Pharm 3 Exam 2 Slides PDF

Diabetes Mellitus Nancy Kamel, PharmD Assistant Professor Transition of Care Pharmacist Hackensack University Medical Center  Objectives 1. Distinguish between Type I and Type II Diabetes Mellitus (DM) with respect to onset, etiology, pathophysiology and tre...

Diabetes Mellitus Nancy Kamel, PharmD Assistant Professor Transition of Care Pharmacist Hackensack University Medical Center  Objectives 1. Distinguish between Type I and Type II Diabetes Mellitus (DM) with respect to onset, etiology, pathophysiology and treatment 2. Describe the normal biological functions of insulin 3. Discuss the general pathophysiology of diabetes mellitus (DM) as follows: early manifestations, acute metabolic abnormalities from lack of insulin, signs and symptoms due to reduction in glucose utilization and hyperglycemia, increased lipolysis, increased protein catabolism 4. Long term complications: microvascular, macrovascular, neuropathic complications 5. List the goals for glycemic control of diabetes 6. Identify the potential complications of diabetes mellitus 7. Discuss the strategies for controlling blood glucose and how these strategies relate to the mechanisms’ of action of the various anti diabetic drugs 8. Distinguish the types of insulin available in terms of time to onset, time to peak, duration of action and route of administration including the insulin pump 2 University of Mount Saint Vincent. Physician Assistant Program  Objectives - cont’d 9. Describe insulin’s role in the management of diabetes mellitus with respect to the following: source of insulin preparations, routes of administration, initial dosing and dosing adjustments, storage, side effects 10. Compare the following insulin preparations: rapid acting, short acting, intermediate acting, long acting, mixture or combination preparations 11. For the following classes of agents used to treat Type II Diabetes Mellitus, list the mechanism of action, treatment guidelines, efficacy in reducing fasting plasma glucose and HgBA1c, contraindications and warnings, pharmacokinetics when appropriate, adverse reactions, monitoring parameters, drug interactions, administration guidelines, use in pregnancy, advantages and disadvantages compared to other classes of antidiabetics and selected examples within each class: sulfonylureas, meglitinides, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, incretin mimetic agents, human amylin analogs, dipeptidyl peptidase IV (DPP-4) inhibitors 12. List the drugs that can affect blood glucose levels 13. Describe the mechanism of action, route, dosage and frequency of administration, adverse effects/ warnings and role of incretin analogs in DM care 3 University of Mount Saint Vincent. Physician Assistant Program  Objectives - cont’d 14. Recognize the need for liver enzyme monitoring in patients taking thiazolidinediones 15. Discuss some of the current controversy regarding Avandia and thiazolidinediones 16. Formulate a treatment plan for diabetes mellitus recognizing the importance of addressing lifestyle modifications, comorbidities and self-blood glucose monitoring 17. List the drugs that can affect blood glucose levels 18. Select the appropriate agent to treat type 2 DM according to ACC/AHA guidelines, provided with a vignette 19. Discuss the principles of combination therapy and know the advantages and disadvantages of various combinations of hypoglycemic medications 20. Identify the signs and symptoms of hypoglycemia and know how to manage it 21. Select the appropriate agent to treat type 2 diabetes mellitus according to American College of 22. Cardiology/American Heart Association (ACC/AHA) guidelines, provided with a vignette 23. Prepare written prescriptions for DM medications for a patient given case studies. 24. Apply lifestyle modifications for diabetes therapy 25. Educate a patient on the proper use and side effects of diabetic medications 4 University of Mount Saint Vincent. Physician Assistant Program  Diabetes Mellitus Diabetes mellitus is a group of metabolic disorders of carbohydrate metabolism that results in impaired glucose regulation and hyperglycemia ○ About 35 million Americans have type II diabetes, with 1.2 million new diagnoses every year ○ About 97.6 million Americans ≥18 years old have prediabetes Type II diabetes accounts for 90-95% of diabetes and is a result of insulin resistance and relative insulin deficiency ○ Average age of onset 45-64 years old ○ ↑ risk with age, obesity, sedentary lifestyle, unhealthy diet ○ ↑ risk of developing macrovascular and microvascular complications 5 University of Mount Saint Vincent. Physician Assistant Program Diabetes Around the World 6 University of Mount Saint Vincent. Physician Assistant Program  Diabetes is a global killer and ranks among the top causes of premature deaths https://diabetesatlas.org 7 University of Mount Saint Vincent. Physician Assistant Program  Pathophysiology of Type II Diabetes important tounderstand Insulin resistance ○ Impaired or decreased response of insulin-responsive cells to insulin → impaired insulin response in target tissues ○ The underlying cause of insulin resistance is attributed to overeating, sedentary lifestyle, and excess weight/obesity Impaired insulin secretion ○ Pancreatic beta cell dysfunction and/or cell death leads to reduced insulin production and lower circulating levels of insulin in the blood Malfunctioning of feedback loops between insulin action and insulin secretion results in abnormally high glucose levels in the blood ○ Hyperglycemia can impair beta cell function and exacerbate insulin resistance 8 University of Mount Saint Vincent. Physician Assistant Program  bet IEEE 9 University of Mount Saint Vincent. Physician Assistant Program  Intestines: state.fm initiallyhaveone Decreased incretin effect t Etey Pancreas: Decreased insulin Fat cells: secretion Increased lipolysis EE Pancreas: Kidneys: Increase glucagon Hyperglycemia Increased glucose secretion reabsorption releastesmor sugarintyte Liver: Increased hepatic Muscle: glucose Decreased production glucose uptake Brain: Neurotransmitter dysfunction 10 University of Mount Saint Vincent. Physician