Update on the Pharmacological Treatments for Diabetes Mellitus Scott K. Stolte, Pharm.D. Chair, Department of Pharmacy Practice Bernard J. Dunn School of Pharmacy Shenandoah University This program has been made possible by an education grant from Pfizer Labs.

Objectives At the completion of this program, the participant will be able to: Identify the mechanisms of action, pharmacology and the other important information for the medications used to treat both types of diabetes. Apply information about diabetes that has application in the daily practice of pharmacy. Enhance the understanding of new treatment approaches for diabetes.

Background About 18.2 million people with DM Approximately 33% undiagnosed 6.3% of US adults have DM Higher prevalence: Ethnic Groups – AA, NA, Latino Increased age and weight

Background Incidence Impact 625,000 cases diagnosed each year Leading cause of adult blindness (25x), renal failure (17x), nontraumatic amputation (5x) 5th leading cause of death due to disease Direct and indirect medical costs > 50 billion

Pharmacotherapy Oral Hypoglycemics Insulin Sulfonylureas Meglitinides Alpha-glucosidase inhibitors Biguanides Thiazolidinediones Insulin

Sulfonylureas Pancreatic Actions Stimulates insulin release from pancreatic β-cells – Primary acute mechanism Down-regulation of this affect over time No stimulation of insulin release in chronic therapy – How do they continue to work? Explanation not clear Reduced plasma glucose may allow circulating insulin to have pronounced effects on target tissues Chronic hyperglycemia impairs insulin secretion

Sulfonylureas Other pancreatic actions: Reduce hepatic clearance of insulin Suppress glucagon release slightly Stimulate somatostatin release

Sulfonylureas Extrapancreatic effects Responsible for long-term efficacy Reduce hepatic gluconeogenesis May increase insulin receptor sensitivity and number Potentiation of post-receptor insulin effects - Stimulate synthesis of glucose transporters

Sulfonylureas Two categories based on potency, duration of action, and drug interaction/side effect profiles First Generation Tolbutamide (ORINASE), Chlorpropamide (DIABINESE) , Tolazamide (TOLINASE) , Acetohexamide (DYMELOR) Second Generation Glyburide (DIABETA, GLYNASE), Glipizide (GLUCOTROL), Glimepiride (AMARYL)

Sulfonylureas Characteristics Administered orally Few therapeutic differences among agents Should be administered 30 min. before breakfast for maximal absorption Dose can be increased every 1-2 weeks Metabolized in liver, mainly excreted in urine (glyburide – 50% in feces)

Sulfonylureas Drug Onset (h) Half-life (h) Duration (h) Starting Dose Max. dose/day Tolbutamide 1 5.6 6-12 1-2g/d in 2 or 3 doses 2-3 g Acetohexamide 5 10-14 250-1500 mg/d 1.5 g Tolazamide 4-6 7 100-250 mg/d in 1 or 2 doses 750mg – 1 g Chlorpropamide 35 72 250 mg/d 500 mg Glyburide 1.5 2-4 18-24 2.5 mg/d 20 mg Glyburide, micronized 1.5 mg/d 12 mg Glipizide 3-7 10-24 5 mg/d 40 mg* Glimeperide 2 18-28 1-2 mg/day 8 mg * - Doses above 15 mg/day should be divided and administered twice daily

Sulfonylureas Adverse effects Drug Interactions Hypoglycemia – fairly common Skin reactions (3%) – rashes, pruritis GI Rare hematologic reactions Drug Interactions Increase in concentration from liver metabolism inhibition or protein binding displacement – fluconazole, warfarin Decrease in effect by increasing liver metabolism or inhibiting insulin release - rifampin, beta-blockers

Meglitinides Repaglinide (PRANDIN) Nateglinide (STARLIX) Nonsulfonylurea moiety of glyburide Nateglinide (STARLIX) Amino acid derivative Pharmacologic effect is the same as sulfonylureas Shorter duration of action

Repaglinide Absorbed rapidly from the GI tract Peak serum concentrations obtained within 1 hour Half-life is about 1 hour Metabolized mainly by the liver – metabolites are inactive 10% metabolized by the kidney

Repaglinide Starting Dose – 0.5 mg po tid taken immediately before eating each meal Can increase dose every week Maximum dose = 4 mg po tid Main adverse effect is hypoglycemia Drug Interactions Metabolized by CYP450 3A4 May interact with inhibitors or inducers of that enzyme Erythromycin, Azole antifungals, cimetidine, etc.

