Diabetes: Don’t Sugar Coat It! A review on for the treatment of diabetes mellitus Anna Delzer, PharmD, BCACP Margit Hansing, PharmD Objectives

• 1. Compare and contrast the mechanisms of action of current medications to treat diabetes.

• 2. Describe the risks and benefits associated with antihyperglycemic agents and review monitoring recommendations.

• 3. Identify the place in therapy of each class of antihyperglycemic agents. Current Treatment Guidelines ADA Treatment Guidelines

American Diabetes Association, 2018 ADA Treatment Guidelines

American Diabetes Association, 2018 Garber, et al., 2018 Garber, et al., 2018 Antidiabetic Review ()

• Mechanism of action ñ ↓hepatic glucose production and ↑ peripheral glucose uptake/use

• Dosing ñ Immediate release ñ Initial dose: 500 mg daily-BID or 850 mg daily ñ Increase by 500 mg/day at weekly intervals or 850 mg/day every 2 weeks ñ Maximum dose: 2550 mg/day ñ Extended release ñ Initial dose: 500 mg daily with the evening meal ñ Increase by 500 mg/day at weekly intervals ñ Maximum dose: 2000 mg/day (Glucophage XR®, Glumetza®), 2500 mg/day (Fortamet®) ñ Typically need dose >1,500 mg/day to see a response

• Strategies to improve tolerability ñ Take with food ñ Titrate dose slowly ñ Use the long-acting formulation (metformin SA) Bristol Myers-Squibb, 2017 Cross. 2016. Biguanide (metformin)

• Adverse effects ñ GI Side effects (nausea, vomiting, diarrhea, flatulence) ñ Rare: macrocytic anemia and lactic acidosis

• Contraindications ñ Renal disease ñ eGFR <30 ml/min: contraindicated ñ eGFR 30-45 ml/min: initiating therapy not recommended; weigh risks vs benefits of continuing therapy in patients already taking metformin ñ Metabolic acidosis, including DKA ñ Hypersensitivity

Bristol Myers-Squibb, 2017 Cross. 2016. Biguanide (metformin)

• Warnings ñ Discontinue metformin at the time of or before an iodinated contrast imaging procedure in the following patients ñ eGFR between 30 and 60 mL/minute ñ in patients with a history of liver disease, alcoholism, or • Risk factors for lactic heart failure acidosis • Renal or hepatic ñ those receiving intra-arterial iodinated contrast. impairment ñ Reevaluate eGFR 48 hours after imaging and restart • ≥ 65 years old metformin if renal function is stable • Radiologic study with contrast ñ Surgery • Surgery ñ Lactic acidosis • Hypoxic states (acute heart failure) ñ Discontinue in any case of hypoxia • Excessive alcohol ñ heart failure exacerbation, respiratory failure, sepsis, acute intake MI, etc • Concomitant use of certain drugs (for example: carbonic • Monitoring anhydrase inhibitors) ñ Renal function ñ B12 levels Bristol Myers-Squibb, 2017 Cross. 2016. Biguanide (metformin)

Advantages Disadvantages Potential cardiovascular benefit Secondary failure rate: 5-10% per year Weight neutral Renal considerations No hypoglycemia when used as Tolerability monotherapy Inexpensive Efficacy

• Efficacy • First-line agent • A1c lowering: 1-2% • Fasting blood sugar primarily affected

American Diabetes Association, 2018. Cross. 2016.

• Mechanism of action ñ Binds to receptor on beta cell ‰ release

Pfizer, 2008. -Aventis, 2009 Sanofi-Aventis, 2013 Cross. 2016. Sulfonylureas

• Dosing ñ Take with food ñ (Glucotrol®) ñ Initial dose: 5 mg daily (2.5 mg daily if elderly or liver disease) ñ Increase dose by 2.5-5 mg per day in weekly increments ñ Doses >15 mg should be split ñ Maximum dose: 40 mg daily ñ Extended release: 2.5-5 mg daily (maximum dose: 20 mg daily) ñ Glyburide (DiaBeta®) ñ Initial dose: 2.5-5 mg daily (1.25 mg daily if increased risk of hypoglycemia) ñ Increase dose by 2.5 mg per day in weekly increments ñ Consider splitting doses >10 mg per day ñ Maximum dose: 20 mg daily ñ Avoid use if CrCl <50 ml/min ñ Glimepiride (Amaryl®) ñ Initial dose: 1 or 2 mg daily ñ Increase dose by 1-2 mg every 1-2 weeks

