Diabetes PDF

ENDOCRINE CONDITIONS CHAPTER 44 DIABETES BACKGROUND Diabetes is a common condition in the United States, affecting > 30 million Americans (just over 1 in 10). The central problem in all types of diabetes is that blood glucose (BG) remains high (hyperglycemia} due to dec1•eased insttlin secretion fr...

ENDOCRINE CONDITIONS CHAPTER 44 DIABETES BACKGROUND Diabetes is a common condition in the United States, affecting > 30 million Americans (just over 1 in 10). The central problem in all types of diabetes is that blood glucose (BG) remains high (hyperglycemia} due to dec1•eased insttlin secretion from the pancreas, decreased insulin sensitivity (i.e., how responsive cells are to insulin} or both. Chronic hyperglycemia can lead to damage throughout the body, including organ and nerve damage. Patients with diabetes have abnormalities in how insulin is produced and used in the body. Insulin is a hormone produced by beta-cells (also called islet cells} in the pancreas. It is responsible for moving glucose out of tl1e blood and into body cells to be used as energy. The glucose is either moved to muscle cells (primarily} for immediate use, or stored for later use by liver cells (as glycogen, the quick glucose reserve} or adipose (fat) cells. Insulin is counter-balanced by glucagon; they have opposite effects, as shown in the diagram below. Glucagon is produced by alpha-cells in the pancreas and works when BG is low. Glucagon pulls glucose back into the circulation by releasing glucose from glycogen. If glycogen is depleted, glucagon will signal fat cells to make ketones as an alternative energy source. Insulin Fat Cell docks to insulin receptor, which enables glucose to enter muscle cells -.....___ • • • - . o0 Glucose • - - - - Glucagon o In the Blood • signals muscle 0 O (from Food) O • • • • • ~f)~o~e~ b:st into glucose Glucagon signals FFAs to make ketones, as alternative Insulin signals liver cells energy source to store glucose as glycogen Glucagon signals liver cells to release glucose 612 from glycogen eel ctlRxPrep iStock.rnm/ttsz 44 I DIABETES SCREENING Risk for diabetes increases with ~- Everyone, even those with no other risk factors, should be tested beginning at 45 years old. All asymptomatic children, adolescents and adults who are overweight (BMI ;:: 25 or :2: 23 in Asian-Americans) with at least one other risk factor (e.g., physical inactivity) should be tested. If the result is normal, repeat testing every 3 years. Typically, the AlC is measured with a blood sample sent to a lab. Point-of-care AlC test kits provide immediate results and can be used by prescribers or patients. Patients can measure their own BG using a glucose meter or with a continuous glucose mon.itoring (CGM) device (discussed later). Testing Frequency Glycemic control (AlC or another test) should be measured: Quarterly (every 3 months) if not yet at goal Biannually (every 6 months, or twice per year) if at goal DIAGNOSIS There are three types of tests used to identify if prediabetes or diabetes is present: Interpreting the A1C with the eAG 1. HemoglobinAlC (or simply AlC) indicates the average BG over approximately the past 3 months. It can be difficult to understand how an AlC value correlates with BG values measured on a glucose meter. The estimated average glucose (eAG) is an interpretation of the AlC value that makes it appear similar to a glucose meter value. 