Module 9

Since the meglitinides are essentially as effective as the sulfonylureas in reducing A1c, why aremedications from this class not used very often

*More expensive than sulfonylureas; not commonly used

How effective are the sulfonylureas in reducing A1c? (Slide 20)

*Reduce A1C by 1 -2%

meglitinides

*Repaglinide (Prandin) *Nateglinide (Starlix) *Stimulate insulin secretion in the presence of glucose *Decreases post-prandial glucose by 60 -70 mg/dL *Reduce A1C by 1 -2% *More expensive than sulfonylureas; not commonly used * *Close ATP sensitive potassium binding channels *Depolarization of the membrane *Facilitation of calcium entry through the calcium channels *Stimulation of insulin release from the pancreatic beta cells *Useful in the elderly and those with renal disease *Taken prior to meals *Absorption: rapid *Onset 15 -30 minutes *Peaks in 60 -90 minutes *Half life 1 hour *Duration: 2 -3 hours *Distribution >98% protein bound *Metabolized : Liver *Excreted: Feces, small amount in urine * *Contraindications *Type 1 Diabetes *DKA *Caution if severe renal impairment, liver dysfunction, or in elderly persons *Adverse effects -hypoglycemia, nausea, dyspepsia, diarrhea, dizziness *

1.What is a common side effect of metformin that becomes less bothersome over time?

1.Metformin is well-known for nausea, loose stools, and GI upset. These effects lessen over time.

1.Which type of insulin is preferred for use in a continuous subcutaneous insulin pump?

1.Rapid-acting insulin is preferred for continuous subcutaneous insulin infusion

1.Which insulin can be administered IV?

1.Regular insulin may be administered IV

Levothyroxine has a relatively long half-life (6-7 days when the person is euthyroid). After changingthe dose, how soon would you re-check the TSH to see if it is appropriate?

5-6 weeks

What mineral is essential to the production of thyroid hormone but must be obtained from the diet?

Iodide

Which of the thionamides has a longer half-life and can be dosed once daily? (Slide 10

MTZ

Three classes of oral medications for T2DM (slide 9) are included in the professional organizationdiabetes management guidelines; however, they are not routinely used mainly due to their adverseeffect profile.

The alpha-glucosidase inhibitors, the dopamine-2 agonists, and the Bile Acid Sequestrants are included in the evidence-based diabetes management algorithms; however, these drug classes will not be discussed further except to present their mechanism of action.

What is the incretin effect? (Side 4

The concept of the incretin effect arose from studies showing that insulin responses to oral glucose exceeded those measured after intravenous administration of equivalent amounts of glucose. Researchers concluded that gut-derived factors, or incretins, influenced postprandial insulin release. Nutrient entry into the stomach and proximal gastrointestinal tract causes release of incretin hormones, which then stimulate insulin secretion. This insulinotropism, or ability to stimulate insulin secretion, can be quantified by comparing insulin or C-peptide responses to oral vs intravenous glucose loads. In this way, it has been shown that the incretin effect is responsible for about 50% to 70% of the insulin response to oral glucose in healthy individuals.

In what part of the body does the synthesis and release of thyroid hormones T3 and T4 occur? (Slide6

The thyroid follicular cell takes

Which drug class is a selective agonist for PPAR-γ?

Thiazolidinediones

Is there a drug-food interaction between thyroid medication and coffee? (Slide 16

interferes with absorp

Consider the age of the patient, insurance coverage, risk for hypoglycemia, health literacy. For arural-dwelling, uninsured, adult with low health literacy, what might be some of the challengesassociated with using CSII?

•Pediatrics: •Continuous Glucose Monitoring (CGM) and use of insulin pump (CSII) is safe at all ages; best way to mimic physiologic insulin profile •Pre-pubertal: 0.5-1.0 U/kg/d; Pubertal: may rise above 1.2 U/kg/d and even up to 2.0 U/kg/d; the "correct" dose is whatever achieves best glycemic control •BID or intensive therapy if not able to use insulin pump •Lower A1c → fewer/delayed microvascular complications •Higher A1c → psychomotor & mental declines •Older adults: •Higher risk of hypoglycemia •Higher incidence of hypoglycemia unawareness •Tight control (intensive insulin therapy) not recommended • 2018 ISPAD Clinical Practice Consensus Guidelines: Diabetes Technologies, Section 3: https://onlinelibrary.wiley.com/doi/full/10.1111/pedi.12731 2020 AACE/ACE Consensus Statement, Role of CGM: https://pro.aace.com/pdfs/diabetes/algorithm-exec-summary.pdf

Would an adolescent going through puberty require a higher or lower units/kg/day insulin dose thanan adult or pre-pubertal child?