Nateglinide Starting and maintenance dose – 120 mg po tid 1-30 minutes before meals Dose should be skipped if meal is skipped Highly bound to plasma proteins Clinical significance unknown Metabolized in the liver by CYP450 2C9 and 3A4 Clinically significant interactions unknown

Alpha-Glucosidase Inhibitors Acarbose (PRECOSE) Miglitol (GLYSET) Mechanism of Action Inhibition of membrane bound intestinal brush border alpha glucosidase enzyme Membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine Enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia

Acarbose Not absorbed from the GI tract Will not induce hypoglycemia with monotherapy Onset – 0.5 hrs. Half-life – 1 to 2 hrs. Duration – 4 hrs. Recommended starting dose – 25 mg/d with first bite of main meal, possibly 25 mg po tid Max. dose/day – 300 mg

Miglitol Dose-dependent absorption from the GI tract Absorption not related to therapeutic efficacy Excreted in urine as unchanged drug (95%) Initial dose – 25 mg po tid with first bite of each main meal, some may need lower dose to minimize GI adverse events Max. daily dose – 100 mg po tid

Adverse Events Mainly GI Skin rash – 4.3% Abdominal pain – 11% Diarrhea – 29% Flatulence – 42% Abdominal pain and diarrhea diminish with continued treatment AE’s minimized by starting at low dose and utilizing slow dosage titration Skin rash – 4.3%

Other Considerations Not recommended for patients with inflammatory bowel disease May alter liver function at high doses Diet and activity may have to be altered to limit production of gas Often used in combination with other antidiabetic agents

Biguanides Metformin (GLUCOPHAGE) Mechanism of action Decreases hepatic glucose production – reduces gluconeogenesis Decreases intestinal absorption of glucose Improves insulin sensitivity (increases peripheral glucose uptake and utilization) Does not produce hypoglycemia as monotherapy

Metformin Absolute bioavailability is 50-60% - fasting Not bound to plasma proteins Excreted unchanged in the urine Does not undergo hepatic metabolism Starting dose – 500 mg bid with morning and evening meals Can be increased at rate of 1 tab/week Maximum daily dose – 2550 mg/day

Metformin Adverse reactions GI N/V/D, bloating, flatulence, anorexia Resolve spontaneously with continued treatment Decreased with gradual dose escalation and administration with food Asymptomatic subnormal Vit. B12 concentrations-reversed by calcium supp. Unpleasant metallic taste (3%)

Metformin Drug Interactions Cationic drugs that are excreted by renal tubular secretion Compete with metformin for excretion Could increase metformin concentrations Cimetidine, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin Theoretical except for cimetidine

Metformin Precautions Lactic acidosis Rare, but very serious (50% mortality) Occurs due to metformin accumulation Plasma levels > 5 mcg/mL 0.03 cases/1000 patient years Increased risk with significant renal insufficiency, CHF Hepatic disease increases risk – not often used Excessive alcohol intake Metformin should be D/C’d prior to radiocontrast dye and held for 24 hours after administration

Metformin Precautions Renal function Should be assessed prior to starting metformin and at least yearly thereafter Not generally used in patients with SrCr above upper limits of normal for age (SrCr > 1.5 for males, 1.4 for females) Caution with elderly patients Contraindicated in CHF requiring drug therapy

Thiazolidinediones Pioglitazone (ACTOS) Rosiglitazone (AVANDIA) Mechanism of Action Improve glycemic control by improving insulin sensitivity Highly selective and potent agonists for the peroxisome proliferator-activated receptor-gamma (PPARg) P.A. receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver Activation of PPARg nuclear receptors regulates transcription of insulin responsive genes involved in the control of glucose production, transport, and utilization PPARg-responsive genes also participate in the regulation of fatty acid metabolism. Require insulin to be present for action May also lower liver glucose production

Rosiglitazone Absolute bioavailability – 99% Half-life – 3 to 4 hours Peak concentration – 1 hr. Maximal clinical effect in 6-12 weeks Highly protein bound, mostly albumin Extensively metabolized, no unchanged drug excreted (mostly CYP2C8, some 2C9) Excreted in urine (64%) and feces (23%)

Rosiglitazone Dose Hepatic Impairment Monotherapy or in combo. with metformin- 4 mg administered qd or divided bid, dose may be increased to 8 mg/day with inadequate response after 12 weeks Taken without regard to meals Hepatic Impairment Therapy not initiated with evidence of active liver disease or increased ALT (>2.5x upper limit of normal) at baseline No evidence of induced hepatotoxicity

Rosiglitazone Adverse reactions Edema and anemia – mild to moderate, did not require drug D/C Drug Interactions – no clinically significant Precautions Ovulation - In premenopausal anovulatory patients, treatment may result in resumption of ovulation

Pioglitazone Characteristics very similar to rosiglitazone Therapy should not be initiated if clinical evidence of active liver disease or ALT exceeds 2.5 times the upper limit of normal No evidence of drug-induced hepatotoxicity Metabolized by CYP 2C8 and to some degree by CYP3A4 Dose – 15 or 30 mg po qd, maximum 45 mg qd Without regard to meals Used in combination with sulfonylureas, metformin, insulin

Pioglitazine Drug Interactions Oral Contraceptives – troglitazine reduced plasma concs. of ethinyl estradiol and norethindrone by 30% Due to 3A4 metabolism May lead to loss of contraception Pioglitazone not investigated Ketoconazole – inhibits metabolism, monitor closely Other potential 3A4 interactions – no studies