ñ Maximum dose: 8 mg daily Pfizer, 2008. Sanofi-Aventis, 2009 Sanofi-Aventis, 2013 Cross. 2016. Sulfonylureas

• Contraindications • Adverse effects ñ Weight gain, hypoglycemia, GI ñ Hypersensitivity upset ñ DKA ñ Rare: rash, photosensitivity ñ Type 1 diabetes

• Monitoring • Warnings ñ Hypoglycema ñ Severe renal or liver disease ñ Hypoglycemic unawareness ñ Hemolytic anemia in patients with G6PD deficiency ñ Increased risk of cardiovascular mortality ñ Sulfa allergy

Pfizer, 2008. Sanofi-Aventis, 2009 Sanofi-Aventis, 2013 Cross. 2016. Sulfonylureas

Advantages Disadvantages Inexpensive Weight gain Efficacy Hypoglycemia Fast onset of action Primary failure rate: 5-10% Secondary failure rate: 5-10% per year

• Efficacy ñ A1c lowering: 1-2% ñ Mixed effect on blood sugar ñ 50% of the maximal dose accounts for 80% of drug efficacy

American Diabetes Association, 2018. Cross. 2016. (TZDs) • Mechanism of action ñ Activates PPAR-γ (peroxisome proliferator–activated receptor γ) receptor; ‰ ↑ insulin sensitivity in skeletal muscle and ↓hepatic glucose production

Takeda Pharmaceuticals America, Inc., 2011 GlaxoSmithKline, 2007 Cross. 2016. Thiazolidinediones (TZDs)

• Dosing ñ (Actos®) ñ Initiate 15 or 30 mg daily ñ Maximum dose: 45 mg daily ñ Maximum dose if taking strong CYP2C8 inhibitor (gemfibrozil): 15 mg daily ñ (Avandia®) ñ Initiate 4 mg daily ñ Maximum dose: 8 mg daily ñ Risk Evaluation and Mitigation Strategy (REMS) added in 2010 due to increased risk of MI ñ Removed in 2013 ñ Adjust dose at 8-12 week intervals

Takeda Pharmaceuticals America, Inc., 2011 GlaxoSmithKline, 2007 Cross. 2016. Thiazolidinediones (TZDs) • Adverse effects • Contraindications ñ Weight gain, swelling, upper ñ Hypersensitivity respiratory tract infection ñ NYHA Class III or IV heart failure ñ Rare: hepatotoxicity, macular ñ Type 1 Diabetes edema • Precautions • Monitoring ñ CHF ñ ALT, AST, total bilirubin, ñ Hepatotoxicity alkaline phosphatase at baseline ñ Don’t initiate if ALT >2.5x upper limit of normal (ULN) ñ Signs and symptoms of heart failure ñ Atypical fractures in women ñ Increased risk of myocardial infarction (rosiglitazone) ñ Bladder cancer (pioglitazone) ñ Macular edema Takeda Pharmaceuticals America, Inc., 2011 GlaxoSmithKline, 2007 Cross. 2016. Thiazolidinediones (TZDs)

Advantages Disadvantages No hypoglycemia Delayed onset of action Can use in renal dysfunction Adverse effect profile Potential cardiovascular benefit Not recommended in hepatic impairment (pioglitazone) Potential beta-cell sparing

• Efficacy ñ A1c lowering: 0.8-1.5% ñ Fasting blood sugar primarily affected

American Diabetes Association, 2018. Cross. 2016. Dipeptidyl peptidase-4 (DPP-4) Inhibitor

• Mechanism of action ñ Inhibits DPP-4 enzyme from breaking down endogenous glucagonlike -1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) ‰ increased endogenous incretin values ‰ glucose-dependent increase in insulin secretion and glucose-dependent decrease in secretion