2. Fasting plasma glucose (FPG) gives the BG at that moment, and is taken after fasting for;:: 8 hours. An AlC of 6% is equivalent to an eAG of 126 mg/dL. Each additional 1% increases the eAG by-28 mg/dL. 3. The OGTT determines how well glucose is tolerated by measuring the BG level 2 hou rs after drinking a liquid that is high in sugar (glucose). No single test is preferred. The criteria for diagnosing diabetes are shown in the Study Tip Gal below. A positive test should be confirmed with a second abnormal test result from either the same sample or a new sample, unless there is a clear clinical diagnosis (e.g., classic symptoms of hyperglycemia plus a random BG ;:: 200 mg/dL). OGTT, A1C(%) FPG (mg/dl) 126 . Diabetes Prediabetes II 2-hr BG (mg/dl) ~200 'I •• TREATMENT GOALS The treatment goals for AlC, preprandial glucose (before meals) and postprandial glucose (PPG, which is BG measured after eating) are shown in the Study Tip Gal below. Example: an AlC of 7% is 126 + 28 =154 eAG. LIFESTYLE MODIFICATIONS Lifestyle modifications, used alone or in combination with medications, are an essential component of all diabetes care plans. The modifications and goals listed below help lower BG, blood pressure and cholesterol. Weight Loss Goal waist circumference is < 35 inches for females and < 40 inches for males. Overweight or obese patients should be encouraged to lose > 5% of their body weight. Medications and/or surgery may be needed to achieve this (see Weight Loss chapter). Individualized Medical Nutrition Therapy Consume natural forms of carbohydrates and sugars (i.e., from vegetables, fruits, whole grains, legumes, dairy). Avoid alcohol or drink in moderation. • Patients with TlD should use carbohydrate-counting, where the prandial (mealtime) insulin dose is adjusted to the carbohydrate intake. A carbohydrate serving is measured as 15 grams, which is approximately one small piece of fruit, 1 slice of bread or 1/, cup of cooked rice/pasta. Physical Activity Perform at least 150 minutes of moderate-intensity aerobic activity per week spread over at least 3 days. Not Pregn11nt Pregnant 'An A1C goal of< 6.5% may be acceptable, if it can be reached without significant hypoglycemia. A less-stringent goal of< 8% may be appropriate (e.g., if severe hypoglycemia, or with a limited life-expectancy). 614 Reduce sedentary (long hours of sitting) habits by standing every 30 minutes, at a minimum. Smoking Cessation Encourage all patients who smoke to quit (see Tobacco Cessation chapter). RxPREP 2022 COURSE BOOK I RxPREP ©2021, ©2022 COMPREHENSIVE CARE In addition to glycemic control, treatment is aimed at preventing the long-term complications of diabetes. Left untreated, diabetes damages nearly all parts of the body. Complications are categorized as microvascular (small vessel) or macrovascular (large vessel), as shown in the Study Tip Gal to the right. I Autonomic neuropathy ~i:_astroparesis, loss of bladder L ntrol, erectile dysfunction) Coronary artery disease (CAD), including Ml Cerebrovascular disease, . including stroke (CVA) -- Peripheral artery disease (PAD) 'Macrovascular disease is the same as atherosclerotic cardiovascular disease (ASCVD) Statin Treatment If allergy: use clopidogrel 75 mg/day. High-intensity statin (atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily) for: Not recommended for primary prevention (in most); the risk of bleeding is about equal to the benefit. Can consider if high risk. Diabetes + ASCVD CAD/PAD: aspirin + low-dose rivaroxaban can be added. Age 50-75 years with multiple ASCVD risk factors Used in pregnancy to .J, risk of preeclampsia. T2D: eye exam with dilation at diagnosis. Disease* Peripheral neuropathy (i.e., loss of sensation, often in the feet), i risk of foot infections and amputations Aspirin 75-162 mg/day (usually given as 81 mg/day)~ recommended for ASCVD secondary prevention (e.g., post-Ml). Diabetic Retinopathy Macrovascular Retinopathy Diabetic kidney disease (i.e., nephropathy) Diabetes is the top cause of lower-extremity amputations, kidney failure and blindness. The primary cause of death is cardiovascular disease, which occurs at a 2 - 4 times higher incidence than in the general population. The American Diabetes Association (ADA) provides recommendations for monitoring, preventing and treating complications of uncontrolled diabetes (see diagram below). Microvascular Disease • If retinopathy, repeat annually. If