Drug Therapy in Diabetes HEATHER TINGLE UK COLLEGE OF PHARMACY, PY4

Transcription

1 Drug Therapy in Diabetes HEATHER TINGLE UK COLLEGE OF PHARMACY, PY4

2 OVERVIEW Characteristic Type 1 DM (10%) Type 2 DM (90%) Formerly known as Juvenile; Insulin-dependent Adult onset; Non-insulin dependent < 30 years > 30 years Abrupt Gradual Type Body Type Lean Overweight/Obese Insulin resistance Absent Present Symptomatic* Often asymptomatic Immediate Years after diagnosis No Rare Common Common Age Onset Symptoms Need for insulin Complications at Dx Microvascular Macrovascular *Polyuria, nocturia, polydipsia, polyphagia, weight loss

3 GOALS OF THERAPY Normal Goal Pre-prandial plasma glucose <100 mg/dl mg/dl Post-prandial plasma glucose <140 mg/dl <180 mg/dl A1c (%) 4-6% <7%* *Note: General goal for all persons; may be more/less aggressive

4 VARIABLE A1C GOALS

5 ORAL HYPOGLYCEMICS

6 BIGUANIDES A1c reduction: 1-2% Metformin (Glucophage ), Metformin ER (Glucophage XR, Fortamet, Glumetza ) MOA: Decreases hepatic glucose production decreasing intestinal absorption of glucose and improving insulin sensitivity Dosing: IR - twice daily with meals, ER - once daily with evening meal Start slow, and titrate up to goal of 1,500-2,000 mg daily Side Effects: GI (upset stomach, diarrhea, nausea, vomiting, bloating, gas), lactic acidosis in renal/hepatic impairment (rare), weight neutral/loss Take with food to minimize side effects or switch to ER Contraindicated in renal impairment (CrCl <60 ml/min) Approved in children 10 years and older Does not cause hypoglycemia when used alone

7 SULFONYLUREAS A1c reduction: 1-2% 1st Gen: Chlorpropamide (Diabinese ), tolazamide, tolbutamide, acetohexamide 2nd Gen: Glimepiride (Amaryl ), Glyburide (Diabeta, Micronase ), Glipizide (Gluctrol, Glucotrol XL ), Micronized glyburide (Glynase ) MOA: Stimulates insulin release from pancreatic beta cells, reduces glucose output from liver, increases insulin sensitivity at peripheral target sites Dosing: once or twice daily If taking more than once daily, take 30 min before a meal If taking once daily, take with breakfast Side Effects: hypoglycemia (glyburide), weight gain, sun sensitivity, dizziness, headache, nausea Glipizide preferred in renal/hepatic impairment

8 MEGLITINIDES A1c reduction: 1-1.5% Repaglinide (Prandin ), Nateglinide (Starlix ) MOA: Stimulates insulin release from pancreatic beta cells that is glucose-dependent Dosing: dosed multiple times per day and must be taken min before meals (skip a dose if a meal is skipped); benefit for irregular meal schedules Dose adjustment for CrCl <40 ml/min (repaglinide) Side Effects: hypoglycemia, headache, upper respiratory tract infection, weight gain

9 THIAZOLIDINEDIONES A1c reduction: % Pioglitazone (Actos ), Rosiglitazone (Avandia ) MOA: insulin sensitizers, lowers blood glucose by improving target cell response to insulin without increasing insulin secretion Dosing: once daily at same time each day without regard to meals Begins to work in several weeks, but full effect may not be seen for 2-3 months Side Effects: edema, upper respiratory infection, headache, weight gain Black Box Warning Congestive Heart Failure Monitor carefully after initiation and dose increases Contraindicated in Class III/IV heart failure Does not cause hypoglycemia when used alone

10 DPP-IV INHIBITORS A1c reduction: 0.5-1% Sitagliptin (Januvia ), Saxagliptin (Onglyza ), Linagliptin (Tradjenta ) MOA: Increases active incretin levels which increases insulin synthesis and release from pancreatic beta cells and decreases glucagon secretion Dosing: once daily at the same time each day without regard to meals Dose adjustment for CrCl< 50 ml/min Side Effects: joint pain, diarrhea, constipation, nausea, weight neutral No generic available ($$$)

11 SGLT2 INHIBITORS A1c reduction: 0.6-1% Canagliflozin (Invokana ), Dapagliflozin (Farxiga ), Empagliflozin (Jardiance ) MOA: SGLT2 is main site of filtered glucose reabsorption; blocking SGLT2 increases urinary excretion of glucose into urine Dosing: once daily before first meal of day with or without food Dose adjustment for CrCl<60 ml/min, contraindicated for CrCl<45 ml/min Side Effects: UTIs, genitourinary infections, increased serum K+, ketoacidosis, increased fracture risk Increase in leg and foot amputations (May 2016)