•Pre-pubertal: 0.5-1.0 U/kg/d; Pubertal: may rise above 1.2 U/kg/d and even up to 2.0 U/kg/d; the "correct" dose is whatever achieves best glycemic control

DPP-4 inhibitors

•Sitagliptin (Januvia) •Saxagliptin (Onglyza) •Linagliptin (Tradjenta) •Alogliptin (Nesina)

Where are the sulfonylurea receptors located? (Slide 14)

*Binds to Sulfonylurea receptors on beta cells *Closure of linked ATP sensitive K+ channels *Decreased K+ influx *Depolarization of beta cell membrane *Opening of calcium channels *Influx of calcium *Translocation, exocytosis of secretory granules of insulin to the cell surface *

What are some of the adverse effects of the sulfonylureas? (Slide 20)

*Hepatic/renal impairment *Type 1 Diabetes *Diabetic ketoacidosis *Hypersensitivity: Cross-sensitivity with allergy to sulfonamides

Discuss the indications, contraindications, adverse effects and precautions in the use ofsulfonylureas and meglitinides?

*Hepatic/renal impairment *Type 1 Diabetes *Diabetic ketoacidosis *Hypersensitivity: Cross-sensitivity with allergy to sulfonamides *Contraindications *Type 1 Diabetes *DKA *Caution if severe renal impairment, liver dysfunction, or in elderly persons *Adverse effects -hypoglycemia, nausea, dyspepsia, diarrhea, dizziness *

Identify the major classes of oral medications used to treat Type 2 Diabetes

*Insulin secretagogues *Sulfonylureas *Meglitinides *Biguanides *Alpha Glucosidase Inhibitors (rarely used) *Thiazolidinediones *Dipeptidyl Peptidase 4 Inhibitors (DPP4 inhibitors) *Selective sodium-glucose transporter-2 (SGLT-2) inhibitors *Dopamine-2 Agonists (rarely used) *Bile Acid Sequestrants (rarely used) *Non-insulin injectables: *Incretin (Glucagon-like peptide-1 or GLP1) agonists/mimetics *Amylinomimetics (rarely used) *

Why are the sulfonylurea drugs called "insulin secretogogues? (Slide 11

*Insulinotropic effect on the beta cells (stimulate the production of insulin; insulin secretagogue)

sulfonylureas

*Insulinotropic effect on the beta cells (stimulate the production of insulin; insulin secretagogue) *Bind to and close ATP- sensitive potassium channels in pancreatic beta cells *Closure of potassium channels causes depolarization, influx of calcium, and release of preformed insulin * *Most-frequently used sulfonylurea class *Dosed in 10's of mg. *Inexpensive *Examples *Glyburide (Diabeta) *Glipizide (Glucatrol) *Glimepiride (Amaryl) *Binds to Sulfonylurea receptors on beta cells *Closure of linked ATP sensitive K+ channels *Decreased K+ influx *Depolarization of beta cell membrane *Opening of calcium channels *Influx of calcium *Translocation, exocytosis of secretory granules of insulin to the cell surface *Onset: < 60 minutes to 3 hours *Duration: up to 24 hours *Half life: 3 -10 hours *Distribution: > 90% protein bound *Metabolized: Hepatic *Excreted: Urine, Feces * *Decrease fasting plasma glucose 60 -70 mg/dL *Reduce A1C by 1 -2% *Can produce hypoglycemia *Promote weight gain *Advantage: Oral *Possibly produce loss of myocardial ischemic tolerance *No evidence that they lead to earlier pancreatic failure * *Hepatic/renal impairment *Type 1 Diabetes *Diabetic ketoacidosis *Hypersensitivity: Cross-sensitivity with allergy to sulfonamides *Hypoglycemia *Nausea, dyspepsia *Weight gain *Drowsiness *Elevated LFTs *Rash, photosensitivity

SGLT-2inhibitors.

0Pharmacodynamics 0Inhibits sodium-glucose co-transporter 2 in proximal renal tubules 0Reduces reabsorption of filtered glucose from tubular lumen 0Increased urinary excretion glucose → reduced plasma glucose 0Canagliflozin; Dapagliflozin; Empagliflozin 0Pharmacokinetics 0Bioavailability: 65% with oral dosing 0Onset of action: within 24 hours; dose-dependent 0Time to peak plasma concentration: 1-2 hours 0Duration of action: suppression of glucose reabsorption throughout 24-hr dosing interval 0Half-life (dose-dependent): 100 mg: 10.6 hr; 300 mg: 13.1 hr 0Highly protein-bound- 99% 0Metabolism: mainly Phase II metabolism; minor CYP-450 metabolism through CYP3A4 isoenzyme pathway 0Advantages 0Moderate lowering serum glucose levels 0Average A1c decrease: 0.6-1% for baseline A1c ≤ 8% 0Induces weight loss 0200-400 calories/day excreted as glucose in urine 02-3 kg weight loss over 6 months 0May reduce blood pressure 0~5-mm Hg reduction systolic 0~2-mm Hg reduction diastolic 0Low propensity for hypoglycemia 0Effective as monotherapy and in combination with existing therapies, including insulin 0Effectiveness independent of severity insulin resistance and beta-cell failure 0Adverse Reactions 0Occurring >10% 0Increased serum potassium 0Increased genital candidiasis 0Renal insufficiency when eGFR 30-50 mL/min or less 0Occurring 1-10% 0Hypovolemia 0Orthostatic hypotension 0UTI 0Increased non-HDL cholesterol 0Avoid initiating if eGFR<60; contraindicated if eGFR <30