not, repeat every 1-2 yrs. Moderate-intensity statin for: Diabetes + age 40- 75 years (no ASCVD) Diabetes + age < 40 years + ASCVD risk factors Add-On Treatment (to Maximally Tolerated Statin) Ezetimibe if ASCVD 10-yr risk> 20%. lcosapent ethyl (Vascepa) if LDL is controlled but TGs are 13S-499 mg/dl. Required, in addition to all childhood vaccines: Monitoring: lipid panel annually and 4-12 weeks after starting a statin or increasing the dose. Hepatitis B virus (HBV) series. Influenza, annually. Pneumovax 23: 1 dose between ages 2-64, and another dose at age 2 65. Annually: a lO·g monofllamenl test and 1 other test (e.g., pinprick, temperature, vibration) to assess sensation (feeling). Blood Pressure Control I • < 140/90 mmHg acceptable if ASCVD risk < 15%. No albuminuria': thiazide, CCB, ACE inhibitor or ARB ... Albuminuria: ACE inhibitor or ARB. refer to podiatrist. CAD: ACE inhibitor or ARB. Treatment options: pregaballn. dulo><etlne or gabapentin. Foot Care Counseling Every day: wash, dry and examine feet. Moisturize the top and bottom of feet, but not between the toes. Each office visit: take off shoes to have feet checked. Annual foot exam by a podiatrist (for most). Trim toenails with nail file; do not leave sharp edges from the clipper. and shoes. ~ < 130/80 mm Hg (esp. if ASCVD or 10-year risk 2 15%) Treatment Comprehensive foot exam at least annually. If high-risk, Wear ~ BP Goal feet when sitting. •I 'Albuminuria is either a urine albumin 2 30 mg/24 hours or a urine albumin-to-creatinine ratio (UACR) 2 30 mg/g '*If pregnant - !!£ ACE inhibitor, ARB or any other RAAS drug Diabetic Kidney Disease Check urine albumin and eGFR: Annually if normal kidney function. Twice yearly if reduced kidney function (eGFR 30-60 ml/ min/1.73 m2 or urine albumin 2 300). 615 44 I DIABETES NATURAL PRODUCTS Natural products are commonly used for T2D, with low or minimal efficacy. Products used to decrease BG include cassia cinnamon, alpha lipoic acid, clll'omium, magnesium and Panax/American ginseng. Most patients will still require the use of prescription drugs. TREATMENT FOR TYPE 2 DIABETES The goals of treatment are to maintain BG levels in the target range (while avoiding hypoglycemia) and to reduce long-term complications of hyperglycemia. The ADA guidelines provide recommendations for initial treatment and add-on therapy (see Study Tip Gal below). Metformin is the first-line treatment; it should be used indefinitely unless contraindications are present or it is not tolerated. A second drug, from a different class, is recommended in the following instances: Start two drugs at baseline if the AlC is 8.5 -10%. Start two drugs at baseline regard.less of AlC if the patient has ASCVD, heart failure or chronic kidney disease. A drug with proven benefit for these conditions should be used (see below). • Add on a second drug if the AlC l'emalns above goal on metformin. In this case, treatment is driven by patient-specific factors (e.g., cost, risk of hypoglycemia and weight). Continue adding medications in this way until the AlC goal is met. Insulin can be used initially if hyperglycemia is severe (AlC > 10% or BG> 300 mg/dL), see Insulin section. TREATMENT ALGORITHM ( FirstDrug J Metformin + Lifestyle Changes 1 A1C ar.10\le goal Reg;itdlriSS of A.1C ( Second Drug l ASCVD or high risk' HF CKD No ASCVD, HF or CKD l l l l SGLT2l with benefit' SGLT21" or GLP·1a Gl?