Insulin Composed of two peptide chains Molecular Mass – 5734 Daltons A chain – 21 AA’s B chain – 30 AA’s Molecular Mass – 5734 Daltons

Insulin Actions Increases glucose uptake by tissues (brain does not require insulin) Increases liver glycogen production Decreases glycogen breakdown Increases fatty acid synthesis Inhibits breakdown of fatty acids to ketone bodies Promotes incorporation of AA’s into proteins

Insulin Traditionally categorized by: Strength Onset and duration of action (PK) Species source Purity Most important consideration now is PK Most US patients on U-100 insulin Most use biosynthetic “human” insulin, may see some porcine or bovine used All US insulin is purified

Onset, Peak and Duration of Human Insulin Preps Insulin Type Onset (h) Peak (h) Effective Duration (h) Rapid-acting Lispro (Humalog) 0.25 0.5-1.5 2-4 Aspart (Novolog) 0.6-1 3-5 Rapid Acting Glulisine (Apidra) 0.25 – 0.5 1-2 3-4 Short-acting Regular 0.5-1 2-3 4-6 Intermediate Acting NPH 4-10 10-16 Intermediate Acting Lente 4-12 12-18 Long Acting Ultralente 6-10 Minimal 14-24 Detemir (Levemir) ?? 6-8 12-24 Insulin Glargine(Lantus) 1-2 hours None 24-28

Insulin Formulations Insulin lispro and aspart made by altering insulin AA structure NPH (neutral, protamine, Hagedorn) insulin made by adding protamine and zinc to neutral regular insulin Lente and ultralente made by adding acetate buffers and zinc Regular, lispro, aspart, and glargine are clear and colorless in vial Glargine precipitates at physiologic pH

Insulin Considerations Regardless of type, potency is the same 1 unit lowers BG by 30-45 mg/dL in normal, healthy subjects Regular insulin, Velosulin (R insulin with added buffers), Humalog, and probably Novolog can be used in insulin pumps Insulin suspensions (intermediate and long-acting) must be administered subQ, not IV

Type 1 Diabetes Insulin Exubera - dosing Do not switch from SQ insulin based on units-to-dose Based on weight – then titrate 1 mg capsule = ~ 3 u SQ insulin 3 mg capsule = ~8 u SQ insulin 1mg + 1mg + 1mg ≠ 3 mg Adjusting dose… Change dose in 1 mg increments Weight (pounds) Pre-prandial dose Total daily dose 66-87 1 mg 3 mg 88-132 1 mg + 1 mg 6 mg 133-176 9 mg 177-220 3 mg + 1 mg 12 mg 221-264 3 mg + 1 mg + 1 mg 15 mg 265-308 3 mg + 3 mg 18 mg 309 + 3 mg + 3 mg + 1 mg 21 mg

Type 1 Diabetes Insulin Contraindications – Exubera Smokers or smoked within 6 months Discontinue immediately if resume smoking Lung disease – asthma, COPD FEV1 < 70% predicted ?? Bronchodilator use – can increase absorption Monitoring – Exubera Spirometry – baseline, then at 6 months, then yearly If  20% decrease in FEV1, repeat; if still  20% decrease in FEV1  discontinue

Average Daily Insulin Requirements Diabetes Type Dose (u/kg ABW) Type 1 Initial Dose 0.5-0.6 Honeymoon Phase 0.1-0.4 Split-dose therapy 0.5-1.2 With ketosis or acute illness 0.5-1.0 Type 2 0.2-0.6 With insulin resistance 0.7-2.5

Terms Honeymoon Phase Type 1 DM patients Occurs soon after initial diagnosis Insulin requirements low Patient should still use insulin: To minimize insulin antibody production To lessen probability of insulin resistance

Terms Split-Dose Therapy Single daily injections not routinely used Doses are divided based on: Intensiveness of therapy Type of insulin used for treatment Regimens try to mimic activity of functioning pancreas

Insulin Adverse Events Hypoglycemia Weight gain Insulin Resistance Injection site effects

Exenatide Incretin mimetic Byetta – biosynthetic form of an incretin, GLP-1 (GLP = glucagon like peptide) Mechanism of action Mimics glucose dependent insulin secretion – first phase response Enhances glucose dependent insulin secretion by pancreatic beta cells Suppresses inappropriately elevated glucagon secretion during postprandial period Slows gastric emptying Administered via SC injection

Pramlintide Acetate Symlin Amylin mimetic Slows gastric emptying Co-located with insulin in secretory granules Secreted with insulin in response to food intake Slows gastric emptying Suppresses inappropriate glucagon secretion Centrally-mediated appetite modulation Administered via SC injection

Sitagliptin Januvia DPP-4 Inhibitor (dipeptidyl peptidase-4) Block the breakdown of incretin via inhibition of DPP-4 Thus, produces similar effects to incretin mimetics

Questions?