Assistant Program  Pathogenesis of Diabetes-Related Complications Acute abnormalities ○ ↓ glucose uptake by muscle and adipose tissue ○ ↑ hepatic output of glucose ○ ↑ catabolism of proteins in muscle tissue ○ ↑ lipolysis and release of fatty acids from adipose tissue ○ ↓ glucose use + ↑ hepatic glucose production → hyperglycemia ○ Hyperglycemia → glycosuria, polyuria, polydipsia Deficits in insulin secretion and/or action → chronic hyperglycemia, dyslipidemia, and other metabolic abnormalities End-result: tissue damage, accelerated atherosclerosis development, organ dysfunction/damage 11 University of Mount Saint Vincent. Physician Assistant Program  Diabetes Associated Vascular Complications Microvascular disease Macrovascular disease Tends to occur predominantly in tissues where Affects mainly the coronary, peripheral, and glucose uptake is independent of insulin cerebral arteries activity (kidneys, retina, vascular endothelium) route eye exams renal functiontests flu cardio The clock starts ticking years before the onset of clinical diabetes 12 University of Mount Saint Vincent. Physician Assistant Program  Microvascular Complications of Diabetes Diabetic retinopathy ○ Damaged blood vessels leak serum or fat from blood into retina ○ Proliferative: formation of abnormal blood vessels on retinal surface, which can cause vitreous hemorrhage and vision loss ○ Responsible for ~10,000 new cases of blindness every year in the US Diabetic neuropathy ○ Burning, tingling, or electric pain vs. numbness and sensory loss to touch, vibration, and temperature ○ May lead to diabetic foot infections, which are the most common cause of lower extremity amputation (>80%) Diabetic nephropathy ○ Structural and functional changes occur in the kidney due to diabetes and result in proteinuria, hypertension, and progressive reduction of kidney function ○ Leading cause of end-stage kidney disease (ESRD) in the US dialysis 13 University of Mount Saint Vincent. Physician Assistant Program  Macrovascular Complications of Diabetes Central pathological mechanism in macrovascular disease: atherosclerosis Diabetes can induce atherosclerosis development and accelerate its progression Atherosclerosis increases risk of vascular occlusion and acute vascular infarction (heart attack, stroke) Cardiovascular disease (CVD) is the leading cause of death and accounts for the greatest component of health care expenditures in people with diabetes! 14 University of Mount Saint Vincent. Physician Assistant Program  Cardiovascular Disease and Diabetes Diabetes is considered a coronary artery disease risk equivalent ○ 5x risk for myocardial infarction (MI) and 2x risk for recurrent MI Controlled trials have ○ Poorer prognosis after MI, ↑ risk for heart failure (HF) and death demonstrated that intensive glycemic Diabetes is a strong independent predictor of cerebrovascular disease control will LOWER the ○ 2-4 times increased risk of stroke risk of microvascular ○ More severe neurological deficits/disability, poorer prognosis, disease complications higher recurrence Targeting lower HbA1C levels has a lasting Diabetes is a major risk factor for peripheral artery disease effect on the reduction ○ 2x increased prevalence, increased morbidity/mortality, of microvascular accelerated disease course complications ○ Nonhealing ulcers, limb amputation, and physical disability 15 University of Mount Saint Vincent. Physician Assistant Program  mean MEEEEE 16 University of Mount Saint Vincent. Physician Assistant Program  ORDER Pharmacotherapy in any Not Biguanides orbigJuan Alpha-glucosidase Thiazolidinediones Amylin analogs Metformin inhibitors s Pioglitazone Pramlintide i Acarbose Rosiglitazone rose einiii. r 17 University of Mount Saint Vincent. Physician Assistant Program  line it is still 1st Metformin onfore mail.me cardiovascular benefits Mechanism of action will be askedabout Enhances the effect of insulin through the following mechanisms: Reduction in insulin resistance via modification of glucose metabolic pathways altering the glucosepath Inhibits mitochondrial glycerophosphate dehydrogenase →↓hepatic gluconeogenesis and intestinal glucose absorption intestinetianlucose Increases peripheral insulin sensitivity→↑peripheral glucose uptake and glycolysis aftereating and fasting blood glucose levels Lowers postprandial Reduces LDL, increases HDL add on therapy Historically, metformin has been recommended as the preferred initial pharmacological agent for the treatment of type II diabetes. It should be started at the time type II diabetes is diagnosed unless there are contraindications, in combination with lifestyle modifications* * Previous ADA Recommendations 18 University of Mount Saint Vincent. Physician Assistant Program  Clinical Utility normal 25 Dm 6.5 Glycemic efficacy: lowers HbA1c by 1.2-2% over 3 months Lareduction Weight loss (often desired) or weight stabilization usually weight neutral No risk of hypoglycemia eremeen.net Beneficial effect on dyslipidemia mgeaiiiEEia Reduces the risk of microangiopathic complications in patients with diabetes Cost-effective 19 University of Mount Saint Vincent. Physician Assistant Program  Hard contraindication Contraindications: Renal failure or in advanced CKD Adverse Effects (if creatinine clearance < 30 mL/min), respiratory failure, shock, alcoholism, severe liver failure , rare buttestedon chronic pancreatitis, ketoacidosis, sepsis Metformin-associated lactic acidosis or ○ Incidence: ~ 8 cases/100,000 patientIn the foremancingmik years High-risk groups (e.g., elderly individuals, renal insufficiency or CHF) ○ Clinical features: frequently nonspecific Gastrointestinal symptoms: nausea, vomiting, diarrhea, abdominal pain, flatulence Eightors Severe symptoms: muscle cramps, hyperventilation, apathy, disorientation, coma ○ Diagnostics: serum lactate, arterial blood gas: metabolic acidosis and anion gap ○ Treatment: Discontinue metformin and treat acidosis if not youcan getdeath Vitamin B12 deficiency after years years of taking orBizclock Metallic taste in the mouth (dysgeusia) Must be paused prior to surgery Must be paused prior to a CT scan that uses IV