Pharmacotherapy of Diabetes: Part 2

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This is part two of the diabetes presentation aimed for pharmacists and allied health professional who are interested in tailoring special pharmaceutical care plans for diabetic patients.

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Pharmacotherapy of Diabetes: Part 2

  1. 1. Week Diabetes Mellitus 2 Part 2 Anas Bahnassi PhD CDM CDE
  2. 2. Oral hypoglycemic agents sites of action PANCREAS MUSCLE LIVER ADIPOSE TISSUE INSULIN Secretion GLUCOSE PRODUCTION Biguanides Thiazolidinediones Sulfonylureas Meglitinides Insulin Amylin PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones (Biguanides) INTESTINE GLUCOSE ABSORPTION α- glucosidase inhibitors INTESTINAL HORMONES Incretin
  3. 3. α-Glucosidase inhibitors Drug Typical dosing Acarbose 25–100 mg with first bite (Precose) 25, of each meal. 50, 100 mg Begin with 25 mg; ↑ by 25 mg/meal every 4–8 weeks. Min and Max Mean daily dose t1/2 Minimum: 25 2.8 hr mg TID; Maximum dose is 50 mg TID if ≤60 kg; 100 mg TID if >60 kg. Miglitol 25–100 mg with first bite Minimum: 25 2 hr (Glyset) 25, of each meal. mg TID 50, 100 mg Begin with 25 mg; ↑ by Maximum: 100 25 mg/meal every 4–8 mg TID weeks. Duration of Activity Bioavailability , Metabolism, and Excretion Comments Affects absorption of complex carbohydrates in a single meal F = 0.5%–1.7%; Titrate doses extensively metabolized slowly to avoid by GI amylases to GI effects inactive products; 50% excreted unchanged in the feces Affects absorption of complex carbohydrates in a single meal Dose of 25 mg is completely absorbed; dose of 100 mg 50–70% absorbed; elimination by renal excretion as unchanged drug
  4. 4. Biguanides Drug Typical dosing Min and Max daily dose Mean t1/2 Duration of Bioavailability , Activity Metabolism, and Excretion Metformin (Glucophage) 500, 850, 1000 mg; 500 mg/mL liquid Begin with 500 mg 0.5–2.5 g BID Plasma, 6.2 hr QD or /BID; ↑ by or TID Whole blood, 500 mg QD every 17.6 hr 1–2 weeks. 6–12 hr Metformin extended-release (Glucophage XR) 500, 750, 1000 mg 500–1,000 mg/QD 1,500–2,000 Active drug is 24 hr with evening mg QD released meal; ↑ by 500 slowly mg every 1–2 weeks. F = 50%–60%; excreted unchanged in urine Comments Take with food. Avoid in patients with renal dysfunction or those who could be predisposed to lactic acidosis (e.g., alcoholism, CHF, severe respiratory disorders, liver failure)
  5. 5. Nonsulfonylurea Insulin Secretagogues (Glinides) Drug Typical dosing Repaglinide If HbA1c is <8% or if this is (Prandin) 0.5, first drug, begin with 0.5 1, 2 mg mg with each meal. For others, begin with 1–2 mg/meal. Nateglinide (Starlix) 60, 120 mg Min and Max Mean daily dose t1/2 0.5–4 mg with each meal (16 mg/day)/TID– QID 120 mg TID 1–30 min 60 or 120 mg before meals; 60 mg TID for TID patients with near-normal HbA1c at initiation. Duration of Activity 1 hr Cmax is at 1 hr; duration is approximately 2–3 hr Bioavailability , Metabolism, and Excretion Comments F = 56%; 92% Take only with metabolized to inactive meals. Skip dose if products by the liver; meal is skipped. 8% excreted as Maximum dose per metabolites unchanged meal is 4 mg. in the urine 1.5 hr Onset, 20 min; F = 73%; metabolized to Skip dose if meal is peak, 1 hr; inactive products skipped. duration, 2–4 (predominantly) that hr are excreted in the urine (83%) and feces (10%)
  6. 6. Thiazolidinediones Drug Typical dosing Min and Mean t1/2 Duration of Bioavailability , Max Activity Metabolism, and daily Excretion dose Rosiglitazone 4 mg QD; ↑ to 8 4–8 mg 3–4 hr Onset and F = 99%; extensively (Avandia) 2, 4, mg QD (or 4 mg daily in duration poorly metabolized in liver 8 mg BID) single or correlated with into inactive divided half-life because metabolites; excreted doses of mechanism of 2/3 in urine and 1/3 action. Onset at in feces 3 weeks; max at Pioglitazone 15–30 mg QD; ↑ 15–45 3–7 hr ≥4 weeks. Offset Extensively (Actos) 15, 30, to 45 mg QD. If mg QD (16–24 hr likely to be metabolized in liver; 45 mg used with insulin, for all similar 15%–30% excreted in ↓ insulin dose by metabolit urine, remainder 10%–25% once FPG es) eliminated in <120 mg/dL. the feces Comments Food has no effect on absorption. BID dosing may have greater HbA1c lowering effect. No dose adjustments required in renal failure. Avoid in patients with liver disease and heart failure. Food delays absorption but is not clinically significant. No dose adjustments required in renal disease. Avoid in patients with liver disease and heart failure.