Biguanide Metformin (Glucophage)

0Reduces hepatic gluconeogenesis and glycogenolysis 0Increases peripheral insulin sensitivity 0Effect on carbohydrate and lipid metabolism 0May promote weight loss 0Used in pre-diabetes (A1c 5.7-6.4%) 0Impaired fasting glucose 0Impaired glucose tolerance 0Used in Polycystic Ovarian Syndrome 0Lowers morning blood glucose 0No hypoglycemia when used as monotherapy 0Decreases hepatic glucose production and increases insulin mediated peripheral glucose uptake 0Decreases fasting plasma glucose by 60 -70 mg/dL 0Decreases A1C by 1 -2% 0 0Oral bioavailability: 50-60% 0Peak plasma concentration 1-3 hrs (IR); 4-8 hrs (ER) 0Half life 6 hours in plasma; steady state 1-2 days 0Absorbed in small intestine 0Excretion: unchanged in the urine 0Distribution: negligible protein binding 0 0Black Box Warning: Potential for Lactic Acidosis 0Hepatic/Renal failure 0No dose adjustment if eGFR>45 0Discontinue if eGFR<30 0Alcoholics 0Cardio-respiratory insufficiency 0Hypersensitivity 0> 80 years old unless normal creatinine clearance 0 0GI upset 0Discontinue until 48 hours after a procedure that requires contrast 0Check renal function before resuming 0Decreased serum B12 levels 0

Alpha-Glucosidase Inhibitors

0Reversibly bind to intestinal alpha glucosidase enzymes 0Delays absorption of carbohydrates 0No hypoglycemia when used as monotherapy 0Decrease postprandial glucose 40 -50 mg/dL 0Decrease fasting plasma glucose 20 -30 mg/dL 0Decrease A1C 0.5 -0.8% 0Decrease CVD events (STOP-NIDDM trial) 0 0Acarbose (Precose): 50 mg bid to 100 mg tid 0Drug Interactions: thiazide diuretics, oral contraceptives, estrogens, thyroid products, corticosteroids, phenothiazines, phenytoin, nicotinic acid, calcium channel blockers, INH, sympathomimetics and digestive enzymes 0Miglitol (Glyset): 25-50 mg tid 0Drug Interactions: Decreases absorption of digoxin, propranolol, ranitidine 0Digestive enzymes reduce the effect of miglitol 0 Adverse Reactions: 0Diarrhea, flatulence and bloating, which are self limiting 0A few individuals may experience a rash 0May elevate liver enzymes Contraindications: 0Hypersensitivity 0Inflammatory Bowel Disease 0Colonic Ulceration 0Intestinal obstruction 0Type 1 Diabetes 0DKA 0Creatinine > 2.0; if eGFR <30

Thiazolidinediones

0Selective agonist for peroxisome proliferator activated receptor gamma receptors (PPAR-γ) 0Decrease gluconeogenesis, reduce insulin resistance in the liver and enhance glucose uptake by skeletal muscle and adipose tissue 0Insulin sensitizers 0Monotherapy: lower A1c 0.5-1.4% 0Can take 6-12 weeks for beneficial effect to be seen 0 0Pioglitazone(Actos) 0Rosiglitazone (Avandia) 0November 2013: FDA lifted restraints Avandia "It does not increase risk of MI." 0Decreases fasting plasma glucose 36 -40 mg/dL 0Reduces A1C by 0.5 -1.5% (more if used in combination with metformin) 0Efficacious especially in combination with metformin 0Work well to decrease postprandial glucose 0Show triglyceride-lowering effect 0Adjunct use 0Any other class of oral therapy 0Insulin 0 Pioglitazone (Actos) 015 -45 mg daily 0Onset: Delayed, several weeks (6-12 weeks) 0Half life: 16 -24 hours 0Distribution: >99% protein bound 0Metabolized by liver enzymes CYP2C8 and CYP3A4 0Excreted: urine, feces 0Cytochrome P450 Effect 0Increased effect with glyburide, metformin, digoxin, warfarin, ethanol and ranitidine 0Decreases bioavailability of estrogen-containing oral contraceptives 0 00Hypersensitivity, Type 1 diabetes, DKA, Heart Failure New York Class III-IV, liver disease, pregnancy, lactation 0May induce ovulation in premenopausal anovulatory women 0Increase in bone fracture rates in women 0May cause or exacerbate heart failure 0Pioglitazone increased risk bladder cancer 0Rosiglitazone greater risk for CV events 0No dose adjustment needed for reduced renal function 0Severe Adverse Reactions 0Hepatotoxicity: monitor LFTs 0Heart Failure 0Edema 0Decreased Bone Mineral Density 0Common Adverse Reactions 0Sinusitis, myalgia 0Fluid retention, edema, dilutional anemia, weight gain

1.Asymptomatic Asian-American adults with BMI ≥ ____ should be screened for T2DM.

1.23 kg/m2

1.Asymptomatic adults of any age with BMI ≥ ____ should be screened for T2DM.