contrast media, and should not take it for 48 hours after the procedure unless emergence pt comesinto ED 20 University of Mount Saint Vincent. Physician Assistant Program  Alpha-glucosidase Inhibitors orwheat brush Mechanism of action sugar despite Inhibit alpha-glucosidase (a brush border enzyme expressed by intestinal epithelial cells) → delayed and ↓ intestinal glucose absorption and↓ carbohydrate breakdown Particularly effective in controlling postprandial blood glucose levels doesnotwhat sin's i j The undigested carbohydrates reach the colon, where they are degraded by intestinal bacteria, resulting in the production of intestinal gas leading to significant gastrointestinal symptoms (flatulence, bloating, abdominal discomfort, diarrhea) Clinical utility notsuper significant EEE Glycemic efficacy: lowers HbA1c by 0.8% over 3 months No risk of hypoglycemia much usedv not Contraindications Severe renal failure, inflammatory bowel disease, conditions associated with malabsorption EE i 21 University of Mount Saint Vincent. Physician Assistant Program  not Einer Thiazolidinediones (TZD) (glitazones) this drugtakestime to work weeks onglitter Mechanism of action need.ptmkfmoa Activation of the transcription factor PPARγ (peroxisome proliferator-activated receptor of gamma type in the nucleus) →↑transcription of genes involved in glucose and lipid metabolism →↑ glucose utilization and ↓ hepatic glucose production glucose being uptaken into the cells iii Clinical utility sina.net Patients with severe renal failure and/or contraindications for insulin therapy Clinical outcomes Glycemic efficacy: lowers HbA1c by 1% in 3 months Favorable effect on lipid metabolism: ↓triglyceride, ↓LDL, ↑HDL No risk of hypoglycemia Onset of action is delayed by several weeks 22 University of Mount Saint Vincent. Physician Assistant Program  Important Side Effects & Contraindications Breakup Important side effects Rosightatone specifically BLACK Box ↑Risk of heart failure vascular complication ↑Risk of bone fractures he orbroken (osteoporosis) ↑Fluid retention and edema Weight gain iriiiiage.it in Rosiglitazone: ↑risk of cardiovascular complications like cardiac infarction or death Contraindications absolute contraind 3 or I Congestive heart failure (NYHA III or IV) Liver failure Pioglitazone ○ History of bladder cancer or active bladder cancer: macrohematuria of unknown origin 23 University of Mount Saint Vincent. Physician Assistant Program  common not very Amylin Analogs Mechanism of action Ii Risk of hypoglycemia with insulin (mealtime insulin doses must be Decrease glucagon release reduced by 50% at drug initiation!) Slow gastric emptying Increase feeling of satiety Clinical utility not super proven Primarily lowers postprandial glucose levels Risk of hypoglycemia, nausea Contraindication Gastroparesis (Delayed gastric emptying) Hypoglycemic unawareness (Neuroglycopenia) Hemoglobin A1c greater than 9% Patients unwilling to self-monitor blood glucose 24 University of Mount Saint Vincent. Physician Assistant Program  Pharmacotherapy- cont’d potters are IEEE I Sodium-glucose cotransporter 2 Dipeptidyl peptidase-4 (DPP-4) Glucagon-like peptide-1 (GLP-1) (SGLT-2) inhibitors inhibitors agonists (incretin mimetic Canagliflozin drugs) Dapagliflozin Saxagliptin Empagliflozin Sitagliptin Exenatide Linagliptin Liraglutide Albiglutide c meÉm t Semaglutide esp heartrelayed Iins University of Mount Saint Vincent. Physician Assistant Program 25  C Glomerulus Proximal Convoluted Tubule Early Distal Glucose reabsorption into systemic circulation Glucose SGLT2 SGLT1 EE.ir En 26 University of Mount Saint Vincent. Physician Assistant Program  Renal Glucose Reabsorption Is Increased In T2DM, Which Contributes To Increasing Plasma Glucose Levels 125 Urinary glucose excretion 100 Healthy T2DM 180 mg/dL1 240 mg/dL1 75 (g/day) RTG RTG 50 25 0 50 100 150 200 250 300 Plasma glucose (mg/dL) 27 University of Mount Saint Vincent. Physician Assistant Program  SGLT-2i Lower Renal Threshold for Glucose Excretion (RTG) 125 Urinary glucose excretion 100 T2DM + Healthy T2DM SGLT-2 180 mg/dL 240 mg/dL 75 (g/day) RTG RTG RTG 50 SGLT2 25 0 50 100 150 200 250 300 Plasma glucose (mg/dL) 28 University of Mount Saint Vincent. Physician Assistant Program Glomerulus Proximal Convoluted Tubule Early Distal Glucose in urine Decreased glucose reabsorption into systemic circulation Glucose SGLT2 SGLT2 inhibitor SGLT1 29 University of Mount Saint Vincent. Physician Assistant Program  Sodium-glucose Cotransporter 2 Inhibitors (gliflozins) Mechanism of action Reversible inhibition of SGLT-2 in the proximal tubule of the kidney→↓ glucose reabsorption in the proximal convoluted tubule of the kidney → glycosuria and polyuria Clinical utility Patients with type 2 DM without significant renal failure Clinical characteristics good not Glycemic efficacy: lowers HbA1c by 0.6% over 3 months Promotes weight loss shouldnot betaken as a weightlossdrug refits ↓Blood pressure make sure pt can handle thedrop ↓Risk of cardiovascular mortality in patients with type 2 DM and cardiovascular disease 30 University of Mount Saint Vincent. Physician Assistant Program  Important Side Effects & Contraindications Important side effects postiglucose Effect Urinary tract infections, genital infections (vulvovaginal candidiasis, balanitis) due to glucosuria Dehydration →weight loss, orthostatic hypotension Severe diabetic ketoacidosis ↑ Risk of lower limb amputation: Studies suggest a small increase in amputation rates under canagliflozin treatment Black BOX stillpickifgivenoption Studies indicate a carcinogenic effect (breast cancer, bladder cancer) Contraindications futeaEa.SEEase take them off if severe renal disease Chronic kidney disease: If GFR decreases, drug efficacy decreases and adverse effects increase Recurrent urinary tract infections (e.g.. in patients with anatomical or functional anomalies of the urinary tract) 31 University of Mount Saint Vincent. Physician Assistant Program Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. 32 University of Mount Saint Vincent. Physician Assistant Program Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. 