  7. 7. Nonsulfonylurea Insulin Secretagogues (Glinides) Drug Typical dosing Repaglinide If HbA1c is <8% or if this is (Prandin) 0.5, first drug, begin with 0.5 1, 2 mg mg with each meal. For others, begin with 1–2 mg/meal. Nateglinide (Starlix) 60, 120 mg Min and Max Mean daily dose t1/2 0.5–4 mg with each meal (16 mg/day)/TID– QID 120 mg TID 1–30 min 60 or 120 mg before meals; 60 mg TID for TID patients with near-normal HbA1c at initiation. Duration of Activity 1 hr Cmax is at 1 hr; duration is approximately 2–3 hr Bioavailability , Metabolism, and Excretion Comments F = 56%; 92% Take only with metabolized to inactive meals. Skip dose if products by the liver; meal is skipped. 8% excreted as Maximum dose per metabolites unchanged meal is 4 mg. in the urine 1.5 hr Onset, 20 min; F = 73%; metabolized to Skip dose if meal is peak, 1 hr; inactive products skipped. duration, 2–4 (predominantly) that hr are excreted in the urine (83%) and feces (10%)
  8. 8. Second generation sulfonylurea Drug Typical dosing Glimepiride 1–2 mg/QD (Amaryl) 1, 2, initially; usual 4 mg maintenance dose is 1–4 mg. Min and Max daily dose 1–8 mg QD Mean Duration t1/2 of Activity 9 hr 24 hr Bioavailability , Metabolism, and Excretion F = 100% completely metabolized by liver. Principal metabolite is slightly active (30% of parent compound). Excreted by the urine (60%) and feces (40%) Comments Probably safe in patients with renal failure, but low initial doses recommended for older patients and those with renal insufficiency. Incidence of hypoglycemia may be lower than other long-acting sulfonylureas
  9. 9. Second generation sulfonylurea Drug Typical dosing Min and Max daily dose Mean Duration t1/2 of Activity Glipizide 2.5 mg/QD in 2.5–40 mg QD 2–4 hr (Glucotrol) 5, elderly, 5 mg QD or BIDa 10 mg in others; ↑ by 2.5 or 5 mg every 1–2 weeks. Glipizide 5 mg/QD; ↑ by 5 5–20 mg QD 4–13 hr extended– mg every 1–2 release weeks. (Glucotrol XL) 5 mg Bioavailability , Metabolism, and Excretion 12–24 hr Metabolized to inactive compounds 24 hr Comments No special precautions daily dose >15 mg should be divided. Dose 30 min before meals Use with caution in patients with preexisting GI narrowing owing to possible obstruction
  10. 10. Second generation sulfonylurea Drug Typical dosing Min and Max daily dose Mean Duration t1/2 of Activity Bioavailability , Metabolism, and Excretion Comments Glyburide 1.25 mg/QD in 1.25–20 mg QD 4–13 hr 12–24 hr (Diabeta, elderly, 2.5 mg or BID Micronase) QD in others; ↑ 1.25, 2.5, 5 mgby 1.25 or 2.5 mg every 1–2 weeks. Metabolized to inactive/weakly inactive compounds; 50% excreted in urine and 50% in feces Caution in elderly patients with renal failure and others predisposed to hypoglycemia. Daily doses >10 mg should be divided Micronized 1.5 mg/QD; ↑ by 1.0–12 mg QD Glyburide 1.5 mg every 1–2 (Glynase weeks. presTab) 1.5, 3 mg Metabolized to inactive/weakly inactive compounds; 50% excreted in urine and 50% in feces Daily doses >6 mg should be divided. ↑ bioavailability relative to original formulation. Resulted in reduced dose 4 hr 24 hr
  11. 11. Incretin based therapy Drug Typical dosing Min and Mean Duration Max daily t1/2 of Activity dose Bioavailability , Metabolism, and Excretion Comments GLP-1 receptor agonists/incretin mimetics Exenatide (Byetta) 5 mcg SC BID; ↑ to 5–10 2.4 hr Cmax is at Glomerular 10 mcg SC BID after mcg BID 2.1 hr; filtration 1 month duration 10 hr Take within 60 min before morning and evening meal. Nausea usually subsides over time DPP-4 Inhibitors Sitagliptin (Januvia) 100 mg QD CrCl ≥30 to <50 mL/min: 50 mg QD CrCl <30 mL/min: 25 mg QD 100 mg QD 12.4 hr 24 hr F = 87%; ~79% Requires dose adjustment in excreted unchanged in renal insufficiency. urine.