· la Qr SGLT2.i with b(!l'efit' wilh beoefit r n- Allvqass Con'Stder hyp0j]ycemia risk. wewht kl>,s/g;iTn poll!ntlal, co$.l Besl fmr hypoglytemia riak, DPP-41, GLP•1~ SGLT21, TZD Best for y;,t!l&hl los . GLP·1a orSGLT21 Best for cost: SU or TZD ( Third Drug J l If A1C above goal Atrydass lfA1Cabovegoal ye started tSGLT2i with benefit: empagliflozin, canagliflozin or dapagliflozin GLP-1a with benefit: dulaglutide, liraglutide, SC semaglutide Combinations to avoid: DPP-4i + GLP-1a, SU+ Insulin taJ @RxPrep ASCVD = atherosc/erotic cardiovascular disease, HF= heart failure, CKD = chronic kidney disease, GLP-1a = glucagon-like peptide 1 receptor agonist, SGLT2i = sodiumglucose co-transporter 2 inhibitor, TZD = thiazolidinedione, SU= sulfonylurea, DPP-4i = dipeptidyl peptidase 4 inhibitor *High risk: age~ 55 with coronary, carotid or lower extremity artery stenosis > 50%, or LVH '*SGLT2i preferred for albuminuria 616 RxPREP 2022 COURSE BOOK I RxPREP ©2021, ©2022 NON-INSULIN MEDICATIONS FOR TYPE 2 DIABETES BIGUANIDE Metformin primarily works by J. hepatic glucose production, .!. intestinal absorption of glucose and t insulin sensitivity. Metformin is first-line treatment for T2D and can be used in prediabetes. Use of metformin is dependent on eGFR. DRUG DOSING SAFETY/SIDE EFFECTS/MONITORING Metformin (Glucophase, Glucophase XR, Fortamet, Glumetza, Riomet) IR: 500 mg daily or BID BOXED WARNING IR: 500,850, 1,000 mg ER: 500, 750, 1,000mg Riomet liquid: 500 mg/5 ml ER: 500-1,000 mg daily with dinner initially Titrate weekly, usual maintenance dose: 1,000mg BID Max dose: 2,000· 2,550 mg/ (varies by product) Lactic acidosis - risk i with renal impairment, radiological studies with contrast, excessive alcohol or certain drugs (see Drug Interactions) CONTRAINDICATIONS eGFR < 30, acute or chronic metabolic acidosis (includes DKA) WARNINGS Not recommended to start if eGFR 30-45; reassess if already taking and eGFR falls< 45 Vita min B12 deficiency Give with a meal to -l- GI upset SIDE EFFECTS GI effects: diarrhea, nausea, flatulence, cramping; usually transient (resolve over time) NOTES -l- A1C 1-2%, weight neutral, no hypoglycemia ER: swallow whole; can leave a ghost tablet (empty shell) in the stool eGFR units: mL/min/1.73 m' Metformin Drug Interactions Intravascular iodinated contrast media (used for imaging studies) can 1 the risk of lactic acidosis. Discontinue metformin before the imaging procedure. Metformin can be restarted 48 hours after the procedure if eGFR is stable. Alcohol can! the risk for lactic acidosis; excessive intake, acute or chronic, should be avoided. The combination of metformin and topiramate can risk of metabolic acidosis. t the SODIUM GLUCOSE CO-TRANSPORTER 2 INHIBITORS The sodium glucose co-transporter 2 (SGLT2) protein, expressed in the proximal renal tubules, is responsible for the reabsorption of filtered glucose. By inhibiting SGLT2, these drugs reduce reabsorption of glucose and i urinary glucose excretion, which J. BG concentrations. SGLT2 inhibitors are dosed based on eGFR. SGLT2 inhibitor names end in "-gliflozin." DRUG DOSING SAFETY/SIDE EFFECTS/MONITORING Canagllflozln (lnvokanal 100 mg daily prior to the first me~I of the day; can i to 300 mg daily CONTRAINDICATIONS eGFR 30-59: max dose 100 mg/day eGFR < 30: not recommended, unless albuminuria > 300 mg/day Dapagliflozin (Farxisal 5 mg daily in the morning; can i to 10 mg daily eGFR 30-45: not recommended eGFR < 30: contraindicated Empagliflozln (Jardiancel 10 mg daily in the morning; can i to 25 mg daily eGFR 30-44: not recommended eGFR < 30: contraindicated Ertugliflozin (Steglatro) Dialysis WARNINGS Ketoacidosis (can occur with BG < 250 mg/dl., D/C prior to surgery due to risk) Genital mycotic infections, urosepsis and pyelonephritis, necrotizing fasciitis of the perineum Hypotension, AKI and renal impairment (due to intravascular vo ume depletion) Canagliflozin: i risk of leg and foot amputations, higher risk with history of amputation, PAD, peripheral neuropathy and/or diabetic foot ulcers; hyperkalemfa risk when used with other drugs that increase potassium; risk o f ~ SIDE EFFECTS Weight loss, T urination, 1' t hirst, hypoglycemia, i Mg/PO4 - - - - - - - - - - - - - - NOTES 5 mg daily in the morning; can i to 15 mg daily -l- A1C 0.7-1%, low hypoglycemia risk (unless used with insulin) eGFR 30-59: not recommended eGFR < 30: contraindicated Ca nagliflozin, dapagllfto.:in and empagliflozin have shown