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•Pharmacologic therapy of DM Management no Treatment ای بسا تدبیر باید تا زقند کرد شیرین کام تلخ درد مند Macrovascular disease & majority of the morbidity and mortality of DM • is associated with more stringent guidelines for the treatment of comorbidities such as dyslipidemia hypertension make the fasting glucose cut points more and , it seems likely that the diagnostic criteria for diabetes will be lowered again to sensitive. • Medical Care for Patients with D M Glycemic control • It is clear that glucose levels above normal but below the current thresholds for diabetes (prediabetes) are associated with increased cardiovascular risk. New Drugs (Increatins memetic drugs) Biguanides •Metformin • is representative of this class of agents. • It reduces : • hepatic glucose production through an undefined mechanism and • improves peripheral glucose utilization slightly. Metformin • reduces fasting plasma glucose • reduces insulin levels, • improves the lipid profile, • promotes modest weight loss Metformin •The initial starting dose of 500 mg once or twice a day can be increased to 1000 mg bid. Metformin • may have fewer gastrointestinal side effects : • • • • diarrhea, anorexia, nausea, metallic taste Metformin •should be discontinued in patients who are: • seriously ill, • can take nothing orally, • receiving radiographic contrast material Metformin • should not be used in patients with: • renal insufficiency [serum creatinine > 1.5 mg/dL in men or > 1.4 mg/dL in women, • any form of acidosis, • CHF, • liver disease, • severe hypoxia. Insulin Secretagogues stimulate insulin secretion by interacting with the ATP- sensitive potassium channel on the beta cell . Insulin Secretagogues • are most effective in individuals with type 2 DM of relatively recent onset (<5 years). Sulfonylureas • reduce both fasting and postprandial glucose and should be initiated at low doses and increased at 1- to 2-week intervals based on SMBG. Sulfonylureas • Most sulfonylureas are metabolized in the liver to compounds (some of which are active) that are cleared by the kidney. • Thus, their use in individuals with significant hepatic or renal dysfunction is not advisable. • Weight gain, a common side effect of sulfonylurea therapy, results from the increased insulin levels and improvement in glycemic control. Properties of Insulin Secretagogues Sulfonylureas • Gliclazide 80 mg 40 to 320 mg daily in two divided doses, • - 30 mg and 60 mg modified release formulation • may be given at a dose of 30 to 120 mg once daily at breakfast. Sulfonylureas • Glyburide (Glibenclamide) 5mg Doses of 1.25, 2.5, and 5 mg, This drug is a major cause of drug induced hypoglycemia. The risk is increased against other sulfonylureas. Cholestatic jaundice is noted. Glibenclamide may be contraindicated in those with G6PD deficiency, as it may cause acute haemolysis. • Recently published data suggest glibenclamide is associated with • • • • • significantly higher annual mortality when combined with metformin than other insulin-secreting medications, after correcting for other potentially confounding patient characteristics. • The safety of this combination has been questioned Sulfonylureas • Glimepiride(Amaryl) 1, 2 ,4 mg • Side effects from taking glimepiride include gastrointestinal tract (GI) disturbances, occasional allergic reactions, and rarely blood production disorders including thrombocytopenia, leukopenia, and hemolytic anemia. In the initial weeks of treatment, the risk of hypoglycemia may be increased. Alcohol consumption and exposure to sunlight should be restricted because they can worsen side effects Thiazolidinediones promote a redistribution of fat from central to peripheral locations. Circulating insulin levels decrease with use of the thiazolidinediones, indicating a reduction in insulin resistance. pioglitazone is 15–45 mg/d in a single daily dose, and for rosiglitazone the total daily dose is 2–8 mg/d administered either once daily or twice daily in divided doses. Thiazolidinediones • The FDA has issued an alert that: • rare patients taking these agents may experience a worsening of diabetic macular edema. • An increased risk of fractures has been noted in women taking these agents. alfa- Glucosidase Inhibitors • Acarbose • Miglitol • reduce postprandial hyperglycemia by delaying glucose absorption; they do not affect glucose utilization or insulin secretion Increatins memetic drugs Increatins memetic drugs • Liraglutide • is a once-daily GLP-1 derivative for the treatment of type 2 diabetes. • It reduces meal-related hyperglycemia (for 24 hours after administration) stimulate insulin secretion • it shows negligible risk of hypoglycemia. • It has the potential for inhibiting apoptosis • stimulating regeneration of beta cells . • It decreases appetite and maintains body weight, • It lowers blood triglyceride levels. nce-weekly exenatide • okayed by FDA for type 2 diabetes • lowered hemoglobin A1c by 1.6 percentage points from baseline. • The most common adverse effects that emerged in clinical trials were nausea (which usually decreased over time), hypoglycemia, vomiting, diarrhea, feeling jittery, dizziness, headache, dyspepsia, constipation, and asthenia. Sitagliptin • Tab Januvia® 25 50 100 mg • dipeptidyl peptidase-4 (DPP-4) inhibitor class. • oral antidiabetic drug less hypoglycemia, • less weight gain • • often recommended to be combined with other agents such as metformin Insulin Preparations • Banting and Best First Human Patient On Jan. 11, 1922, 14-year-old Leonard Thompson was the first human patient to receive insulin made by Banting and Best. NPH insulin • - Neutral Protamine Hagedorn • - insulin treated with protamine and zinc protamine is a basic protein that readily complexes with insulin zinc to yield particles that slowly dissolve in body fluids • onset