33 University of Mount Saint Vincent. Physician Assistant Program  a II Imagine 34 University of Mount Saint Vincent. Physician Assistant Program Ingestion of food Glucose-dependent ↑Glucose ↑ Insulin from beta cells uptake by (GLP-1 and GIP) muscles ↓Blood Glucose Glucose dependent ↓Glucose ↓ Glucagon from production alpha cells (GLP-1) by liver the den thisenzyme DPP-IV Release of gut enzyme Inactive GLP-1 3 E.EE E hormones (Incretins) Active GLP-1 & GIP Inactive GIP-1 35 University of Mount Saint Vincent. Physician Assistant Program IV Oral The Incretin Effect: Greater Insulin Response After Oral vs IV Glucose in Healthy Individuals Plasma insulin concentration, pmol/L 400 Incretin 300 Effect Oral IV Glucose 200 100 0 60 90 120 150 180 210-30 0 30 Minutes 36 University of Mount Saint Vincent. Physician Assistant Program The Incretin Effect in Subjects Without and With Type 2 Diabetes E.EE E E 37 University of Mount Saint Vincent. Physician Assistant Program  not as good as GLPI'S Dipeptidyl Peptidase-4 Inhibitors (DPP-4i or gliptins) teas Mechanism of action LÉEEFinjectable Inhibits the enzyme DPP-4 from breaking down endogenous GLP-1 and GIP, resulting in 2-3X increased endogenous Emin GULP incretin levels resulting in: ○ Glucose-dependent ↑ insulin secretion ○ Glucose-dependent ↓ glucagon secretion Clinical utility Lowers HbA1c by 0.5-0.75% over 3 months No risk of hypoglycemia unless insulin and/or insulinotropic drugs are used simultaneously because insulin release is glucose-dependent Usually no weight changes 38 University of Mount Saint Vincent. Physician Assistant Program  Side Effects & Contraindications Side effects Gastrointestinal symptoms: diarrhea, constipation (milder than in GLP-1 agonist exposure) Arthralgia Dermatologic reactions Heart failure (saxagliptin) ↑Risk of pancreatitis Need to know Worsening renal function, acute renal failure Headaches, dizziness Contraindications Liver and renal failure 39 University of Mount Saint Vincent. Physician Assistant Program  caksretion Glucagon-Like Peptide-1 Receptor Agonists (incretin mimetics) big GULP victoza is now generic Mechanism of action injectingincretins Synthetic analog of human glucagon-like peptide-1, resistant to DPP-4, results in supraphysiologic (pharmacologic) incretin levels, causing: ○ A glucose-dependent increase in insulin secretion ○ A glucose-dependent inhibition of glucagon secretion decrease 8141980 ○ ↓ gastric emptying & ↑satiety not hungry Clinical utility Lowers HbA1c by 0.5-1.5% over 3 months Subcutaneous injection Weight loss (may be wanted) No risk of hypoglycemia 40 University of Mount Saint Vincent. Physician Assistant Program  Important Side Effects & Contraindications Important side effects Gastrointestinal symptoms ○ Nausea, vomiting ○ Strong feeling of satiety (often desired) ○ Pancreatitis and potentially pancreatic cancer) Potential risk of medullary thyroid cancer (MTC): further investigation required in rats onlyshown BLACK BOX warning for Contraindications Preexisting symptomatic gastrointestinal motility disorders Chronic pancreatitis or a family history of pancreatic tumors Personal or family history of MTC or multiple endocrine neoplasia syndrome type 2 (MEN 2) 41 University of Mount Saint Vincent. Physician Assistant Program In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. 42 University of Mount Saint Vincent. Physician Assistant Program Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. 43 University of Mount Saint Vincent. Physician Assistant Program  Both are targeted 44 University of Mount Saint Vincent. Physician Assistant Program  Pharmacotherapy- cont’d ammo Sulfonylureas Meglitinides Glyburide orgloomybrides Nateglinide Glimepiride Repaglinide Glipizide sura int 45 University of Mount Saint Vincent. Physician Assistant Program  Sulfonylureas Mechanism of action Block ATP-sensitive potassium channels of the pancreatic β cells→ depolarization of the cellfrom membrane → calcium influx→insulin secretion Extrapancreatic effect:↓ hepatic K+ gluconeogenesis, ↑ peripheral insulin sensitivity Clinical utility K+ K+ K+ K+ X Patients who are not overweight, do not 2 consume alcohol, and adhere to a consistent dietary routine Generally not frequently used Lowers HbA1c by 1.2% over 3 months low cost 46 University of Mount Saint Vincent. Physician Assistant Program  Contraindications: Hypoglycemic Important Side Effects unawareness, severe liver or kidney disease willasked be Life-threatening hypoglycemia; increased risk under the following circumstances: not Simultaneous intake of CYP2C9 inhibitors kYÉ BACHRM sulfonyloneasBeta-blockers may mask (e.g., amiodarone, trimethoprim, fluconazole) the warning signs of Patients with renal failure 65 glyburide (use another drug if needed) Elderly esp. hypoglycemia (e.g., roshquestion tachycardia) and decrease Decreased carbohydrate intake (diets or periods of fasting) Elevated glucose utilization (e.g., unaccustomed physical activity) serum glucose levels even Sulfonylurea overdose further. Since sulfonylureas Weight gain also increase the risk of hypoglycemia, the Less common: Rash, photosensitivity, dyspepsia, nausea combination of these two ○ β-cell apoptosis: Studies suggest that sulfonylureas induce substances should be β-cell apoptosis in human islet cells ○ Cardiovascular risk? BAD avoided! 