Merck & Co., Inc., 2006 AstraZenecaa, 2017 Takeda Pharmaceuticals America, Inc.,2016 Boehringer Ingelheim Pharmaceuticals, Inc.,2017 Dipeptidyl peptidase-4 (DPP-4) Inhibitor

• Dosing ñ (Januvia®) ñ CrCl ≥ 50ml/min: 100 mg daily ñ CrCl 30-50 ml/min: 50 mg daily ñ CrCl <30 ml/min: 25 mg daily ñ Saxagliptin (Onglyza®) ñ eGFR ≥ 45 ml/min: 5 mg daily ñ eGFR <45 ml/min or if taking strong CYP 3A4/5 Inhibitor: 2.5 mg daily ñ (Nesina®) ñ CrCl ≥ 60 ml/min: 25 mg daily ñ CrCl 30-60 ml/min: 12.5 mg ñ CrCl <30 ml/min: 6.25 mg daily ñ Linagliptin (Tradjenta®) ñ 5 mg daily (no dose adjustment required in renal or hepatic insufficiency) Merck & Co., Inc., 2006 AstraZenecaa, 2017 Takeda Pharmaceuticals America, Inc.,2016 Boehringer Ingelheim Pharmaceuticals, Inc.,2017 Cross.2016. Dipeptidyl peptidase-4 (DPP-4) Inhibitor

• Adverse effects • Contraindications ñ GI upset, upper respiratory tract ñ Type 1 diabetes infection, headache ñ Hypersensitivity ñ Rare: pancreatitis, skin reaction (bullous pemphigoid), arthralgia • Warnings • Monitoring ñ Pancreatitis ñ Renal function ñ Heart failure ñ Signs and symptoms of ñ Hepatotoxicity (alogliptin) pancreatitis and heart failure ñ Arthralgia ñ Bullous pemphigoid

Merck & Co., Inc., 2006 AstraZenecaa, 2017 Takeda Pharmaceuticals America, Inc.,2016 Boehringer Ingelheim Pharmaceuticals, Inc.,2017 Cross. 2016. Dipeptidyl peptidase-4 (DPP-4) Inhibitor

Advantages Disadvantages Potential beta-cell sparing effect Expensive Weight neutral Modest efficacy No hypoglycemia as Require dose adjustment in renal monotherapy impairment Tolerability

• Efficacy ñ A1c lowering 0.6%-0.8% ñ Postprandial glucose primarily affected

American Diabetes Association, 2018. Cross. 2016. GLP-1 Receptor Agonists

• Mechanism of action ñ glucose-dependent ↑ in insulin secretion, glucose-dependent inhibition of glucagon secretion, ↓ gastric emptying, ↑ satiety

Lexicomp. 2018 Cross. 2016. Meier. 2012. GLP-1 Receptor Agonists

ñ Dosing ñ (Byetta®) ñ (Adlyxin®) ñ Initial: 5 mcg BID before meals ñ Initial: 10 mcg once daily for 14 days ñ Max: 10 mcg BID before meals ñ Maintenance: 20 mcg once daily (after 4 weeks) ñ (Ozempic®) ñ Exenatide XR (Bydureon®) ñ Initial: 0.25 mg once weekly x4 ñ 2mg once weekly weeks ñ (Victoza®)* ñ Increase to 0.5 mg once weekly x4 ñ 0.6mg once daily weeks ñ If tolerated, increase to 1.2 mg daily, ñ Maximum: 1 mg once weekly then 1.8 mg daily ñ (Tanzeum®) – discontinued ñ (Trulicity®) July 2017 ñ 0.75 to 1.5 mg once weekly

Lexicomp. 2018 *Concomitant use with insulin and/or insulin secretagogues: reduced dose of insulin and/or secretagogues may be needed Cross. 2016. GLP-1 Receptor Agonists

• Adverse Effects ñ Nausea, vomiting, diarrhea, headache, injection-site nodule ñ Rare: pancreatitis/renal dysfunction

• Contraindications ñ Gastroparesis ñ Pancreatitis history ñ CrCl <30 mL/min (exenatide only) ñ Personal or family history of medullary thyroid carcinoma; multiple endocrine neoplasia syndrome type 2 (liraglutide, exenatide XR, albiglutide, dulaglutide)

