Oral Management Of Diabetes Type Ii

Oral Management of Diabetes Type II Yasser Gebril Inpatient Pharmacy

Saad Specialist Hospital Al Khubar, KSA

Introduction 1.Diabetes mellitus is a group of metabolic disorders of fat, carbohydrate, and protein metabolism that results from defects in: 1. Insulin secretion 2. Insulin action (sensitivity), or 3. Both.

2.The incidence of type 2 diabetes mellitus (dm) is increasing. This has been attributed in part to: 1. Increasing obesity 2. Sedentary lifestyle

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Classifications of DM The two major classes are:

3. Type 1 (insulin deficient) 4. Type 2 (combined insulin resistance and relative deficiency in insulin secretion). They differ in: – – –

Clinical presentation Onset, etiology, and Progression of disease.

– –

Microvascular and Macrovascular disease complications.

Both are associated with:

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Diagnosis of diabetes 1. Fasting plasma glucose ≥126 mg/dL 2. A 2-hour value from a 75-g oral glucose tolerance test ≥200 mg/dL 3. A random plasma glucose level of ≥200 mg/dL with symptoms of diabetes; with results confirmed by any of the three criteria on a separate day.

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Goals of therapy 1. 2.

3. 4.

Reducing symptoms of hyperglycemia Reducing the onset and progression of retinopathy, nephropathy, and neuropathy complications Intensive therapy for associated cardiovascular risk factors, and Improving quality and quantity of life.

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Treatment of Type II DM • •

Insulin Oral agents 1. 2. 3. 4.

α-glucosidase inhibitors Biguanides Meglitinides Peroxisome proliferator activated receptor γ agonists (which are also commonly identified as thiazolidinediones or glitazones), and 5. Sulfonylureas.

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Sulfonylureas Pharmacology The primary mechanism of action of sulfonylureas is enhancement of insulin secretion. Sulfonylureas bind to a specific sulfonylurea receptor (SUR) on pancreatic β cells. Binding closes an adenosine triphosphate– dependent K+ channel, leading to decreased potassium influx and subsequent depolarization of the membrane. Voltage-dependent Ca+2 channels open and allow an inward flux of Ca+2. Increases in intracellular Ca+2 cause translocation of secretory granules of insulin to the cell surface and resultant exocytosis of the granule of insulin. 7

Classification. • Sulfonylureas are classified as: – First-generation and – Second-generation agents.

• First-generation agents consist of: – acetohexamide, chlorpropamide, tolazamide, and tolbutamide

• Second-generation drugs: – glimepiride, glipizide, and glyburide

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Effecacy. • All sulfonylureas are equally effective at lowering blood glucose. • On average, HbA1c will fall 1.5% to 2%, with fasting plasma glucose reductions of 60 to 70 mg/dL. A majority of patients will not reach glycemic goals with sulfonylurea monotherapy. • Microvascular Complications. – Sulfonylureas showed a reduction of microvascular complications in type 2 DM patients in the UKPDS.53 A more in-depth discussion follows later in the chapter.

• Macrovascular Complications.

– In the largest study to date, the UKPDS, no significant benefit or harm was seen in newly diagnosed type 2 DMpatients given sulfonylureas over 10 years. 9

Dosing & Administration

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Side effects. The most common side effect of sulfonylureas is hypoglycemia. • Weight gain is also common with sulfonylureas. • Other notable, although much less common, adverse effects of sulfonylureas are skin rash, hemolytic anemia, gastrointestinal upset, and cholestasis.

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Drug interactions Interactions

Drug

Displacement from protein binding sites.