1.25 kg/m2

1.At what age should asymptomatic adults without risk factors first be tested (screened) for diabetes or pre-diabetes?

1.45 years

1.Children/adolescents age ≥10 yrs or after onset of puberty with BMI >___ %-tile and one additional risk factor should be screened for T2DM.

1.85th percentile

1.Of the four classes of oral agents discussed in this presentation, which one binds to an enzyme and slows absorption of carbohydrates?

1.Alpha-glucosidase inhibitors

1.How often should screening be repeated in asymptomatic adults?

1.At least every 3 years

1.Which basal analog insulin is pregnancy category B?

1.Detemir is Pregnancy Category B

1.Which patient/disease factor(s) would cause you to consider recommending a target A1c of >7%: a)No established vascular complications b)Age 75 years c) Lives alone d)Newly diagnosed with T2DM

1.Factors b and c should cause you to consider a target A1c of >7%. An older adult living alone may be at risk for hypoglycemia unawareness or may not have support available to help if hypoglycemia occurs.

1.True or False? Sea salt contains about the same amount of iodine as table salt

1.False. Sea salt is a negligible source of iodine.

1.Where are T4 and T3 synthesized within the thyroid gland?

1.Follicular cells of the thyroid gland

Match the insulin with its type: 1.Glargine (Lantus) 2.Aspart (Novolog) 3.Humulin R 4.Detemir (Levemir) 5.Glulisine (Apidra) 6.Insulin isophane (NPH) 7.Lispro (Humalog) 8.Degludec (Tresiba) 9.Afrezza a.Rapid acting b.Long-acting (Basal) c.Short-acting d.Ultra-rapid-acting

1.Glargine (Lantus): B 2.Aspart (Novolog): A 3.Humulin R: C 4.Detemir (Levemir): B 5.Glulisine (Apidra): A 6.Insulin isophane (NPH): B 7.Lispro (Humalog) A 8.Degludec (Tresiba): B 9.Afrezza: D a.Rapid acting b.Long-acting (Basal) c.Short-acting d.Ultra-rapid acting

1.Which disorder decreases GFR: hypo or hyperthyroidism?

1.Hypothyroidism

1.Why must insulin be given by injection and not orally?

1.Insulin is a protein that is digested in the stomach. For this reason it may not be administered orally.

1.Which oral agent is used in the treatment of Polycystic Ovarian Syndrome (PCOS)?

1.Metformin

1.Following the AACE algorithm, if a person's A1c at diagnosis is 7.1%, they are not high risk for and do not established ASCVD, CKD, or HF, which medication should be prescribed first?

1.Metformin is the first-line drug for a person without high-risk for or established ASCVD, CKD-stage 3, or HF. The drugs listed in the "Entry <7.5%" box are listed by suggested hierarchy of usage.

1.Which class of oral agents reduces absorption of filtered glucose from the renal tubular lumen, increasing urinary excretion of glucose?

1.SGLT-2 Inhibitors

1.With the exception of glipizide, when (in relation to a meal) should a person take a 2nd generation sulfonyurea? When (in relation to a meal) should glipizide be dosed?

1.Sulfonyureas should be taken with a meal to prevent hypoglycemia and produce maximum effect. Glipizide should be given 30 minutes before a meal.

1.Condensation of two molecules of diiodotyrosine (DIT) molecules yields what substance?

1.T4

1.T/F: While there are multiple criteria for diabetes diagnosis, one option is a fasting plasma glucose (FPG) ≥126 mg/dL

1.TRUE

1.Which drug class acts as a selective agonist for peroxisome proliferator activated receptor gamma receptors (PPAR-γ)?

1.TZDs

1.MJ is a 42 y/o woman recently diagnosed with Grave's disease (GD). She will be started on a thioamide and a beta blocker. Which of the following characteristics regarding thionamides are true? a.Methimazole (MTZ) has longer T1/2 and may be dosed once daily b.Propylthiouracil (PTU) can cause pretibial myxedema c.MTZ interacts with amiodarone therapy d.PTU therapy typically induces euthyroid state after 12 mos.

1.The correct responses are: a, c 1.Hyperthyroidism causes pretibial myxedema, not PTU 2.PTU returns thyroid hormones to normal range in 4-12 weeks; however, treatment is continued at a maintenance dose for 12-18 months which sometimes results in GD going into remission

1.JC is a 31 y/o female with GD in her 1st trimester of pregnancy. Which of the following statements regarding PTU are true? a.PTU can increase the peripheral conversion of T4 to T3 b.PTU is safer than MTZ in 1st trimester pregnancy since it has lower risk for teratogenicity c.PTU is typically first-line anti-thyroid drug choice in adults and children PTU can be used during myxedema crisis (thyroid storm)

1.The correct responses are: b, d 1.PTU blocks the peripheral conversion of T4 to T3 2.MTZ is considered the drug of choice in adults and children except during first trimester pregnancy and in patients who are allergic or intolerant to MTZ

1.Which oral agents are more likely to cause hypoglycemia?