reductions in HF and CKD progression. Most renal data is with canagliflozin and dapagliflozin. Most heart failure data is with empagliflozin and dapagliflozin. eGFR units: mL/min/1.73 m' 617 44 I DIABETES SGLT2 Inhibitor Drug Interactions i risk of intravascular volume depletion (causing hypotension and acute kidney injury) if used in combination with diuretics, RAAS inhibitors or NSAIDs. Uridine diphosphate glucuronosyltransferase (UGT) inducers (e.g., rifampin, phenytoin, phenobarbital) can J, levels of canagliflozin; consider using 300 mg dose if used in combination and eGFR 2': 60 mL/min/1.73 m2 • GLUCAGON-LIKE PEPTIDE 1 AGONISTS 1 Glucagon-like peptide 1 (GLP-1) agonists are analogs of the incretin hormone GLP-1, which glucose-dependent insulin secretion, J, glucagon secretion, slows gastric emptying, improves satiety and can result in weight loss. They are all subcutaneous injections available in either single-dose or multidose pens, except semaglutide also comes as an oral tablet. Some are available in combination with long-acting insulin. GLP-1 agonist names end in" -tide." DRUG Liraglutide (Victoza) Saxenda - for weight loss Dulaglutide (Trulicity) i Exenatide (Byetta) DOSING SAFETY/SIDE EFFECTS/MONITORING 0.6 mg SC~ x 1 week, then i to 1.2 mg SC daily; can i to 1.8 mg SC daily BOXED WARNING All (except Byetta and Adlyxin): risk of thyroid C-cell carcinomas; do not use if personal or family history of medullary thyroid carcinoma (MTC) or with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 0.75 mg SC once weekly; can to 1.5 mg SC once weekly I i 5 mcg SC Bl D for 1 month; can to 10 mcg SC BID WARNINGS Pancreatitis (can be fatal, risk factors: gallstones, alcoholism or i CrCI < 30: not recommended Exenatide ER ~ (Bydureon, Bydureon BCise) Lixisenatide (Adlyxin) Semaglutide (Ozempic - SC, Rybelsus - oral) mg SC once weekly -- CrCI < 30: not recommended ! 10 mcg SC daily x 14 days, then • i to 20 mcg SC daily i TGs) Not recomm ended in patients with severe GI disease, including gastroparesis Bydureon: serious injection-site reactions (e.g., abscess, cellulitis, necrosis) with or without SC nodules Ozempic: i complications with diabetic retinopathy SIDE EFFECTS Weight lo s. nausea, vomiting, diarrhea, hypoglycemia, injection site reactions I NOTES t A1C 0.5- 1.5%; t postprandial BG, low hypoglycemia risk eGFR < 15: not recommended Do not use with DPP-4 inhibitors (overlapping mechanism) SC: 0.25 mg SC once weekly x 4 weeks, then i to 0.5 mg SC weekly; can i to 1 mg SC weekly Llraglutlde. dulaglutide and semaglu Ide have demonstrated ASCVD benefit PO: 3 mg PO daily x 30 days, then i to 7 mg daily; can i to 14mg Byetta and Adlyxin: give dose within 60 minutes of meals; others anytime Pen needles are not provided with Byetta, Victoza, or Adlyxin; provided with all others (which are the weekly injections) eGFR units: mL!min/1.73 m2 , CrCI units: ml/min GLP-1 Agonist Drug Interactions These drugs slow gastric emptying and can reduce the absorption of orally administered drugs. Use caution with narrow therapeutic index drugs or drugs that require threshold concentrations for efficacy (e.g., antibiotics, oral contraceptives). Take oral contraceptives at least one hour before exenatide or Adlyxin and at least 11 hours after Adlyxin. Can i the INR in patients on warfarin, monitor INR. 618 RxPREP 2022 COURSE BOOK I RxPREP ©2021, ©20 22 INSULIN SECRETAGOGUES Sulfonylureas (SUs) and meglitinides are known as insulin secretagogues; they work by stimulating insulin secretion from the pancreatic beta-cells to decrease postprandial BG. Meglitinides have a faster onset (15 - 60 minutes) and a shorter duration of action compared to the SUs. Older, first generation SUs (chlorpropamide, tolazamide and tolbutamide) should not be used as they can cause prolonged hypoglycemia. Meglitinide names end in" -glinide" and sulfonylurea names start with "Q" and end in "-ide." Sulfonylureas