Lexicomp. 2018 Cross. 2016. GLP-1 Receptor Agonists

• Precautions ñ Gallbladder and bile duct disease ñ Pancreatitis ñ US Boxed Warning: Thyroid c-cell tumors (exenatide XR, liraglutide) ñ GI disease/gastroparesis ñ CV effects (liraglutide, dulaglutide) ñ Hepatic impairment (liraglutide, dulaglutide) ñ Renal impairment ñ Injection site reactions

• Monitoring ñ Renal function, s/sxs of pancreatitis, s/sxs of gallbladder disease, changes in thoughts/behaviors

Lexicomp. 2018 Cross. 2016. GLP-1 Receptor Agonists

Advantages Disadvantages

Weight loss Subcutaneous injection

Cardiovascular benefit with May reduce rate and extent of absorption of liraglutide drugs that require rapid absorption

Convenient dosing

Beta cell-sparing effect

• Efficacy • A1c lowering: 0.6-1.5% • Primarily postprandial glucose reduction with twice-daily exenatide • Mixed postprandial BG and FBG reduction with liraglutide and weekly exenatide

Lexicomp. 2018 Cross. 2016. SGLT2 Inhibitors • Mechanism of action ñ ↓reabsorption of filtered glucose, lowers renal glucose threshold, and increases urinary excretion of glucose

Lexicomp. 2018 Cross. 2016. SGLT2 Inhibitors

• Dosing ñ (Invokana®) ñ (Jardiance®) ñ eGFR ≥60 ml/min: 100-300 mg ñ 10-25 mg before the first meal before the first meal of the day of the day ñ eGFR 45-59 ml/min: 100mg daily ñ eGFR <45 ml/min: not ñ eGFR <45 ml/min: not recommended recommended ñ ertugluflozin (FDA approved ñ (Farxiga®) 12/2017) ñ 5-10 mg before the first meal of the ñ Initial: 5mg once daily day ñ Max: 15mg once daily ñ eGFR <60 ml/min: not ñ eGFR <60 mL/min: use not recommended recommended

Lexicomp. 2018 Cross. 2016. SGLT2 Inhibitors

• Adverse effects • Contraindications ñ Hypotension, hyperkalemia, genital ñ Hypersensitivity mycotic infections, urinary tract ñ eGFR <30 mL/min, ESRD, or infections, increased urination dialysis

• Monitoring • Warnings ñ Renal function and volume status ñ Dehydration ñ Liver function (prior to initiation of ñ Bone fractures canagliflozin, dapagliflozin, ñ Ketoacidosis ) ñ Lipid abnormality ñ Bone density for patients at risk for falls and fracture ñ Bladder cancer (dapagliflozin) ñ FDA Black Box Warning: risk of amputation (canagliflozin)

Lexicomp. 2018 Cross. 2016. SGLT2 Inhibitors

Advantages Disadvantages Specific mechanism of action Expensive Weight loss Adverse effects (mycotic infections, fracture) No hypoglycemia as Requires dose adjustment in renal monotherapy impairment Macrovascular benefits

• Efficacy • A1c lowering: 0.8-1.2% • Mixed effect: lowers both postprandial and fasting hyperglycemia

Lexicomp. 2018 Cross. 2016.

• Mechanism of action ñ Binds to receptor ‰ insulin release

• Dosing ñ (Starlix®) ñ 60 mg before meals if near A1c goal, otherwise 120 mg before meals ñ Given 1-30 minutes before meals ñ (Prandin®) ñ A1c <8% or CrCl <40 ml/min: 0.5 mg before each meal ñ A1c ≥ 8%: 1-2 mg before each meal ñ Maximum dose: 16 mg/day ñ Take 15-30 minutes before meals ñ Dose adjustments recommended in patients taking strong CYP3A4 or CYP2C8 inhibitors Novartis, 2017 Novo Nordisk, 2009 Cross. 2016. Meglitinides