1.The sulfonylureas and meglitinides are more likely to cause hypoglycemia as they stimulate the pancreas to produce more insulin

1.What enzyme, stimulated by TSH, oxidizes iodide to iodine?

1.Thyroid peroxidase

Which drug has a major adverse effect of GI upset (specifically diarrhea) which may be lessened bygradual up-titration

Alpha Glucosidase Inhibitors

Which drug class delays absorption of carbohydrates and has also been shown to decreasedcardiovascular disease events?

Alpha-Glucosidase Inhibitorsppa

Of the three basal insulins, which one would be best for a person with an irregular work schedulewho finds it difficult to inject the insulin at the same time each day?

Basal insulin degludec Approved for adults with Type 1 or 2 diabetes Injected SC once daily, duration up to 42 hours Onset 1 hr No true peak Also marketed as a pre-mix insulin with aspart (Ryzodeg) New agent: degludec/liraglutide (Xultophy) May use in pregnancy; no human data available; no known risk teratogenicity based on animal data

Identify the major combinations of insulin regimens that are commonly used for Type 1 andType 2 Diabetes Mellitus

Basal-Bolus Coverage Based on blood sugar values Goal: avoid hyperglycemic and hypoglycemic values A pro-active adjustment

What is the difference between basal and bolus dosing of insulin?

Bolus Insulin A planned pre-meal dose Used to correct hyperglycemia Types of Bolus Insulin Regular Human Insulin Rapid-acting insulin analogs Insulin Lispro (Humalog) Insulin Aspart (Novalog) Insulin Glulisine (Apidra) Basal Insulin Maintains glycemic control in an NPO patient Proper use results in normal morning blood sugars Important: The goal of basal insulin is to suppress hepatic glucose production and improve fasting hyperglycemia ! Types Insulin Isophane (NPH)- some consider it intermediate-acting and others basal insulin Insulin Glargine (Lantus, Toujeo, Basaglar) Insulin Detemir (Levemir) Insulin Degludec (Tresiba)

The ADA Type 2 diabetes guidelines recommend that the prescriber first identify if the patient hascertain co-morbid conditions. What are these conditions? (Slide 4

CVD, CKD< HF

Discuss the physiology of insulin synthesis and secretion

Diabetes Mellitus refers to a group of conditions characterized by hyperglycemia resulting from defects in any or all of the following areas: glucose production, glucose metabolism, insulin production, insulin action or insulin effectiveness. Glucose is essential for the production of energy for the body, and the healthy body produces glucose as well as appropriately metabolizes ingested foods containing glucose. However, insulin is required for glucose uptake into the body cells where it can0 be used. Insulin acts like a key to unlock the cell membrane so that glucose can enter the cell. Impaired insulin production or function results in abnormal carbohydrate, protein, and fat metabolism because of impaired glucose transport. Insulin enhances glucose uptake by increasing the number of glucose transporters in the plasma membrane of cells. Insulin stimulation of cells mobilize transporters from intracellular compartments to the plasma membrane to facilitate glucose transport. This relocation of receptors to the plasma membrane has been demonstrated to occur within 30 seconds of insulin stimulation; and as the stimulus dissipates, the decrease in the number of plasma membrane receptors declines simultaneous with the decline in the glucose transporter GLUT4. The impaired ability of insulin to signal Glut4 relocation from intracellular stores to the cell membrane is currently believed to be an important contributory factor to post-meal hyperglycemia in diabetes.

What is the action of dipeptidyl peptidase-4 (DPP-4) in relation to the incretin hormones? (Slide 16

Dipeptidyl Peptidase 4 or DDP-4 is the enzyme that degrades the incretin hormones GIP and GLP-1. By blocking the action of DPP4, these agents increase circulating GIP and GLP-1 levels which ultimately decreases post-prandial glucose excursions. DPP4 inhibitors are FDA approved as adjuncts to diet and exercise in the treatment of T2DM in persons who have failed to meet target glycemic goals. Four DPP4 inhibitors are currently available on US markets: sitagliptin, saxagliptin, linagliptin, and alogliptin.

GLP-1 DPP-4 inhibitors

GLP-1 (Incretin) Mimetics •GLP-1 = Glucagon-like peptide 1 receptor agonists •Derived from Gila monster saliva •All forms are injectable except semaglutide (Rybelus) •Exenatide (Byetta) oExtended-release formulation (Bydureon) •Liraglutide (Victoza) •Dulaglutide (Trulicity) •Semaglutide (Ozempic) •Semaglutide (Rybelsus)- oral preparation • GLP1 •Enhances glucose dependent insulin secretion •Suppresses inappropriate glucagon secretion •Promotes satiety, regulates rate of gastric emptying •Increased beta cell survival •

What are some of the effects of the most widely studied incretin hormone, GLP-1? (Slides 5-6

Incretins are gut-derived peptides normally secreted in response to meals. The most widely studied incretin, glucagon-like peptide-1 (GLP-1), has several effects on glucose homeostasis: glucose-dependent stimulation of insulin, suppression of glucagon, delaying of gastric emptying, and the promotion of satiety. This slide summarizes the pharamcodynamics of the incretin GLP-1 as explained in the previous slide. GLP-1 is released into the gut in a biphasic pattern with an early phase 10-15 minutes after a meal, and a longer, second phase 30-60 minutes after a meal.