47 University of Mount Saint Vincent. Physician Assistant Program  Dosed multiple times a day taken w food to preypto Meglitinides (Sulfonylurea Analogue) glycemia Shatformted Mechanism of action moa as sulfonal urea's same Blockage of ATP-sensitive potassium channels of the pancreatic beta cells→ depolarization of the cell membrane calcium influx →insulin secretion Meglitinides should be taken shortly before meals Clinical utility Targets postprandial peaks in blood glucose levels (rarely prescribed) Lowers HbA1c by 0.75% over 3 months Tolerated well by patients with chronic kidney disease Important side effects lesser in theory Life-threatening hypoglycemia, especially in patients with renal failure (less of a risk than with sulfonylureas), weight gain Hepatotoxicity (rare) 48 University of Mount Saint Vincent. Physician Assistant Program  recognize glucose Symptomatic Hypoglycemia d target B Definition ○ Blood glucose level as ≤ 70 mg/dL in a diabetic patient ○ Blood glucose level < 55 mg/dL with symptoms of hypoglycemia in a non diabetic patient Signs and symptoms ○ Diaphoresis, palpitations, shaking , dizziness, hunger ○ Confusion, drowsiness, speech difficulty, odd behavior, incoordination onlysign not blocked is sweating Beta blockers can mask signs of hypoglycemia 49 University of Mount Saint Vincent. Physician Assistant Program  Reversing Hypoglycemia (Adults) Monitor patients regularly for rebound hypoglycemia after treatment Alert and oriented patients ○ Oral glucose 15–20 g pills sugartablets, candy, or fruit juice) ○ Fast-acting carbohydrates (e.g., glucose Patients with altered mental status (or impaired oral intake) ○ IV dextrose (e.g., D50W): Repeat after 15 minutes if hypoglycemia persists; multiple doses may be required ○ IM glucagon: if neither oral nor IV routes of administering glucose are feasible ovenap Hyper in EE EEmmi ALWAYS give glucagon When in doubt, treat for hypoglycemia iiiii 50 never give insulincould make wase kill them University of Mount Saint Vincent. Physician Assistant Program  Reversing Hypoglycemia (Pediatric) 1. 2. won't be asked on pham test Estimate weight (2 × Age in years) + 8 Apply formula look thffs Age Dextrose concentration Dose < 1 year D10 2-5 mL/kg 1-8 years D25 2 mL/kg >8 D50 1 mL/ kg Example: A 2-year-old hypoglycemic child...should receive 24 mL of D25 1. (2 × 2) + 8 = 12 kg 2. 2 ml/kg x 12 kg = 24 mL of D25 51 University of Mount Saint Vincent. Physician Assistant Program  Others.. use not approegoydo Bile Acid Sequestrant Dopamine Agonist Colesevelam (Welchol ®) Bromocriptine (Cycloset ®) 52 University of Mount Saint Vincent. Physician Assistant Program  Contraindications: Bowel obstruction, Colesevelam (Welchol ®) triglycerides greater than 500 mg/dL, history of hypertriglyceridemia-induced pancreatitis Mechanism of action Don't Memorize Farnesoid X receptor (FXR) antagonist. Bile acids activate the farnesoid X receptor (FXR), which leads to increased expression of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme necessary for hepatic gluconeogenesis Colesevelam inhibits bile acid reabsorption, thus preventing FXR activation and upregulation of PEPCK, leading to decreased hepatic glucose production Efficacy not good Hemoglobin A1c lowering of 0.4%–0.6% Primarily a fasting blood glucose–lowering effect LDL-C reduction of 15%–18% Adverse Effects Constipation/dyspepsia (could be added if diarrhea with metformin) Potential TG increase (don’t use if TG > 500 mg/dL) 53 University of Mount Saint Vincent. Physician Assistant Program  DONIE Contraindications: Hypersensitivity to Bromocriptine (Cycloset ®) ergot derivative or dopamine, lactation (may inhibit), syncopal migraines Mechanism of action Dopamine receptor agonist. Glucose-lowering mechanism is unknown but improves glucose and energy metabolism and does NOT increase plasma insulin concentration; acts to reset aberrant central neurometabolic control of peripheral metabolism toward normal in patients with diabetes, resulting in a reduction in insulin resistance; improves glucose and energy metabolism through activation of central nervous system dopaminergic pathways responsible for metabolic control (Cylcoset PI). Efficacy Hemoglobin A1c lowering of 0.4%–0.6% Postprandial glucose effect (modest fasting) Adverse Effects Nausea/vomiting, constipation Dizziness, somnolence 54 University of Mount Saint Vincent. Physician Assistant Program  55 University of Mount Saint Vincent. Physician Assistant Program  Amylin is the JÉÉÉÉÉ É fnom Insulin only drug appomedoff Rapid-acting insulin Short-acting insulin Intermediate-acting Long-acting insulin Mixed insulin insulin Insulin lispro Regular insulin Insulin glargine Humulin 30/70 Q Insulin aspart NPH insulin Insulin detemir Novolin 30/70 Insulin glulisine Neutral Protamine Hagedorn Insulin degludec Humalog Mix 50/50 (NPH) need to know these 3 area Ig 56 University of Mount Saint Vincent. Physician Assistant Program  Overview of Insulin Mechanism of action uptake the extragucose Binds to insulin receptors, facilitating cellular glucose uptake Additional Information Hormone produced by the pancreas (beta cells of the islets of Langerhans) Regulates blood glucose levels by promoting glucose uptake into cells Insulin resistance: A hallmark of Type 2 diabetes Insulin deficiency: A hallmark of Type 1 diabetes Essential for carbohydrate, fat, and protein metabolism Used in the management of diabetes mellitus (primarily Type 1, and sometimes Type 2) & hyperkalemia Delivery methods: Subcutaneous injections, insulin pumps, inhaled insulin nobody is using IV insulin 57 University of Mount Saint Vincent. Physician Assistant Program  Mimicking Nature with Insulin Therapy 24-hr Profile 50 (µU/mL) Insulin 25 0 Basal Insulin Breakfast Lunch Dinner 150 (mg/dL) Glucose 100 50 Basal Glucose 0 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 AM Time of Day PM 58 University of Mount Saint Vincent. Physician Assistant Program  The Concept of Basal/Bolus acting intermediate longdetemir, glargine, NPH) Basal Insulin (degludec, acting ○ Decreases fasting glucose production ○ Requires consistent (constant) insulin levels if ○ Approximates 50% of daily insulin needs ○ Equivalent doses Bolus Insulin (regular, aspart, glulisine, lispro, inhaled) ○ Limits postprandial hyperglycemia (PPHG) there is insulin dosing gestion ○ Requires immediate insulin peak re ○ Each meal requires 10-20% of daily insulin requirements INSULIN EEEvaries depending on day ligrams 59 University of Mount Saint Vincent. Physician Assistant Program  basal should Aspart, Lispro, Glulisine (3–5 hr) control fasting Regular (4-6 hr) NPH (10–16 hr) E.EE Plasma Insulin Levels meal Detemir (6–24 hr) Glargine (~24 hr) 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (hr) 60 University of Mount Saint Vincent. Physician Assistant Program  FYI overtime peoefstabnf.to fnInEEenwatea 3bounits.mn untits c 100 in 1 me 1 EE 61 END OF LECTURE 10.25.24 University of Mount Saint Vincent. Physician