Warfarin, salicylates, phenylbutazone, sulfonamides

Alters hepatic metabolism (cytochrome P450)

Chloramphenicol, MAO-I, cimetidine, rifampin

Altered renal excretion

Allopurinol, probenecid

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Short-Acting Insulin Secretagogues • Though structurally unrelated to sulfonylureas, the meglitinide class of hypoglycemic drugs bind to the same KATP channel as do the sulfonylureas, but it is unclear whether they bind to the same SUR1 subunit within the KATP complex. • As a class, the meglitinides are incapable of stimulating insulin secretion in nutrient starved cells, but in the presence of glucose, they demonstrate hypoglycemic effects by augmenting the release of insulin. • Consequently, meglitinides seem relatively unlikely to cause fasting hypoglycemia. 13

Repaglinide • Repaglinide is taken before each meal, three times a day, and is rapidly absorbed; it is metabolized by the liver and has a half life of an hour. • Insulin levels transiently rise postprandially after repaginates administration but generally return to baseline by the next meal. • Although repaglinide does not appear to offer any advantage over the sulfonylureas, it may be helpful in patients with a known allergy to sulfa drugs. • Hypoglycemia is the most common side effect. 14

Nateglinide (Starlix) • A newer drug in the meglitinide class, is a phenylalanine derivative that also works by binding to a specific site on the K–ATP–sensitive channel on the surface of -cells. • Nateglinide binds with a higher affinity than does repaglinide and has a faster onset of action and a shorter duration of action. • Like repaglinide, it is approved for both monotherapy and in combination with metformin. Nateglinide is taken three times a day before meals and achieves peak plasma levels within an hour. • Nateglinide administration results in plasma insulin levels that peak within 2 hours; they return to baseline by 4 hours. Nateglinide is metabolized by the liver and excreted by the kidney. • The main side effect of nateglinide is hypoglycemia, though its effects on fasting insulin levels is not substantially reduced. 15

Biguanides • Metformin does not affect insulin secretion but requires the presence of insulin to be effective. • The exact mechanism of metformin’s action is not clear, but it does decrease hepatic glucose production and increase peripheral glucose uptake. • When used as monotherapy, metformin rarely causes hypoglycemia.

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Metformin uses • Metformin works best in patients with significant hyperglycemia and is often considered first-line therapy in the treatment of mild to moderate type II overweight diabetics who demonstrate insulin resistance. • The United Kingdom Prospective Diabetes Study demonstrated a marked reduction in cardiovascular comorbidities and diabetic complications in metformin treated individuals. • Metformin has also been used to treat hirsutism in individuals with polycystic ovarian syndrome and may enhance fertility in these women, perhaps by decreasing androgen levels and enhancing insulin sensitivity. 17

Side effects • Adverse gastrointestinal symptoms (nausea, vomiting, anorexia, metallic taste, abdominal discomfort, and diarrhea) occur in up to 20% of individuals taking metformin; this can be minimized by starting at a low dose and slowly titrating the dose upward with food. • Like phenformin, metformin can cause lactic acidosis, but its occurrence is rare except when renal failure, hypoxemia, or severe congestive heart failure is present or when coadministered with alcohol.

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Contraindications. • Metformin is contraindicated in persons with hepatic dysfunction, but it appears to be safe for use in the hepatic steatosis that often occurs with fatty infiltration of the liver in poorly controlled type II diabetics

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New forms • Two relatively new formulations of metformin are available. • Glucovance is a combination of metformin and glyburide that may be helpful for diabetics who require both a sulfonylurea and metformin, and Glucophage XR is an extended-release product of metformin that may be better tolerated in some patients who are prone to gastrointestinal side effects. Metformin is usually given two to three times a day at mealtimes.

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Thiazolidinediones • Thiazolidinediones (sometimes termed glitazones) are a novel class of drugs that were initially identified for their insulinsensitizing properties. • They all act to decrease insulin resistance and enhance insulin action in target tissues.

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FDA Special Alerts (August 20, 2007) • The strengthened warning advises healthcare professionals to observe patients carefully for the signs and symptoms of heart failure, including excessive, rapid weight gain, shortness of breath, and edema after starting drug therapy. • Patients with these symptoms who then develop heart failure should receive appropriate management of the heart failure and use of the drug should be reconsidered

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a-Glucosidase Inhibitors • The a-glucosidase inhibitors primarily act to decrease postprandial hyperglycemia by slowing the rate at which carbohydrates are absorbed from the gastrointestinal tract.