• Adverse effects • Contraindications ñ Hypoglycemia, weight gain ñ DKA ñ Type 1 diabetes • Monitoring ñ Gemfibrozil and repaglinide ñ No routine safety ñ Hypersensitivity monitoring required • Warnings ñ Increased risk of MI when taking repaglinide with insulin NPH ñ Not indicated to be used concomitantly ñ Concomitant repaglinide and clopidogrel not recommended ñ Hypoglycemic unawareness Novartis, 2017 Novo Nordisk, 2009 Cross. 2016. Meglitinides

Advantages Disadvantages Fast onset of action Weight gain Less hypoglycemia/weight gain than Hypoglycemia sulfonylureas Dosed multiple times per day Secondary failure Expensive

• Efficacy ñ A1c lowering: 0.5-1% ñ Postprandial blood sugar primarily affected

American Diabetes Association, 2018. Cross. 2016. α-Glucosidase inhibitors

• Mechanism of action ñ inhibit the enzyme α-glucosidase, found in the brush border of the small intestine, which is responsible for the breakdown of complex carbohydrates into thus delaying and reducing post meal carbohydrate absorption

• Dosing ñ (Precose): 25 mg with first bite of meal; start once daily and then increase to twice daily; then, take three time daily with meals ñ Typical maintenance dose: 50-100 mg with meals ñ Maximum dose: ≤60 kg: 50 mg 3 times daily; >60 kg: 100 mg 3 times daily ñ (Glyset): 25mg three times daily at the start of each meal ñ Typical maintenance dose: 50 mg three times daily ñ Maximum dose: 100mg three times daily

Lexicomp. 2018 Cross. 2016. α-Glucosidase inhibitors

• Adverse effects ñ Common: transient flatulence, abdominal discomfort, diarrhea ñ Rare: elevated LFTs

• Contraindications ñ IBD, intestinal obstruction, malabsorption, DKA, cirrhosis

• Precautions ñ Renal impairment, use only simple sugar or skim milk to treat hypoglycemia (acarbose may delay absorption time of sucrose (cane sugar))

• Monitoring ñ Renal function, LFTs

Lexicomp. 2018 Cross. 2016. α-Glucosidase inhibitors

Advantages Disadvantages No hypoglycemia as monotherapy TID dosing may decrease adherence Weight neutral Modest efficacy Poorly tolerated GI side effects Requires slow titration

• Efficacy • A1c lowering: 0.5-1% • Reduces postprandial BG values

Lexicomp. 2018 Cross. 2016. Analog

• Mechanism of action ñ Glucose-dependent inhibitor of glucagon secretion, reduced rate of gastric emptying, increased satiety

• Dosing ñ (Symlin) ñ Type 1 ñ Initial: 15 mcg immediately prior to major meals ñ Titrate to target dose of 30-60 mcg prior to major meals ñ Maximum: 60 mcg with meals* ñ Type 2 ñ Initial: 60 mcg immediately prior to major meals ñ Increase to 120 mcg prior to each major meal if not significant nausea occurs Lexicomp. 2018 Cross. 2016. Amylin Analog

• Adverse effects ñ Nausea, vomiting, hypoglycemia with insulin

• Contraindications ñ Gastroparesis, hypoglycemia unawareness

• Warnings ñ A1C >9% ñ Patients non-compliant with BG self-monitoring

Lexicomp. 2018 Cross. 2016. Amylin Analog

Advantages Disadvantages

Targets postprandial blood sugar Requires three injections per day values (cannot mix with insulin)

Weight loss May reduce rate and extent of absorption of drug that require

Poorly tolerated GI side effects

Modest efficacy

• Efficacy • A1c lowering: 0.5-0.7%

• Reduces postprandial BG values Lexicomp. 2018 Cross. 2016. Medication A1C Hypo- Weight Renal Other Considerations Effect glycemia Effect Consideration metformin 1-2% No Neutral Yes GI side effects common, potential for B12 deficiency Sulfonylureas 1-2% Yes Gain Yes Caution in sulfa allergies

TZDs 0.5-1.4% No Gain No FDA Black Box: CHF, risk of bone fractures, risk of bladder cancer, increased LDL