12 A1c reduction: % ALPHA-GLUCOSIDASE INHIBITORS Acarbose (Precose ), Miglitol (Glyset ) MOA: inhibits pancreatic α-amylase and intestinal α-glucosidases delaying hydrolysis of carbohydrates and absorption of glucose Dosing: three times daily with the first bite of each main meal Not recommended if SrCr>2 mg/dl (not studied) Contraindicated in IBS or intestinal obstruction Side Effects: flatulence, diarrhea, abdominal pain Tends to decrease with time Diabetic diet recommended to decrease side effects (titrate slowly) Low risk of hypoglycemia and no weight gain If hypoglycemia occurs, administer oral glucose not sucrose Monitor serum transaminases every 3 months during first year, then periodically

13 BILE ACID SEQUESTRANTS Colesevelam (Welchol ) MOA: unknown; possibly due to effect on glucose metabolism in liver and absorption in intestines Indicated for use with metformin, sulfonylurea, or insulin Dosing: once or twice a day with meals and a liquid (3-6 tablets per day) Use oral suspension form for any patient who has trouble swallowing tablets A1c reduction: % and LDL reduction: 15-19% Can increase TG levels (caution if TG>500 mg/dl) Side Effects: constipation, headache, diarrhea, heartburn, nausea Must take 4 hours before sulfonylureas, levothyroxine and oral contraceptives to avoid any potential for impaired absorption No renal or hepatic dose adjustments Fasting lipid profile recommended before starting, 3 months after initiation, and every 6-12 months thereafter

14 DOPAMINE-2 AGONIST A1c reduction: % Bromocriptine (Cycloset ) MOA: unknown; possibly increases insulin sensitivity by affecting circadian neuro-endocrine rhythms Dosing: 0.8 mg daily with food, increase weekly to 4.8 mg daily Dose adjustment needed for CYP3A4 inhibitors Administer within 2 hours of waking in the morning Side Effects: dizziness, fatigue, headache, constipation, nausea/vomiting, weakness, hypotension

15 COMBINATION PRODUCTS Pioglitazone/Metformin Actoplus Met Glyburide/Metformin Glucovance Glipizide/Metformin Metaglip Sitagliptin/Metformin Janumet Saxagliptin/Metformin Kombiglyze Repaglinide/Metformin Prandimet Pioglitazone/Glimepiride Duetact Dapagliflozin/Metformin Xigduo XR Empagliflozin/Metformin Synjardy - FDA approval 2015

16 Drug Class Glycemic Effect Expected A1c Diet + Exercise Fasting, prandial 0.5-2% Sulfonylurea Fasting, prandial 1-2% Biguanides Fasting, prandial 1-2% TZD Fasting, prandial % GLP-1 agonists Prandial: short-acting Fasting: long-acting % DPP-IV Inhibitors Prandial 0.5-1% SGLT2 Inhibitors Fasting, Prandial 0.6-1% Meglitinides Prandial 1-1.5% α-glucosidase inhibitor Prandial % Bromocriptine Fasting, prandial % Colesevelam Prandial %

17 Obesity Preferred Agents DPP-IV inhibitors Metformin SGLT2 Inhibitors GLP-1 agonists All are weight neutral or have some weight loss

18 INJECTABLES

19 GLP-1 AGONISTS Exenatide (Byetta, Bydureon ), Liraglutide (Victoza ), Albiglutide (Tanzeum ), Dulaglutide (Trulicity ) MOA: glucose dependent insulin secretion, suppresses glucagon, delayed gastric emptying, promotes early satiety Short acting agents target post-prandial blood sugar only Long acting agents target fasting and post-prandial A1c reduction: % Bydureon = Trulicity > Tanzeum = Victoza > Byetta Dosing: varies, daily to weekly SQ injection Exenatide, Liraglutide contraindicated if CrCl <30 ml/min Side Effects: nausea/vomiting (10-40%), diarrhea, hypoglycemia (if combined with SFU/insulin), injection site reaction, weight loss Less nausea with Victoza, Bydureon, and Trulicity Less injection site reaction with Byetta

20 Multi-dose prefilled pens = Byetta and Victoza Single dose, prefilled pens = Trulicity Only stable at room temperature for 14 days Single dose pen, requires reconstitution = Tanzeum and Bydureon Stable at room temperature for 28 days Pen needles required for Byetta and Victoza Rx or OTC

21 Amylin Mimetic A1c reduction: % Pramlintide (Symlin ) MOA: synthetic amylin, delayed gastric emptying promoting satiety Dosing: before meals, usually at the same time as insulin But must be administered in separate injections Administer in abdomen or thigh (not arm due to variable absorption) and rotate injection sites Side Effects: nausea, vomiting, weight loss, hypoglycemia (esp. with insulin), headache

