusting the timing of iron supplement intake is the best approach to optimize levothyroxine absorption and potentially improve TSH levels.
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