DPP4 0.5-0.8% No Neutral Yes Potential risk of acute pancreatitis inhibitors GLP1 0.8-1.9% No Loss Some agents FDA Black Box (risk of thyroid C-cell agonists tumors); GI SEs, acute pancreatitis risk

Liraglutide, semaglutide CV benefits SGLT2 0.7-1% No Loss Yes FDA Black Box (risk of amputation with inhibitors canagliflozin)

Empagliflozin CV benefits Insulin HIGHEST Yes Gain No Injection site reaction, higher risk of hypoglycemia

American Diabetes Association, 2018. Insulin

• Cornerstone of therapy for type 1 diabetes

• Severe hyperglycemia ñ A1C >10% ñ BG ≥ 300 mg/dL ñ Inadequate glycemic control with 2 or 3 agents

• Patient is markedly symptomatic

• Disadvantages: ñ ↑ risk of hypoglycemia ñ Frequent monitoring required ñ Weight gain American Diabetes Association, 2018. Comparison Chart Onset Peak Duration Rapid Acting (Humalog) 15-30 minutes 1-2 hours 3-5 hours (Novolog) 15-30 minutes 1-2 hours 3-5 hours Insulin glulisine (Apidra) 15-30 minutes 1-2 hours 3-5 hours Short Acting 30-60 minutes 2-3 hours 5-8 hours Intermediate Acting Isophane (NPH) insulin 2-4 hours 4-6hours 8-12 hours Long Acting (Lantus) 4-5 hours None 22-24 hours (Levemir) 2 hours None 12-20 hours ~2 hours None >40 hours . (Tresiba) Van Gilder, 2015. Cross, 2016. Medscape Education © 2015 WebMD Global, LLC Methods for Dosing Insulin

• Basal-Bolus ñ Most common

• Carb counting ñ Correction factor ñ Carbohydrate coverage ratio

• Split-mix insulin therapies ñ “Rule of Thirds”

• Sliding Scale ñ Not recommended

American Diabetes Association, 2018. Van Gilder, 2015. Cross, 2016. General Dosing Guidelines Type 2:

• Fix the fasting FIRST! ñ Basal insulin ñ 10 units or 0.1-0.2 units/kg

• Adjust dose according to FBG concentration (treat to target) ñ Adjust dose by 1-2 units or 10-15% once or twice weekly

• If not at goal, consider adding rapid acting insulin prior to the largest meal of the day ñ Recommended starting dose: ñ 4 units or 0.1 units/kg or 10% of the basal dose ñ If not at goal, progress to injections prior to 2-3 meals

Type 1 : ñ Initial TDD: 0.2-0.6 units/kg (50% basal and 50% bolus) ñ Titrate insulin doses to BG values American Diabetes Association, 2018. Cross, 2016. Basal Insulin

• Long-acting insulin products ñ glargine: typically lasts 24 hours ñ detemir: rarely lasts 24 hours, may require twice daily dosing ñ degludec: longest duration >40 hours

• No peaks or valleys

• Decreases fasting glucose ñ Covers blood sugars overnight and in-between meals

• Typically given once daily in the morning or evening (usually at bedtime)

• Intermediate-acting ñ Insulin NPH: lasts ~12 hours

ñ Some peak coverage for meals American Diabetes Association, 2018. Cross, 2016. Bolus Insulin

• Available products ñ Short-acting ñ Regular ñ Rapid-acting ñ Aspart (Novolog®), glulisine (Apidra®), lispro (Humalog®)

• Limits postprandial hyperglycemia

• Characterized by immediate onset of activity

• Short-acting: give 30 min prior to a meal

• Rapid-acting: give 15 min prior to a meal or immediately after

American Diabetes Association, 2018. Cross, 2016. Using Blood Glucose Test Results to Adjust Insulin Test Time Target Insulin Dose Target Meal/Snack Pre-breakfast Pre-dinner/bedtime Bedtime snack (FASTING) intermediate- or long- acting Pre-lunch Pre-breakfast regular Breakfast/mid-morning or short-acting snack Pre-dinner Pre-breakfast Lunch/mid-afternoon intermediate-acting snack and/or pre-lunch regular or short-acting Bedtime Pre-dinner short- Dinner acting 2-hour post-prandial Pre-meal short-acting Preceding meal or snack Van Gilder, 2015. Cross, 2016. Concentrated Insulin Products