22 INSULINS

23 RAPID ACTING INSULINS Lispro (Humalog, Humalog KwikPen), Aspart (Novolog, Novolog FlexPen), Glulisine (Apidra, Apidra Solostar) Onset: minutes Faster than human insulin Duration: 3-5 hours Shorter duration than human insulin Decreased risk of hypoglycemia between meals Allows injection immediately before eating Glulisine may be given up to 20 minutes after meal Use in combination with long or intermediate acting agents Can be mixed with NPH insulin Do not mix with glargine or detemir Ideal for insulin pumps Flexibility for people with erratic eating habits

24 SHORT ACTING INSULINS Regular (Humulin R, Novolin R ) Onset: 30 minutes to 1 hour Duration: 5-8 hours Covers insulin needs for meals eaten within minutes If mixing with another insulin, draw regular insulin into syringe first Humulin R U-500 now available Consider for insulin resistant patients who need >200 units/day

25 INTERMEDIATE ACTING INSULINS NPH (Humulin N, Novolin N, Humulin N KwikPen) Onset: 1-2 hours Duration: hours Covers insulin needs for about half the day or overnight Often combined with rapid or short acting insulin

26 LONG ACTING INSULINS Glargine (Lantus, Lantus Solostar, Toujeo Solostar ), Detemir (Levemir, Levemir Flextouch), Degludec (Tresiba FlexTouch ) Onset: 1-2 hours Duration: hours Tresiba is ultra long acting (duration 42 hours) Tresiba FDA approved 2015 A1c reduction similar to Lantus Similar risk for hypoglycemia For insulin-naïve: 10 units once daily at any time of day If patient has been on insulin: use same total daily long- or intermediate-acting unit dose Stable at room temperature up to 56 days

27 Insulin glargine Taken once daily as a basal insulin Virtually without peak and lasts 24 hours New to insulin therapy 10 units or 0.2 units/kg once daily Switched from NPH daily Initiate at same dosage Switched from NPH BID Decrease total daily dose by 20%, give as one injection Do not pre-fill syringes Draw up dose within a few minutes before injecting TOUJEO units/ml 3x a much insulin as Lantus More effective at preventing nocturnal hypoglycemia than Lantus

28 Insulin detemir Given once or twice daily as basal insulin Duration is dose-dependent 0.2 units/kg 12 hours >0.3 units/kg 24 hours New to insulin therapy 10 units once/twice daily or 0.2 units/kg once daily Switch from another basal insulin Give equivalent dose

29 PRE-MIXED INSULINS Humulin 70/30 (NPH/regular) Novolin 70/30 (NPH/regular) Novolog 70/30 (Protamine susp/aspart) Humalog 50/50 (Protamine susp/lispro) Humalog mix 75/25 (Protamine susp/lispro) Ryzodeg 70/30 (insulin degludec/aspart) FDA approval 2015 Onset: 30 minutes Duration: hours Generally taken two to three times daily before mealtime

30 Injection Sites - SQ Thigh Upper buttocks Abdomen Upper arm Rotate the injection site Rate of absorption may be significantly different Faster for arm and abdomen

31 Side Effects of Insulin Hypoglycemia Increased risk if a meal is missed/delayed, exercising without eating a snack first, or drinking alcohol on an empty stomach Weight gain Single bedtime injections not associated with significant weight gain Metformin + bedtime insulin best minimizes weight gain Lipodystrophy if injected into same site

32 Insulin Pearls Clear insulins Do not have to be mixed prior to use May be given SubQ or IV in emergencies Except for detemir and glargine Insulin Suspensions ( Cloudy ) i.e. NPH Must be mixed prior to administration Do not shake vigorously Roll between hands to mix

33 Insulin Pearls Expiration Unopened and refrigerated (date on vial/pen) Opened or room temperature (28 days) Novolin N, Novolin 70/30 (30 days) Detemir (42 days) Pen: Humulin N, Novolog Mix 70/30 (14 days) Pen: Humalog Mix 75/25 & 50/50, Humulin 70/30 10 days after starting pen Do not refrigerate opened pens Never freeze insulin

34 Potential Insulin Regimens Basal-Only Insulin Works best for patients who Have high fasting glucose Are reluctant to multiple daily injections (MDI) Are reluctant to multiple daily monitorings Once or Twice Daily Premixed insulins (rapid/intermediate or R/NPH) Works best for patients who Have consistent daily routines (consistent meal sizes and times) Are reluctant to MDI Have cost issues (R/NPH relatively inexpensive) Will monitor at least twice daily Basal-Bolus (MDI) Works best for patients who Have erratic schedules Are motivated to achieve tight glycemic control Are willing to monitor frequently (before meals and bedtime at minimum)