How would you counsel a person taking levothyroxine who typically takes the medication in themorning with breakfast? (Slide 15

Levothyroxine should always be taken on an empty stomach with only water. Absorption of this drug may be decreased by foods such as soybean flour, cotton seed meal, walnuts, dietary fiber, and calcium-products, including calcium-fortified juices.

Describe the onset, peak, and duration of common insulin preparations

Lispro 15-30 mins 30-90 mins 3-5 hrs NPH (N) 1-2 hrs 4-12 hrs 18-24 hrs Glargine 1-1.5 hrs No peak 20-24 hrs

Would you recommend a sulfonylurea to a patient who takes wafarin?

Numerous drugs potentiate the action of the sulfonylureas via the mechanisms outline on this slide. Drugs that increase Sulfonylurea action include NSAIDs, warfarin, salicylates, sulfonamides, allopurinol, probenecid, guanethidine, MAOIs, chloramphenicol, alcohol, ß-blockers.

Which drug class inhibits sodium-glucose co-transporter 2 in the proximal renal tubules

SGLT-2 inhibitors

Which drug class may have an adverse effect of genital mycotic infections? Why?

SGLT-2 inhibitors

Identify the signs and symptoms of hyperthyroidism and hypothyroidism

Signs/Symptoms of Hypothyroidism }Constipation }Cold intolerance }Fatigue, loss of energy, weakness }Menstrual abnormalities or infertility }Muscle/joint pain }Cool, dry skin }Depression, sadness or irritability }Coarse, brittle hair and nails; hair loss (scalp, axillary, pubic hair) }Weight gain }Hoarseness }Facial puffiness (especially periorbital) }Decreased perspiration }Edema hands or feet }Delayed reflexes Symptoms of Hyperthyroidism }Heat intolerance }Tremors }Enlarged thyroid gland (goiter) }Heart palpitations }Increased sweating }Nervousness, irritability }Erythema, swelling, and protrusion of the eyes; lid lag }Shortness of breath }Increased number of bowel movements }Irregular menses or amenorrhea }Weakness and muscle fatigue }Mild polyuria }Increased basal metabolic rate }Hyperglycemia

As T4 levels rise in the body, what happens to the levels of TSH? (Slide 4

TSH lowers

Identify some possible combinations of insulin and oral hypoglycemic medications

Thiazolidinediones

Discuss the current management guidelines for T2DM

This slide is not an actual algorithm, but it illustrates the fact that type 2 diabetes is a chronic, progressive disease in which pathologic hyperglycemia must be controlled with oral or injectable medications. Lifestyle interventions involving diet, weight reduction, and increased physical activity are essential in diabetes management as indicated by the first step of this diagram. Several factors should be considered when choosing a medication regimen including desired glycemic control, patients' weight and lipid profile, contraindications, and cost. Evidenced-based treatment algorithms have been developed and are revised regularly to assist primary care providers to make accurate clinical decisions in caring for persons with diabetes.

At what point in the patient encounter should you routinely ask about symptoms presented onslides 4-5, regardless of whether or not hyperthyroidism is one of your DD's? (Slide 5

This table shows the relative frequency of signs and symptoms of hyperthyroidism. When asking review of systems questions it is important to include these symptoms, especially in females aged 40 and older and in persons with a family history of thyroid disorders.

Discuss the mechanisms of thyroid hormone synthesis, secretion, and transport

Thyroid activity is regulated by a series of external and internal factors, of which the pituitary-derived thyroid stimulating hormone (TSH or thyrotropin) plays a central role. Note TSH near the center of this flow diagram. The synthesis and release of TSH from anterior pituitary thyrotropic cells is regulated by the hypothalamus. The pituitary thyrotopic cells are stimulated by thyrotropic-releasing hormone (TRH), and they subsequently release TSH which in turn stimulates all aspects of thyroid function, including the release of T3 and T4. T3 and T4 also regulate the TSH release through negative feedback using various mechanisms. The pituitary TSH-producing cells are inhibited by T4, so as T4 levels rise, TSH levels fall. In healthy people, the thyroid produces mainly T4 (about 80-100 micrograms/day) and only a limited amount of T3 (25-32 mcg/day). Most T3 is produced through de-iodination of the outer ring of T4. In this sense, T4 can be thought of as a pro-hormone for T3; and, consequently, T3 is the hormone that exerts the main biological effects. Both T3 and T4 pass from the circulation into the peripheral tissue target cells; and after passage across the cell membrane, T4 is converted to T3. T3 passes into the cell nucleus and is bound to the specific intranuclear receptors where it exerts its effect.

Persons with what drug allergy should not take sulfonylureas? (Slide 21

allergy to sulfonamides

From what part of the brain is TSH synthesized and released? (Slide 4

pituitary

Discuss the mechanism of action, adverse effects, and contraindications of medications used totreat hyperthyroidism.