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Mechanism of action • They act by competitively inhibiting aglucosidases, a group of enzymes in the intestinal brush border epithelial cells that includes glycoamylase, sucrase, maltase, and dextranase. • The prolongation of the intestinal absorption of carbohydrates results in a blunted insulin response, keeping postprandial hyperglycemia under control. • To be effective, a-glucosidase inhibitors must be taken before or with meals. • The a-glucosidase inhibitors are most beneficial in patients with mild to moderate diabetes whose diet is more than 50% carbohydrates. Glucosidase inhibitors are not approved for used in type I diabetes. 24

Acarbose (Precose) • Acarbose is an oligosaccharide derivative that has a higher affinity for the a-glucosidase enzymes than do other dietary oligosaccharides. • Systemic absorption of acarbose is very low (~2%), with most being broken down in the intestine to several metabolites. • About half of the orally administered acarbose is excreted unchanged in the feces, while the remainder, some of which is systemically absorbed, is renally excreted. • Acarbose may be associated with hepatotoxicity in rare instances. 25

Miglitol (Glyset) • Miglitol is another a-glucosidase inhibitor, but in contrast to acarbose, miglitol is systemically absorbed prior to its activity in the small intestine. It also appears to inhibit the enzymes sucrase and maltase to a greater extent than does acarbose. • It does not undergo metabolism and is renally excreted unchanged.

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Uses. • Unlike the sulfonylureas, insulin, and the thiazolidinediones, a-glucosidase inhibitors do not cause weight gain. • Insulin levels do not change in the presence of aglucosidase inhibitors, so fasting hypoglycemia does not occur when a-glucosidase inhibitors are used as monotherapy. • Although the a-glucosidase inhibitors may be used as monotherapy, they are usually used in combination with metformin, sulfonylureas, or insulin. • Under the best circumstances, a-glucosidase inhibitors can be expected to promote a 0.5 to 1% reduction in a patient’s hemoglobin A1c. • Leaving aside their gastrointestinal side effects, a-glucosidase inhibitors appear to be relatively 27 safe.

Side effects • Gastrointestinal disturbances (loose stools, flatulence, and abdominal cramping) are the most frequently observed side effects of the glucosidase inhibitors. • These effects can be minimized by starting patients on a low dose and then slowly advancing the dose as tolerance develops; curtailment of carbohydrate consumption also can alleviate these effects. • Patients should be counseled that these side effects will occur and that tolerance should develop; otherwise, compliance will below and about one-third of patients will stop their medication. 28

Prevention of NIDDM • Aggressive management of cardiovascular disease risk factors in type 2 DM is necessary to reduce the risk for adverse cardiovascular events or death. • Smoking cessation, use of anti-platelet therapy as a primary prevention strategy, aggressive management of dyslipidemia minimally to goal low density lipoprotein-cholesterol (LDL-C) (<100 mg/dL) and secondarily to raise high-density lipoprotein-cholesterol (HDL-C) to ≥40 mg/dL, and treatment of hypertension (again often requiring multiple drugs) minimally to <130/80 mm Hg are vital.

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Prevention of NIDDM • Prevention stratigies for prevention of NIDDM are established: – Lifestyle modification – Dietary restriction of fat – Aerobic exercises for 30 minutes 5 times a week, and – Weight loss • To date, medications have been less effective than lifestyle changes to prevent progression to type 2 DM.

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Patient Education • Patient education and ability to demonstrate selfcare and adherence to therapeutic lifestyle and pharmacologic interventions are crucial to successful outcomes. • Multidisciplinary teams of health care professionals including physicians (primary care, endocrinologists, ophthalmologists, and vascular surgeons), podiatrists, dietitians, nurses, pharmacists, social workers, behavioral health specialists, and certified diabetes educators are needed to optimize these outcomes in persons with diabetes mellitus.

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Team approach to the treatment of the diabetic patient Nurse Educator

Physician

Pharmacist

Fitness Trainer

Dietician 32

Questions?

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