  12. 12. Second generation sulfonylurea Drug Pramlintide (Symlin) Typical dosing Type 1 DM: 15 mcg SC before major meals; ↑by 15-mcg increments after minimum of 3 days Type 2 DM: 60 mcg SC before major meals; ↑ to 120 mcg after 3–7 days Min and Max daily dose Type 1: 15–60 mcg before major meals Type 2: 60 or 120 mcg before major meals Mean t1/2 Duration of Activity 48 min Cmax is 20 minutes Bioavailability , Metabolism, and Excretion F = 30%–40%; metabolized by kidneys Comments Reduce mealtime insulin dose by 50%. Titrate dose if no significant nausea.
  13. 13. Potential combinations of antihyperglycemic agents Eat healthy, Weight Control, Increase Physical Activity Metformin Proceed to 2-drug combination if A1c goals are not reached Metformin + Sulfonylurea (SU) Thiazolidinedione DDP-4 Inhibitors GLP-1 receptor agonist Basal insulin (TZD) (DPP-4-I) (GLP-1-RA) Metformin + Sulfonylurea (SU) +TZD or DPP-4-I or GLP-1-RA Consider beginning at this stage in patients wih very high A1C (eg, ≥9%). Thiazolidinedione DDP-4 Inhibitors GLP-1 receptor agonist Basal insulin (TZD) (DPP-4-I) (GLP-1-RA) +SU +SU +SU +TZD or DPP-4-I or TZD or TZD or DPP-4-I or GLP-1-RA or insulin or insulin or GLP-1-RA Consider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas Certain noninsulin agents may be continued with insulin
  14. 14. A case approach to type-2 diabetes L.H. is a 45-year-old, moderately overweight, Mexican-American (height, 5 feet 5 inches; weight, 160 lbs; BMI 26.6 kg/m2). She was treated for recurrent monilial infections, when noted glucosuria on routine urinalysis. On 2 separate occasions: her FPG was 150 mg/dL and 167 mg/dL. L.H. denies any symptoms of polyphagia or polyuria, although lately she has been more thirsty than usual. She does complain of lethargy and often takes afternoon naps. Other medical problems include HTN, which is well controlled on lisinopril 20 mg/day, and recurrent monilial infections, which are treated with fluconazole. She has given birth to four children (birth weights, 7, 8.5, 10, and 11 lb) and was told during her last pregnancy that she had “borderline diabetes.”
  15. 15. A case approach to type-2 diabetes She currently works as a loan officer in a local bank and spends her weekends “catching up on her sleep” and reading. L.H. has been smoking one pack of cigarettes per day for 20 years and drinks an occasional glass of wine She drinks at least two regular sodas daily and has “large” glass of orange juice every morning. Her family history is significant for a sister, aunt, and grandmother with type 2 diabetes; all have “weight problems.” L.H.'s mother is alive and well at age 77; her father died of a heart attack at age 47. Laboratory assessment reveals an FPG of 147 mg/dL (normal, 70– 100); fasting plasma triglycerides of 400 mg/dL (normal, <150 mg/dL); and an HbA1c of 9.2% (normal, 4%–6%). All other values (including the complete blood count, electrolytes, LFTs, and renal function tests) are within normal limits. L.H. is given the diagnosis of type 2 diabetes.
  16. 16. What features in L.H.'s history and physical examination are consistent with this diagnosis? FPG concentration of 126 mg/dL or higher on more than one occasion An elevated HbA1c, High BMI with central obesity Age greater than 40 Family history of diabetes Mexican American descent. Delivering large babies, (undiagnosed gestational diabetes) Mild signs and symptoms of hyperglycemia (including increased thirst and lethargy), recurrent monilial infections, hypertriglyceridemia, and indications of CVD (hypertension) also are typical in patients with type 2 diabetes
  17. 17. What should the goals of therapy be for L.H. ? Which biochemical indices should be monitored? Eliminating acute symptoms of hyperglycemia Avoiding hypoglycemia Reducing cardiovascular risk factors Preventing or slowing the progression of both microvascular and macrovascular diabetic complications. Biochemical indices that should be followed to monitor L.H.'s response to therapy include fasting, postprandial, and preprandial blood glucose concentrations, HbA1c values, fasting triglyceride levels, as well as LDL and HDL cholesterol concentrations. Initial metabolic goals for L.H. should be an HbA1c value of <7%, an FPG of <130 mg/dL, postprandial glucose concentrations below 180 mg/dL, LDL-cholesterol below 100 mg/dL, and triglycerides below 150 mg/dL.