} }Two major drugs: propylthiouracil (PTU); methimazole (MTZ) }Major mechanism: prevent hormone synthesis by inhibiting thyroid peroxidase-catalyzed reactions & blocking the incorporation of iodine into thyroglobulin }They also block coupling of the iodotyrosines }Do not block iodide uptake by thyroid gland }PTU & to a much lesser extent MTZ inhibit peripheral de-iodination (conversion) of T4 to T3 }Slow onset: often takes 3-4 weeks before T4 stores are depleted; remission occurs in 50% within 12 months }MTZ is at least10x more potent than PTU, therefore MTZ is drug of choice } } }Most common: }GI distress }Maculopapular, pruritic rash }Less serious/less frequent ADRs }Urticarial rash }Vasculitis }Exfoliative dermatitis }Arthralgia }Hepatitis (PTU) }Asymptomatic elevation transaminases }Most serious - agranulocytosis }Risk of agranulocytosis is increased with: }Persons who already have reduced bone marrow reserve }Persons older than 40 years of age }Persons receiving > 40 mg/day MTZ }

Discuss the mechanism of action, adverse effects, and contraindications of medications used totreat hypothyroidism

}Absorption & Distribution of Thyroid Hormones }Absorbed variably from GI tract - duodenum, jejunum, ileum }Absorption decreased in presence of PPIs }Limited volume of distribution; 99.8% bound to plasma proteins }Bioavailability 60-80% } }Metabolism & Excretion }Metabolized primarily in liver via deiodination }Excreted unchanged in stool (20%) }Primarily eliminated by kidneys }Urinary excretion of T4 decreases with age }Half-life T4 >9 days for persons 80 years and older }Gastrointestinal System }Diarrhea, abdominal cramps, weight loss, increased appetite }Neuromuscular/Skeletal System }Decreased bone mineral density, tremor }Cardiovascular System }Palpitations, sweating, tachycardia, hypertension, angina, arrhythmias }Central Nervous System }Anxiety, emotional lability, headache, heat intolerance, insomnia, irritability }Hypersensitivity (to inactive ingredients) }Urticaria, pruritus, flushing, angioedema, fever, GI symptoms, wheezing }Some PPIs decrease absorption }Cholestyramine, colestipol, Al and Mg hydroxide, dietary fiber, Ca+2 and iron supplements, reduce absorption }Phenytoin, furosemide, heparin, NSAIDs: displace levothyroxine from protein-binding sites, temporarily increasing levels of free T4 }Estrogen-containing drugs, androgens: affect TBG concentration }Propranolol, amiodarone, glucocorticoids: ↓conversion T4 to T3 }Carbamazepine, phenytoin, phenobarbital, & rifampin increase metabolism of thyroid hormones, reducing their efficacy }Coumadin: thyroid hormone increases catabolism of clotting factors }Antidiabetic agents: levothyroxine may result in ↑ requirements }

What medication could you give a patient to treat the symptoms of hyperthyroidism even beforethe lab test results are obtained? (Slide 15)

}Beta-blockers without ISA for rate control }Propranolol (first line) 20-40 mg qid }Atenolol 25-100 mg qd-bid }Metoprolol 25-50 mg bid-tid }Diltiazem (calcium channel blocker) if beta-blocker contraindicated

Identify signs and symptoms of ...hypothyroidism

}Constipation }Cold intolerance }Fatigue, loss of energy, weakness }Menstrual abnormalities or infertility }Muscle/joint pain }Cool, dry skin }Depression, sadness or irritability }Coarse, brittle hair and nails; hair loss (scalp, axillary, pubic hair) }Weight gain }Hoarseness }Facial puffiness (especially periorbital) }Decreased perspiration }Edema hands or feet }Delayed reflexes

Identify the signs and symptoms of hyperthyroidism

}Heat intolerance }Tremors }Enlarged thyroid gland (goiter) }Heart palpitations }Increased sweating }Nervousness, irritability }Erythema, swelling, and protrusion of the eyes; lid lag }Shortness of breath }Increased number of bowel movements }Irregular menses or amenorrhea }Weakness and muscle fatigue }Mild polyuria }Increased basal metabolic rate }Hyperglycemia

What is the effect of hypothyroidism on serum lipids? (Slide 4)

}Increased risk for heart disease secondary to altered lipoprotein metabolism; high ldl

Identify medications used in the treatment of hyperthyroidism

}Low TSH (<0.03 miu/L) }Elevated total and free T4 }Elevated free T4 index }Elevated free T3 }Elevated thyroid autoantibodies }Thyroglobulin antibodies (Anti-thyroglobulin) } Thyroid peroxidase antibodies (TPOAb; Anti-thyroid peroxidase) }TSH receptor antibodies (TRAb) ¨Thyroid-stimulating antibodies (TSAb) ¨TSH-receptor blocking antibodies (TBAb)

How would you calculate the dose of levothyroxine to use in a person who wants to change from aporcine preparation (Armour thyroid) to a synthetic T4 preparation (levothyroxine)? (Slide 9