• High risk

• Humulin R (U-500) ñ Considered in patients with significant insulin resistance and total daily insulin doses that are greater than 500 units/day ñ Dosed either 3 or 4 times daily

• U-300 glargine (Toujeo®) and U-200 degludec (Tresiba®) ñ Allow higher doses of basal insulin administration per volume used ñ U-300 glargine has longer duration of action than U-100 glargine ñ Dose adjustments the same as glargine/detemir ñ ONLY available dosage form: Pens

American Diabetes Association, 2018. Van Gilder, 2015. Cross, 2016. Pen-Like Devices

ADVANTAGES DISADVANTAGES

• Greater dosing accuracy • Longer injection time necessary • Patient adherence • May need 2 pens if on 2 • Less pain/discomfort • Compact/convenient • Cost of therapy may be higher

American Diabetes Association, 2018. Van Gilder, 2015. Cross, 2016. Hypoglycemia

Signs and Symptoms Treatment: “Rule of 15”

• Shakiness, dizziness, weakness, • 15g rapidly absorbed sweating, hunger, nausea carbohydrates ñ Orange juice, regular non-diet • Blood glucose <70 mg/dL soda, glucose tablets

• Causes: • Repeat in 15 minutes if glucose ñ Irregular eating concentration remains <70 mg/dL or if symptomatic ñ Exercise ñ Drugs • Follow with complex carbohydrate/protein snack if meal time not soon

American Diabetes Association, 2018. Van Gilder, 2015. Questions? References • American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes- 2018. Diabetes Care 2018;41(Suppl. 1): S73–S85

• Garber, A. J., Abrahamson, M. J., Barzilay, J. I., Blonde, L., Bloomgarden, Z. T., Bush, M. A., . . . Umpierrez, G. E. (2018). Consensus Statement By The American Association Of Clinical Endocrinologists And American College Of Endocrinology On The Comprehensive Type 2 Diabetes Management Algorithm – 2018 Executive Summary. Endocrine Practice, 24 (1), 91-120. doi:10.4158/cs-2017-0153.

• Cross LB. Diabetes Mellitus: ACCP Updates in Therapeutics®: Ambulatory Care Pharmacy Preparatory Review and Recertification Course. 2016; 0(0): 641- 675.

• Meier JJ. Nat Rev Endocrinol. 2012;8:728-742

• Bristol Myers-Squibb. (2017). Glucophage (metformin hydrochloride tablets). Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020357s037s039,021202s021s023lbl.pdf

• Pfizer. (2008). Glucotrol – glipizide tablet. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017783s019lbl.pdf

• Sanofi Aventis. (2009). DiaBeta® (glyburide) Tablets USP. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017532s030lbl.pdf

• Sanofi Aventis. (2013). Amaryl® (): Highlights of Prescribing Information. Retrieved from http://products.sanofi.us/amaryl/amaryl.pdf

• Novartis. (2017). Starlix® (nateglinide): Highlights of Prescribing Information. Retrieved from https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/Starlix.pdf

• Novo Nordisk. (2009). Prandin® (repaglinide): Highlights of Prescribing Information. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020741s041s042lbl.pdf

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• Takeda Pharmaceuticals America, Inc. (2016). Nesina (alogliptin): Highlights of Prescribing Information. Retrieved from http://general.takedapharm.com/content/file.aspx?FileTypeCode=NESINAPI&cacheRan domizer=cf79ef92-1e03-4ac1-bba8-5bfb4a56623b

• Boehringer Ingelheim Pharmaceuticals, Inc. (2017). Tradjenta (): Highlights of Prescribing Information. Retrieved from http://docs.boehringer- ingelheim.com/Prescribing%20Information/PIs/Tradjenta/Tradjenta.pdf

• GlaxoSmithKline. (2007). Avandia (rosiglitazone): Highlights of Prescribing Information. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021071s031lbl.pdf

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• AstraZeneca. (2017). Onglyza (): Highlights of Prescribing Information. Retrieved from https://www.azpicentral.com/onglyza/pi_onglyza.pdf#page=1

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