Assistant Program  aetgancia.si Rapid-acting Short-acting EiiEsstsiaingaowntoeat Intermediate-acting Long-acting Mixed insulin Agents Agents Agents Agents Agents lispro Regular insulin NPH insulin glargine Humulin 30/70 aspart glulisine Pharmacokinetics EEn Pharmacokinetics detemir degludec Novolin 30/70 Combo of 30% regular Onset: ~ 30 minutes Onset: 1-2 hours and 70% NPH insulin Pharmacokinetics Peak: 2-3 hours Peak: 6-10 hours Pharmacokinetics Humalog Mix 50 Onset: 5-15 mins Duration: 4-6 hrs Duration: 10-16 hrs Onset: 1-4 hours Combo of 50% lispro Peak: ~ 1 hour Peak: none, flat and 50% lispro dosed2xida Kday Duration: 3-4 hrs Clinical Utility Clinical Utility Duration: ~ 24 hours protamine insulin Standard insulin option Glucocorticoid-induced Clinical Utility Clinical Utility Pharmacokinetics for lowering blood hyperglycemia lispro and aspart Administered once Biphasic effect glucose levels in an acute Usually administered are most setting twice daily or twice daily well-studied Often used in Clinical Utility The only insulin suitable antihyperglycemic combination with Administered 2-3 for intravenous use upE.GE agents in short-acting insulin times daily Often used in pregnancy combination with Etio s Usually combined long-acting insulin with long-acting insulin EniEe i 62 University of Mount Saint Vincent. Physician Assistant Program Aim rapid Long acting 511am 63 University of Mount Saint Vincent. Physician Assistant Program  Pharmacokinetics The absorption time determines the onset, peak, and duration of effect Increasedlonger takes Quicker insulin absorption time Decreased insulin absorption time P erature Cold injection site or coldpen 19 Manipulative therapy (e.g., massages) Obesity Deep subcutaneous injection Peripheral injection site Injection into the abdominal skin around the navel Superficial subcutaneous injection makeneffewtfs.no The most common places to inject insulin are the abdomen (belly), the back of the upper arms, the upper buttocks, and the outer thighs 64 University of Mount Saint Vincent. Physician Assistant Program  Initiating MDI (Multiple Daily Injections) Therapy expectedto dose on exam Empiric Dosing - Insulin Analogues ○ Type 1: 0.5 units/kg/d or Type 2: 0.7-1.0 units/kg/d insulinnaive ○ Calculate Daily Dose goes to meal time Give 50% as Basal Insulin 50 insulin Give 50% as Bolus Insulin ○ Split into three doses the onergogivided Adjust accordingly Algorithm (The Rule of 1800) Carbohydrate Counting 65 University of Mount Saint Vincent. Physician Assistant Program  Basal-Bolus Insulin: Example Calculation is 80 kg type 1 DM; SCr 0.9 mg/dl exage 0.5 units/kg = 40 units of insulin/day Glargine (Detemir, Degludec) 20 units QD Aspart (Glulisine, Lispro) 6 units pre-breakfast Aspart (Glulisine, Lispro) 7 units pre-lunch add to 20 Aspart (Glulisine, Lispro) 7 units pre-dinner Titrate insulin doses to blood sugars (ratio may vary considerably from 50:50) 66 University of Mount Saint Vincent. Physician Assistant Program  I p stem wing basal Correctional Insulin Dosing wettpineftents Rule of 1800 (Rapid acting insulin) 1800/current daily insulin dose equals the mg/dl change of glucose per 1 unit insulin Titrate dose using algorithm ○ Example: Patient from last example t ○ 40 units insulin/day 1800/40= 45 mg/dl per unit (that is insulin sensitivity that’s the factor that you are changing by) ○ Blood Glucose termermea < 80 Subtract 1 unit from usual premeal insulin dose 80-125 Use usual premeal dose target 126-170 Add 1 unit to usual premeal dose 171-215 Add 2 units to usual premeal dose 216-260 Add 3 units to usual premeal insulin dose 67 University of Mount Saint Vincent. Physician Assistant Program  Correctional Insulin Dosing Rule of 1500 (Regular insulin) 1500/current daily insulin dose equals mg/dl change of glucose per 1 unit insulin Titrate dose using algorithm ○ Example: 50 units insulin/day 1500/50= 30 mg/dl per unit ○ Blood Glucose < 80 Subtract 1 unit from usual premeal insulin dose 80-110 Use usual premeal dose 111-140 Add 1 unit to usual premeal dose 141-170 Add 2 units to usual premeal dose 171-200 Add 3 units to usual premeal insulin dose 68 University of Mount Saint Vincent. Physician Assistant Program  Insulin to Carbohydrate Ratio (ICR) Be familiar Rule of 500 (500/total current daily insulin dose) equals the insulin/carbohydrate ratio ○ Titrate dose using algorithm ○ Example: 50 units insulin/day 500/50 = 10 Insulin/carbohydrate ratio equals 1 unit of insulin for every 10 grams of CHO ingested 40 units insulin/day 500/40 = 12.5 Insulin/carbohydrate ratio equals 1 unit of insulin for every 12.5 grams of CHO ingested ratifiers 69 University of Mount Saint Vincent. Physician Assistant Program  ETI see Initiating Basal Insulin Therapy in T2DM Continue oral agent(s) at same dosage (may eventually reduce or DC - especially secretagogue therapy) esxawee.ro sEgEe I Add single insulin dose (10-20 units or 0.1-0.2 units/kg) ○ Detemir or NPH Insulin – HS dosing ○ Degludec or Glargine insulin – once daily dosing Adjust insulin dose according to fasting blood sugars Adjust the insulin dose every 3-4 days as needed ○ Increase 2 U if FBG 100–120 mg/dL ○ Increase 4 U if FBG 121–140 mg/dL ○ Increase 6 U if FBG 141–180 mg/dL ○ Increase 8 U if FBG >180 mg/dL Reduce dose immediately if experience fasting hypoglycemia Treat to target (usually FPG 80–100 mg/dL) The “Target” depends on the patient 70 University of Mount Saint Vincent. Physician Assistant Program  Sick Day Rules for Insulin-Treated Patients Certain conditions require temporary insulin adjustments Increased insulin demand Decreased insulin demand Illness Physical exercise: Increase carbohydrate intake and/or reduce prandial and/or basal insulin Stress either before or after exercise. Vomiting and diarrhea: can lead to decreased glucose uptake, increasing the risk of hypoglycemia DO NOT STOP INSULIN! Keep usual basal insulin (even if the person isn’t eating) 71 University of Mount Saint Vincent. Physician Assistant Program  Type 2 Diabetes Management Recommendations regarding indications for treatment and target diabetes differ between clinical practice guidelines The following