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36 HYPOGLYCEMIA MANAGEMENT Symptoms: shaking, sweating, nervousness, hunger, heart palpitations, headache, irritability, fatigue BG <70 mg/dl (check prior to treating) STEP 1: Get a quick boost of sugar Rule of 15 (15 g) STEP 2: Wait 15 minutes and then check your sugar. If <70 mg/dl, repeat step 1 STEP 3: Eat a small snack STEP 4: Check in with doctor NOTE: Beta blockers mask a lot of the symptoms Sweating may be only sign of hypoglycemia

37 TESTING SUPPLIES NEW UPDATE: TRUEresult meters and TRUEtest test strips have been discontinued as of June 1st 2016 Consider switching patients to new meters/strips Consider writing Rx for glucometer with lancets and strips so that the pharmacy can choose the meter that is covered on the patient s insurance Or, consider calling ahead to the pharmacy to see what meter will be covered for the patient Free meters often offered via the manufacturer website for patient s without state insurance i.e. CONTOUR NEXT meter, ACCU-CHEK, OneTouch, FreeStyle are some options available

38 MEDICARE PART D STAR RATINGS Highly recommended component of pharmacy practice Allows the pharmacy to qualify for preferred status allowing them to offer lower copays for patients Expect to be called on these! Examples: Statin use in diabetics age y/o or high risk of CV event (smoking, CKD, etc.) ACEI/ARB if BP >140/90 or at high risk of CV event (JNC-8) Shown to reduce morbidity and mortality in diabetics High risk medication in elderly (Beers criteria) Chlorpropamide and glyburide 65 y/o

39 IMMUNIZATIONS IN DIABETICS Shingles vaccine 50 y/o and older Or younger with a prescription Pneumococcal-13 (Prevnar) All patients 65 y/o Pneumococcal-23 (Pneumovax) All diabetic patients even if <65 y/o 1 dose Again after age 65 y/o 1 year after Prevnar and at least 5 years after previous Pneumovax shot Influenza Annually Hepatitis B 3 shot series (0,1,6 month) All patients <60 y/o with diabetes >60 y/o discretion of health care provider

40 Emerging Therapies

41 PEGylated insulin lispro Large molecular size alters tissue distribution, delays absorption, and reduces renal clearance Increased half life (24-48 hours) and duration (36 hours) May have preferential transport to the liver rather than peripheral tissues Decreased risk of weight gain In clinical studies, compared to insulin glargine Less glycemic variability Less hypoglycemia No weight gain Lower HDL and higher LDL/TG is downside Currently in Phase III trials to assess potential liver toxicity

42 Imeglimin Still in early clinical trials, but promising data released In studies, has shown to reduce fasting plasma glucose, A1c, and inhibit hepatic glucose production similar to metformin Increases skeletal muscle glucose intake Protection against beta-cell apoptosis Enhances insulin secretion in response to glucose Weight neutral

43 Affordability

44 Prescription savings and coupons available via the manufacturer website for patients without state insurance LillyCares.com offers a program called LillyTruAssist Eli Lilly offers free prescription coverage of insulin and other medications for those without insurance or who meet the qualifications Only applies to Lilly products Charles Ray III Diabetes Association Provides meters, strips and pump supplies to those who cannot afford them Novo Nordisk Patient assistance program that provides free insulin, pen needles, and glucagon kits for those who fail to qualify for government-sponsored program, do not have private insurance and fall below certain income

45 References Handelsman, Yehuda. Role of bile acid sequestrants in the treatment of type 2 diabetes. Diabetes Care 34. Supplement 2 (2011): S244-S250 Fonseca, Vivian A., Yehuda Handelsman, and Bart Staels. Colesevelam lowers glucose and lipid levels in type 2 diabetes: the clinical evidence. Diabetes, Obesity and Metabolism 12.5 (2010): American Diabetes Association. Management of diabetes in pregnancy. Sec. 12. In Standards of Medical Care in Diabetes Diabetes Care 2015;38(Suppl. 1):S77 S79 Bennett, Wendy L., et al. "Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations." Annals of internal medicine (2011): OnlineTM, Lexi-Comp, Lexi-Drugs OnlineTM, and Ohio Hudson. "Lexi-Comp." (2011). Vuylsteke, Valerie, et al. "Imeglimin: A Potential New Multi-Target Drug for Type 2 Diabetes." Drugs in R&D 15.3 (2015): Arauz-Pacheco C, Parrott MA, Raskin P. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003;26(Suppl 1):S80 2.

46 References Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT) JAMA. 2002;288: James, Paul A., et al. "2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8)." Jama (2014): Riddle MC, Bolli GB, Ziemen M, et al. New insulin glargine 300 Units/mL versus glargine 100 units/ml in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDI- TION 1). Diabetes Care. 2014;37(10): Yki-Jarvinen H, Bergenstal R, Ziemen M, et al. New insulin glargine 300 Units/mL versus glargine 100 units/ml in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care. 2014;37(12):

47 Questions?