}Mean Replacement Dose is 1.7 mcg/kg body weight/day }Best to calculate using lean body weight }Initial dose may range from 12.5 mcg to 75 mcg/day }Dosing considerations include severity and duration of the hypothyroidism, weight, age, cardiac status }Pregnancy: higher dose needed in first trimester }Equi-effective doses }1 grain (60 mg) of desiccated thyroid }100 mcg of levothyroxine }25 mg of liothyronine }Shelf life: }Synthetic hormone maximum 2 years (25⁰ C, 60% humidity, closed container with desiccant and inner seals) }For Desiccated Hormone is unknown, but potency is better preserved if it is kept dry

}What additional drug would you consider giving this patient to quickly achieve euthyroid state? a.Levothyroxine b.Glucocorticoid (hydrocortisone) c.Methimazole d.Cholestyramine

}Methimazole. This thionamide drug is preferred due to its longer duration of action allowing for once-daily dosing. A glucocorticoid and cholestyramine may be appropriate if the patient is in thyroid storm.

T2DM

}More common than Type 1 }Insidious onset }Progressive beta cell dysfunction }Decrease in circulating insulin }Increasing insulin resistance }Relative insulin deficiency }Can cause hyperosmolar, nonketotic acidosis → coma } }Does NOT have }Autoimmune component }Human leukocyte antigen (HLA) markers }Ketosis }Environmental insult (e.g. virus) as a role }May require oral medication or insulin for blood sugar regulation but not for survival }

}When considering an appropriate drug regimen for treating acute hyperthyroid status without thyroid storm in an older adult with heart disease, which of the following drugs is typically given first to diminish the associated symptoms? a.Levothyroxine b.Methimazole c.Propranolol d.Propylthiouracil

}Propranolol (or another beta blocker) should be started in most patients as soon as the dx of hyperthyroidism is made as this will ameliorate the symptoms (tachycardia, palpitations, anxiety, heat intolerance) associated with hyperthyroidism.

What test would you use to assess the adequacy of levothyroxine therapy? (Slide 16)

}Serum thyrotropin (TSH) concentration }Single screening test of choice }Normal range 0.4-5.0 mU/L }Upper range limit controversial }Serum total thyroxine (T4) concentration }Normal range 4.6-11.2 mcg/dL }Serum total triiodothyronine (T3) concentration }Serum free T4 (or T3) concentration }More accurate than total T4 or T3 }Free T4 most helpful

: Identify medications used in the treatment of hypothyroidism

}Synthetic T4 is recommended }80% absorption }Half-life 7 days }Once-daily dosing }Steady-state 4-5 weeks }Levothyroxine sodium (Synthroid, Levoxyl, Tirosint, Euthyrox, Unithroid) }Contains T4 }Liothyronine sodium (Cytomel) }Contains T3

What is the most serious adverse effect of the thionamides? (Slide 11

}agranulocytosis (granulocyte count < 500 cells/mm3), an infrequent but potentially fatal adverse reaction. It occurs in 0.1-0.5% of patients taking thionamides, but the risk may be increased in older patients and in those receiving more than 40 mg/d of methimazole.

What signs might be present in an infant with hypothyroidism? (Slide 4)

}cretinism - stunted growth

How do the thionamides lower the amount of thyroid hormone in the body? (Slide 9

}prevent hormone synthesis by inhibiting thyroid peroxidase-catalyzed reactions & blocking the incorporation of iodine into thyroglobulin

What are the two thionamide medications used to treat hyperthyroidism? (Slide 7

¨Methimazole ¨Propylthiouracil (PTU)

What is the typical total insulin requirement in units/kg/day?

•0.5 -1 unit/kg/day

For basal-bolus dosing, what percent of the total daily dose should be basal and what percent bolus?

•Basal dose glargine, detemir, degludec is 50% of the total dose at bedtime •Preprandial bolus is 50% of the total dose, divided before 2-3 meals daily

What are some important contraindications to the use of the GLP-1 receptor agonists? (Slide 12)

•GLP-1 receptor agonists oMonotherapy oCombination with sulfonylureas, metformin, TZD's or insulin glargine •Contraindications •Hypersensitivity to the drug or components •Type 1 diabetes •Treatment of diabetic ketoacidosis •Gastroparesis •Reglan use •Pancreatitis •Bydureon: personal/family history medullary thyroid cancer

Identify the side effects of insulin therapy

•Hypoglycemia •Ketoacidosis (DKA) •Immune Insulin Resistance •Immunopathology- insulin allergy rare •Local reaction to injections •Weight gain •Lipodystrophy

What is the starting dose in patients who have never taken insulin? (Slide 7

•If insulin-naïve with T2DM, start with 10 units and titrate up 1 unit each evening until morning fasting blood sugar is 100-120.

Discuss the indications, contraindications, adverse effects and precautions in the use of theGLP-1 receptor agonists and the DPP-4 inhibitors

•Nausea •Hypoglycemia •Vomiting •Diarrhea •Jitteriness •Dizziness •Headache •Dyspepsia • •Hypersensitivity Reactions •Common oURI, nasopharyngitis oHeadache oAbdominal pain/diarrhea oArthralgia •