recommendations are consistent with those in the 2024 ADA guidelines unless specified otherwise 72 University of Mount Saint Vincent. Physician Assistant Program  Diagnostic Criteria Hemoglobin A1C Fasting Plasma Glucose (FPG) 2-hour PG / oral glucose tolerance (HbA1C) Last thing am test (OGTT) Normal 160) is a major challenge Patient may need multiple medications to control blood pressure in CKD ○ Many patients need >3 medications to control BP RAAS inhibitors (angiotensin-converting-enzyme inhibitor (ACE-I), angiotensin II receptor antagonist (ARB), direct renin inhibitor) 1st real life Aldosterone antagonists, diuretics, beta-blockers, calcium channel blockers, direct vasodilators, alpha-blockers, centrally acting alpha-adrenergic agonists 18 University of Mount Saint Vincent. Physician Assistant Program  ACEis & ARBS 25 Ear Aldosterone antagonists Diuretics Beta-blockers aspirepter MOA S E A T Thiazide Used in CKD pts w/ Vasodilate the efferent arteriole & ↓ glomerular Usually administered May not be beneficial evidence-based capillary pressure twice daily with markedly indications Beneficial in the early stages CKD (↓ albuminuria) Adjunct to other agents reduced kidney ○Congestive heart It can be prescribed to lower albuminuria in for resistant function failure normotensive patients (eGFR < 30) hypertension ○Post myocardial Contraindications May reduce urine Loop infarction Bilateral renal-artery stenosis, pregnancy albumin levels Used to lower BP and Caution w/ atenolol Caution in CKD patients: treat edema in and bisoprolol due Common adverse effects advanced CKD to accumulation of Hyperkalemia (↑ risk of hyperkalemia with ○Reduction in GFR parent drug (renally ○Increased risk of so foredema acettineliminated) and higher dose and reduced kidney function Potassium-sparing diuretics → hyperkalemia hyperkalemia Potassium-sparing metabolites Cough with ACEi and angioedema Monitor Usually avoided due to Monitor ↑ of serum creatinine (Scr) up to ~30-35%EEng ○ SCr/eGFR increased risk of hyperkalemia ○Heart rate ○ SCr 35% change may require dose hypoglycemia modification 19 University of Mount Saint Vincent. Physician Assistant Program  manEroadbuyemia CCB Direct Vasodilators Alpha-blockers Centrally Acting zosins Alpha-Adrenergic Dihydropyridine Hydralazine Causes peripheral Agonists Can increase urine Peripheral-vasodilating effect through a direct vasodilation albumin excretion relaxation of vascular smooth muscle Used in CKD when Clonidine due to vasodilator No dose adjustment needed for renal dysfunction ○Other BP lowering Should NOT be effects Must be dosed multiple times per day agents are not stopped abruptly → Monitor: headache, May be used in HF if ACEi/ARBs not tolerated tolerated rebound HTN peripheral edema Limited use due to adverse drug reactions ○Adjunctive therapy Monitor Non-dihydropyridine Headache, drug-induced systemic lupus is needed, especially ○Depression Limited evidence for erythematosus (rare) with markedly ○Sedation reduction of Monitor: antinuclear antibody titer (SLE suspected) reduced kidney ○Dry mouth proteinuria in diabetic function Minoxidil kidney disease (2nd ○If the patient needs Guanfacine, line) Direct vasodilation of arterioles with little effect on an alpha-blocker for methyldopa Avoid in pts w/ severe venous system treatment of BPH Should NOT be left ventricular Limited use due to adverse drug reactions Monitor stopped abruptly → dysfunction, sick ○Headache, hirsutism (hair growth) ○ Peripheral edema rebound HTN sinus syndrome, or Adjunctive therapy w/ beta-blockers and loop ○ Orthostatic Methyldopa 2nd or 3rd degree diuretics to reduce tachycardia and fluid retention hypotension monitor Coombs' III heart block Monitor: serial echocardiograms for pericardial (caution fall risk) Monitor: ECG, HR test (low risk of effusion hemolytic anemia) 20 University of Mount Saint Vincent. Physician Assistant Program  “Resistant” Hypertension Before adding additional anti-hypertensives consider these potential issues: Adherence-barriers to taking medications as prescribed Side effects ○ Fatigue, headache, dizziness, sexual dysfunction ○ High pill burden Sodium restriction ○ Re-education should be part of medication management ○ Consider dietician referral ○ Consider whether dose of diuretic is adequate, may require higher doses for natriuresis 21 University of Mount Saint Vincent. Physician Assistant Program  Knowledge Check 55 year old male presents to the primary care clinic this morning. His PCP asks you to evaluate him and start a medication for his hypertension (average BP ~144/82 mmHg). PMH: Newly diagnosed hypertension; diabetes x 7 years; poor A. Metoprolol 25mg BID medication adherence B. Doxazosin 2mg qHS Labs: sCr = 1.3; FBG = 99; A1C = 7.8; K = 3.0; eGFR = 55 ml/min/1.73m2, UACR = 350 mg/g ALE C. Lisinopril 10mg daily D. Amlodipine 10mg daily Current Medications E. Verapamil 80mg TID Glyburide - 5 mg BID Metformin- 500 mg BID Which of the following medications would you suggest for this patient? 22 University of Mount Saint Vincent. Physician Assistant Program  Diabetes Hyperglycemia is associated with hyperfiltration There is evidence that good control of newly diagnosed Glycemic diabetes may help prevent CKD control Circulating insulin levels are higher as CKD advances re The risk for hypoglycemia increases with CKD EEHypoglycemia Insulin needs may change unexpectedly as kidney disease progresses 23 University of Mount Saint Vincent. Physician Assistant Program  cont Metformin Insulin Sulfonylureas Meglitinides Thiazolidinedione No dose 1/3 of a dose of insulin is Glipizide is the preferred Increased risk of Onset slower during adjustment if degraded by kidneys and agent as clearance and hypoglycemia due to which time there is a eGFR >45 ml/min thus prolonged half life half-life are not affected decreased renal low hypoglycemia risk per 1.73m2 in renal impairment by a reduction in eGFR clearance of the Metabolized by the Do not initiate or Mainstay of therapy in ○Less hypoglycemia parent drug and liver assess risk/benefit patients with CKD due to risk in CKD compared metabolites Fluid retention and if currently on lack of