DRUG DOSING SAFETY/SIDE EFFECTS/MONITORING Gllpizide (Glucotrol, G/ucotrol XL, Glipizide XL) IR: 5 mg daily, titrate to a max dose of 40 mg/day CONTRAINDICATIONS Doses > 15 mg should be divided BID XL: 5 mg daily, titrate to a max dose of 20 mg/day Gllmepirlde (Amaryl} 1-2 mg daily, titrat max dose of 8 mg/ ___ Glyburide Micronized glyburide (Glynase} __ _ Glyburide: 2.5-5 mg daily, titrate to a max dose of 20 mg/day G/ynose: 1.5-3 mg daily, titrate to a max dose of 12 mg/day Sulfa allergy (not likely to cross-react, see Drug Allergies & Adverse Drug Reactions chapter) WARNINGS I Hypoglycemia SIDE EFFECTS Weight gain, nausea NOTES J, AlC 1-2%; J, efficacy after long-term use (as pancreatic beta-cell function declines) Glipizide IR: take 30 minutes before a meal; all other products are taken with breakfast or the first meal of the day; may need to hold doses if N PO Glucotrol XL is an OROS formulation and can leave a ghost tablet (empty shell) in the stool Glimeplride, glyburide not preferred in elderly (on the Beers er terla) due to hypoglycemia risk Patients with G6PD deficiency can be at increased risk of hemolytic anemia with sulfonylureas Meglitinides DRUG DOSING SAFETY/SIDE EFFECTS/MONITORING Repaglinide 0.5-2 mg TIO AC Max dose: 16 mg daily CONTRAINDICATIONS Nateglinide (Star/ix) Type 1 diabetes, OKA Take 15-30 minutes before meals WARNINGS 60-120 mg TIO AC SIDE EFFECTS Take 1-30 minutes before meals Hypoglycemia, caution with severe liver/renal impairment Weight gain, headache, upper respiratory tract infections (URTls) NOTES J, AlC 0.5-1.5% Sulfonylurea and Meglitinide Drug Interactions Insulin in combination with either SUs or meglitinides i risk of hypoglycemia and should be avoided. Use caution with other drugs that can decrease BG (see Hypoglycemia section). Gemfibrozil and clopidogrel cant repaglinide, leading to J, BG. Repaglinide is contraindicated with gemfibrozil. Alcohol can t the risk for delayed hypoglycemia when taking insulin or insulin secretagogues. SUs are CYP2C9 substrates; use caution with 2C9 inducers or inhibitors. 619 44 I DIABETES DIPEPTIDVL PEPTIDASE 4 INHIBITORS Dipeptidyl peptidase 4 (DPP-4) inhibitors prevent the enzyme DPP-4 from breaking down incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones help to regulate BG levels by insulin release from the pancreatic beta-cells and J, glucagon secretion (which J, hepatic glucose production) from pancreatic alpha-cells. These drugs enhance the effects of the body's own incretins. DPP-4 inhibitor names end in "-gliptin." 1 DRUG DOSING SAFETY/SIDE EFFECTS/MONITORING Sltagllptln (Januvla) 100 mg daily WARNINGS Llnagllptin (Tradjenta) Pancreatitis, severe arthralgia ijoint pain), acute renal failure, hypersensitivity reactions, CrCI 30-49: 50 mg daily bullous pemphigoid (blisters/erosions requiring hospitalization) CrCI < 30: 25 mg daily - - - - - - - Risk of heart failure seen with saxagllptin and alogllptln, but warning added for class 5 mg daily Alogliptin: hepatotoxicity No renal dose adjustments - - - - - - - - - - ~ SIDE EFFECTS Saxagliptin (Onglyza) Alogliptin (Nesina) 2.5-5 mg daily eGFR < 45: 2.5 mg daily 25 mg daily CrCI 30-59: 12.5 mg daily CrCI < 30: 6.25 mg daily Generally well tolerated, can cause nasopharyngitis, URTls, UTls, peripheral edema, rash NOTES - - - , J, AlC 0.5-0.8%, weight neutral, low hypoglycemia risk Do not use with GLP-1 agonists (overlapping mechanism) 1 CrC/ units: ml/min, eGFR units: mL/min/1.73 m2 DPP-4 Inhibitor Drug Interactions Saxagliptin is a major substrate of CYP450 3A4 and P-gp. Limit the dose to 2.5 mg with strong CYP3A4 inhibitors, including protease inhibitors (e.g., atazanavir, ritonavir), clarithromycin, itraconazole, ketoconazole. Linagliptin is a major substrate of CYP3A4 and P-gp. Linagliptin levels are J, by strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort). THIAZOLIDINEDIONES Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor gamma (PPARy) agonists that i perlpheral insulin sensitivity (i uptake and utilization of glucose by the peripheral tissues, also known as insulin sensitizers). Names of TZDs end in "-glitazone." DRUG DOSING SAFETY/SIDE EFFECTS/MONITORING Ploglltazone (Actos) Initial: 15-30 mg daily BOXED WARNINGS Max dose: 45 mg daily Can cause or exacerbate heart failure, do not use with NYHA Class Ill/IV heart failure Rosiglitazone: increased risk of Ml WARNINGS Hepatic failure. edema (including macular edema), risk of fractures Can stimulate ovulation, which can lead to unintended pregnancy; may need contraception Roslglltazone (Avandla) i 4·8 mg daily Pioglitazone: Max dose: 8 mg daily SIDE EFFECTS risk of bladder cancer; do not use in patients with a history of bladder cancer Peripheral edema, weight gain, URTls, myalgia Rosiglitazone: i LDL, HDL and total cholesterol IJ,NOTES AlC 0.5-1.4%, low risk of hypoglycemia Thiazolidinedione Drug Interactions TZDs are major substrates of CYP2C8; use caution with CYP2C8 inducers (e.g., rifampin) or inhibitors (e.g., gemfibrozil). 620 RxPREP 20 2 2 COURS E BOOK I RxPRE P ©2021. ©202 2 OTHER MEDICATIONS The following classes of drugs can be used in specific situations, but given their modest efficacy, side effects and/or frequency of administration, they are not used routinely for the treatment of T2D. DRUG CLASS Alpha-Glucosida Inhibitors Acarbose (Precose) Miglitol (Glyset) COMMENTS -- MOA: inhibit the metabolism of intestinal sucrose, which delays glucose absorption. Do not cause hypoglycemia alone, but if hypoglycemia occurs due to another drug, it cannot be treated with sucrose (present in fruit juices, table sugar or candy); glucose tablets or gel need to be purchased to treat hypoglycemia. Each dose should be taken with the first bite of each meal. GI side effects are common (flatulence, diarrhea, abdominal pain). BIie Acid Binding Resins Colesevelam (Welchol) ----------------------- AIs o indicated for Dyslipidemia (see Dyslipidemia chapter). Constipation is the most common side effect. Can bind and decrease absorption of other drugs and fat-soluble vitamins (A, D, E, K). Dopamine Agonlst Bromocriptine (Cycloset) Amylin Analog Contraindicated in patients with syncopal migraines (can cause hypotension and orthostasis) and those who are breastfeeding (inhibits lactation). -- Should not be used with metoclopramide or other dopamine agonists. ------- Pramlintide (Symlin) MOA: helps control PPG by slowing gastric emptying, which suppresses glucagon secretion following a meal and satiety. SC injection Can be used in type 1 or type 2 diabetes, administered SC prior to each major meal. Skip dose if skipping meal. i Contraindicated in gastroparesis. Significant hypoglycem ia risk; must reduce mealtime insulin dose by 50% when starting. Side effects include~- vomiting, anorexia and weight loss. COMBINATIONS METFORMIN + SU Metformin/glipizide METFORMIN + SGLT2 INHIBITOR DPP-4 INHIBITOR+ SGLT2 INHIBITOR Metformin/canagllflozin (lnvokamet, lnvokamet XR) Linagliptin/empagliflozin (Glyxambi) Metformin/glyburide Metformin/dapagliflozin (Xigduo XR) Saxagliptin/dapagliflozin /Qtern) Metformin/empagliflozin (Synjardy, Synjardy XR) Saxagliptin/dapagliflozin/metformin (Qtemmet XR) Sitagliptin/ertugliflozin (Steg/ujan) METFORMIN + TZD Metformin/pioglitazone (Actoplus Met) Metformin/ertugliflozin (Segluramet) METFORMIN + MEGLITINIDE GLP-1 AGONIST + LONG-ACTING INSULIN Metformin/repaglinide (PrandiMet) Liraglutide/insulin degludec (Xultophy) Lixisenatide/insulin glargine (Soliqua) Metformin/linagliptin (Jentadueto, Jentadueto XR) SULFONVLUREA + TZD Metformin/sltagllptln (Janumet, Janumet XR) Glimepiride/pioglitazone (Duetact) Does not include premixed insulins - see Insulin section METFORMIN + DPP-4 INHIBITOR Metformin/alogliptin (Kazano) Metformin/ saxagliptin (Kombiglyze XR) DPP-4 INHIBITOR+ TZD Alogliptin/pioglitazone (Oseni) 621