  18. 18. How should L.H. be managed initially? Lifestyle changes that will minimize insulin resistance and risk for CVD. Overweight (BMI 25.0–29.9) or obese (BMI ≥30.0) type 2 individuals need to be on lower calorie, low-fat, low-cholesterol diet. Regular exercise Smoking cessation Aggressive management of dyslipidemia and hypertension. When signs and symptoms are mild, diet and exercise alone can correct glucose intolerance. SMBG monitoring and patient education.
  19. 19. Diabetes type-2 initial treatment Metformin is favored as a first-choice agent for overweight, type 2 diabetics as long as there are no contraindications to its use. This is because metformin lowers blood glucose by decreasing hepatic glucose output and insulin resistance (indirectly) without causing weight gain or hypoglycemia. Metformin also has beneficial effects on plasma lipid concentrations as well. A drawback to metformin is that it requires multiple daily dosing and its dose also must be titrated to minimize GI effects. After the dose is established, it is possible to use a long-acting product that can be dosed once daily. Further adjustments and more drugs Basal insulin SU, TZD Lifestyle + Metformin Renal function tests should be evaluated before the drug is initiated.
  20. 20. L.H. is started on metformin 500 mg BID with food and instructed to increase her dosage to 500 mg Q AM and 1,000 mg Q PM after 1 week. Three days after starting metformin, she phones the clinic complaining of nausea and diarrhea. She admits to taking her doses on an empty stomach. How should L.H.'s symptoms be addressed? GI disturbances such as diarrhea, bloating, anorexia, abdominal discomfort, nausea, and metallic taste often dissipate with time and can be minimized by initiating metformin in a single, 500- or 850-mg dose at breakfast or with the patient's largest meal of the day. Consistently taking metformin with food significantly minimizes the GI side effects. The dosage should be slowly increased (e.g., 500 mg/day every 2 weeks) until the appropriate clinical effect is achieved or the patient is taking the maximum dose (1,000 mg twice daily or 850 mg three times a day).
  21. 21. How should metformin therapy be monitored in L.H.? L.H. should be encouraged to perform SMBG. Have an HbA1c test performed quarterly until goals achieved. Additional evidence may include an improved lipid profile and some weight loss. Initially, it is important to follow GI problems L.H. should be warned to bring to the attention of her physician any sudden symptoms of shortness of breath, weakness, and malaise (Lactic Acidosis). A baseline SrCr, LFTs, and complete blood count should be obtained . Lifestyle changes that will minimize insulin resistance and risk for CVD.
  22. 22. What are the advantages and disadvantages of SMBG tests? When and how often should L.H. be instructed to test her blood glucose concentrations? We often recommend SMBG for motivated type 2 patients who are learning to adjust their carbohydrate intake and portion sizes and want to measure how well medications and lifestyle changes are working to improve their glucose control. Initially, we may suggest testing four times daily before meals and at bedtime for 1 week so that the patient can observe his or her glucose profiles. Later, once the desired HbA1c has been achieved, we recommend a minimum of testing blood glucose twice daily, but at various times to evaluate fasting glucose concentrations
  23. 23. Treatment algorithm for type-2 diabetes Diagnosis Lifestyle modifications + Metformin Yes Add basal insulin Most effective HbA1c≥7 Add sulfonylurea Least expensive HbA1c≥7 No yes Intensify insulin Add glitazone No hypoglycemia HbA1c≥7 yes Add glitazone Add Insulin HbA1c≥7 yes Intensive insulin + metformin ± glitazone HbA1c≥7 yes Add Sulfonylurea yes
  24. 24. Treating diabetes under special circumstances Circumstance Avoid Consider Patients with decreased renal Acarbose function Long-acting SFUs (e.g., glyburide) Metformin Glipizide Glimepiride Insulin Glinides (Repaglinide/ nateglinide) Sitagliptin Thiazolidinediones Patients with impaired liver function Acarbose Metformin Thiazolidinediones ? SFUs (severe liver dysfunction) Insulin Repaglinide Exenatide Sitagliptin Miglitol Patients who are obese or gaining excessive weight Insulin Sulfonylureas Repaglinide ? Thiazolidinediones Acarbose Miglitol Metformin
  25. 25. Treating diabetes under special circumstances Circumstance Avoid Consider Patients with preexisting edema Thiazolidinediones SFUs Glinides Exenatide Sitagliptin Patients with heart failure Thiazolidinediones Metformin SFUs Glinides Exenatide Sitagliptin Insulin Patients experiencing Insulin hypoglycemia due to irregular Long-acting SFUs eating patterns Acarbose Metformin Repaglinide/nateglinide Thiazolidinediones Exenatide Sitaglipin
  26. 26. Pharmacottherapy Anas Bahnassi PhD CDM CDE abahnassi@gmail.com http://www.twitter.com/abpharm http://www.facebook.com/pharmaprof http://www.linkedin.com/in/abahnassi

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