evidence for oral to other agents acute heart failure are Lower doses are major limiting side Glyburidedonterest metformin if and non-insulin and required in CKD effects eGFR=30-45 injectable Glimepiride are avoided Concern in CKD ml/min per 1.73m2 antihyperglycemic in patients with CKD patients with mineral Discontinue if agents because of active and bone disease due eGFR 10% Statin initiation is not indicated for patients on dialysis 29 University of Mount Saint Vincent. Physician Assistant Program  Anemia Anemia may develop as eGFR declines A complication of CKD Anemia may ○ Result from inadequate erythropoietin synthesis ○ Develop early and worsen as CKD progresses ○ Occur earlier in people with diabetes ○ Involve inadequate iron intake, impaired iron absorption and chronic inflammation 30 University of Mount Saint Vincent. Physician Assistant Program  Kidneys Act as Oxygen Sensors in the Body Renal tissue hypoxia triggers Generaltmechanism erythropoietin production Erythropoietin stimulates erythrocyte (red blood cell) synthesis in bone marrow startstedifnfsttmi Hemoglobin is the primary iron-containing protein in erythrocytes that transports and delivers oxygen to tissues wittttrfect.vn dseffective Both erythropoietin and iron are required to produce hemoglobin (Hgb) and correct hypoxia dothey not 31 University of Mount Saint Vincent. Physician Assistant Program  Additional Factors for Inadequate Iron in CKD Both a spontaneous decrease in intake and aversion to foods with protein may occur as eGFR declines Anemia in CKD is associated with morbidity and mortality Hepcidin may accumulate in CKD Observational data show association with: Hepcidin is the hormone that controls iron Coronary artery disease homeostasis Left ventricular hypertrophy Hospitalization for cardiac disease This hormone regulates iron absorption in Death from congestive heart failure the gut and mobilization of stored iron All-cause mortality Inflammation may reduce absorption of iron 32 University of Mount Saint Vincent. Physician Assistant Program  Hepcidin-Master Iron Regulator on Need won't beEked Emethietin iron Iron regulates hepcidin; increased iron levels stimulates hepcidin production Increased erythropoietin activity reduces hepcidin levels Inflammation and infection increases hepcidin synthesis Hepcidin inhibits iron release from macrophages as well as intestinal iron absorption 33 University of Mount Saint Vincent. Physician Assistant Program  Knowledge Check Which of the following is a possible cause of anemia in chronic kidney disease patients? A. Increased GI iron absorption B. Decreased erythropoietin synthesis C. Increased red blood cell life span D. Decreased inflammation 34 University of Mount Saint Vincent. Physician Assistant Program  Iron Therapy - Boxed Warning for ESAs Hemoglobin target is controversial emigienetta in during dialysis ○ In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL 10 11 12waddeadly ○ No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks ○ Use the lowest ESA dose sufficient to reduce the need for red blood cell (RBC) transfusions Treatment Goals ○ Reduce blood transfusion requirements ○ Minimize hospitalizations ○ Decrease signs and symptoms of anemia Dosedinunits ○ Improve quality of life Treatment Approaches ○ Typically utilizes the combination of iron therapy and erythropoiesis stimulating agents (ESA) 35 University of Mount Saint Vincent. Physician Assistant Program  36 University of Mount Saint Vincent. Physician Assistant Program  Tips on Oral Iron Supplements Impaired absorption with Caffeinated beverages (especially tea) SE constipation Calcium (foods and beverages, supplements) Antacids H2 receptor blockers Amount of elemental iron differs between Proton pump inhibitors oral iron supplements Consider Absorption: Ferrous+2 iron > ferric+3 iron A 325 mg dose of: Start with half of the could be everyday or 2x recommended dose, gradually increase Ferrous fumarate has 108 mg elemental iron (33%) Take with food Ferrous sulfate has 65 mg elemental iron (20%) Try different preparation Ferrous gluconate has 35 mg elemental iron (12%) Take in divided doses Stool softener may help fE.tt onassuption 37 University of Mount Saint Vincent. Physician Assistant Program  Treating Anemia With Erythropoiesis Stimulating Agents ESA are genetically engineered forms of erythropoietin Biological so only dosed parenterally Must advise patient of risks and benefits IV Iron may be used in CKD patients Recombinant EPO first available in 1989 to treat anemia Five formulations available in the US in end-stage renal disease (ESRD) Iron dextran Prior to availability, patients often symptomatic with ○ BOXED WARNING: Anaphylactic Hemoglobin (Hb) in 6-7 g/dL range reactions (requires test dose) Sodium ferric gluconate Formulations IV or subcut Iron sucrose blood volume Ferumoxytol Epoetin alfa induces HTN ○BOXED WARNING: Anaphylaxis (no Darbepoetin alfa test dose specification) Methoxy polyethylene Glycol-epoetin beta Ferric carboxymaltose 38 needto do test deselectPgd University of Mount Saint Vincent. Physician Assistant Program  Adverse Effects Blood transfusions are associated with many risks Patients required frequent blood transfusions before Common adverse events (≥20%) ESA were available ○ Hypertension (most common) Risks associated with blood transfusions include: ○ Infection ○ Volume overload ○ Hypotension ○ Iron overload ○ Myalgia ○ Allosensitization (i.e. sensitization to donor ○ Nausea blood) ○ Diarrhea ○ Transfusion reactions ○ Bloodborne infection Monitoring Parameters ○ Hemoglobin once weekly upon initiation of an ESA and until stable; then once monthly ○ Evaluate transferrin saturation and serum ferritin not 11 or 12 39 University of Mount Saint Vincent. Physician Assistant Program  Hemoglobin in CKD: Guidelines Suggestions No dialysis CKD If Hb ≥ 10 g/dL do not initiate an ESA If Hb < 10 g/dL, consider rate of fall of Hb, prior response to iron, risk of needing a transfusion, risk of ESA therapy, and presence of anemia symptoms before initiating an ESA Do not use ESAs to maintain Hb above 11.5 g/dL Hemodialysis CKD Use ESAs to avoid drop in Hb to