of 1-2 hrs, peak of 6-12 hrs, duration of 1824 hrs Insulin Preparations Regular insulin NPH insulin Blood Glucose Protamine zinc insulin Hours Lente Insulins • suspensions of insulin in • • acetate buffer at neutral pH - physical state and crystal size influences the rate of absorption from the site of injection Semilente insulin Blood Glucose Lente insulin Ultralente insulin Hours • Rapidly acting analogue: Aspart (NovoRapid) Lispro(Humalog) Glulisine(Apidra) • Long-acting insulin analogue : Glargine(lantus) Detemir(Levemir) Short acting &Rapid acting insulin • Short acting (regular) insulin is given30–45 min prior to a meal. • Rapid acting insulin analoguesshould be injected just before (<20 min) or just after a meal. Aspart& Lispro • available as a rapidly acting alternative to Regular insulin and • as an Biphasic insulins (rapidly acting+ intermediate-acting complex with protamine). Biphasic insulins (mixed insulins) oproviding for both immediate and prolonged action. ocombination insulin formulations do not allow independent adjustment of shortacting and long-acting activity. oSeveral insulin formulations are available as insulin "pens," which may be more convenient for some patients. Insulin glargine( Lantus) • given once daily • It consists of microcrystals that slowly release insulin, giving a long duration of action of 18 to 26 hours, • peakless • Pharmacokinetically, it resembles basal insulin secretion of non-diabetic pancreatic beta cells. • Sometimes, in type 2 diabetes and in combination with a short acting sulfonylurea (drugs which stimulate the pancreas to make more insulin), it can offer moderate control of serum glucose levels. • In type 1 diabetes, depleted type 2 (in some cases) insulin glargine needs the support of fast acting insulin taken with food to reduce the effect of prandially derived glucose. Insulin regimens Multiple injection regimens, • 1)Combination of Rapid-Acting Insulin Given with Meals and Long-Acting Insulin at Bedtime (Basal plus approach ) • 2)Combination of Rapid-Acting and Intermediate-Acting Insulin with Breakfast and Dinner Intermediate-Acting Insulin at Bedtime. (basal-bolus approach ) a continuous subcutaneous infusion of insulin (CSII) via an insulin pump Basal plus approach • Addition of basal insulin (glargine, detemir, or NPH/neutral protamine lispro insulin) to previous treatment is accepted as the simplest way to start insulin therapy in those patients. But even when basal insulin is adequately titrated, some patients will also need prandial insulin to achieve or maintain individual glycemic targets over time. • In reducing hyperglycemia, this modality still remains the most effective option, even in people with type 2 diabetes. • . Diabetes Technol Ther. 2011 Jun;13 Suppl 1:S75-83. doi: 10.1089/dia.2011.0001 Basal-bolus approach • Starting with premixed insulin is an effective option, but it is frequently associated with increased hypoglycemia risk, fixed meal schedules, and weight gain. • Diabetes Technol Ther. 2011 Jun;13 Suppl 1:S7583. doi: 10.1089/dia.2011.0001 Continuous subcutaneous insulin infusion) (CSII) (external pump ) Open-loop systems comprise an infusion pump with the infusion rate programmed or controlled manually according to manual blood-glucose monitoring. Closed-loop systems (the 'artificial pancreas') consist of an insulin pump, a glucose sensor, and a computer for analysis of blood-glucose data. Stability and storage Preparations of Insulin • should not be subjected to storage conditions that lead to freezing. • preparations in a refrigerator at 2 degrees to 8 degrees. • protected from excessive heat ,light, and sunlight. • most insulin preparations consider that storage by the patient at a temperature of up to 25 degrees would be acceptable for up to one month. Glycemic management of type 2 diabetes Strategy • 1)Reduce hypoglycemia • 2)minimize weight gain • 3)Minimal Insulin Resistance • 4)Minimal Effort • 5)Postprandial Targeting Strateg 1)Reduce hypoglycemia. AGIs and glitazones • The have been reported in small studies to reduce reactive hypoglycemia. Theoretically, exenatide and metformin should not be associated with hypoglycemia. 2) strategy to minimize weight gain would emphasize • Diet and exercise and would almost certainly employ metformin as initial therapy. • Exenatide is associated with substantial weight loss in most patients with longterm use . 3)Minimal Insulin Resistance Strategy • The possible atherogenic effects of insulin have been widely touted in the lay press and by marketing programs within the pharmaceutical industry. The relationship between circulating insulin levels and cardiovascular risk in nondiabetic populations is incontrovertible but probably related to the presence of insulin resistance rather than the insulin concentrations per se. 3)Minimal Insulin Resistance Strategy • There are no clinical data to suggest that exogenous insulin is associated with adverse side effects or long-term complications • beyond its hypoglycemic associated weight gain effects and the 3)Minimal Insulin Resistance Strategy • The thiazolidinediones have the greatest efficacy in reducing insulin resistance, • metformin is second, • and AGIs are third. • Exenatide has been demonstrated in animal models to produce modest improvement in insulin sensitivity and would be assumed to reduce insulin resistance in parallel with weight; • however, exenatide does increase postprandial insulin levels . • Nateglinide is associated with more specific stimulation of insulin levels after meals than the other insulin secretagogues, which all increase peripheral insulin levels less than injected insulin. 4)Minimal Effort Strategy • Taking a once-a-day • sulfonylurea or thiazolidinedione requires the least effort by the patient. • At least one combination tablet taking advantage of this concept is available: • rosiglitazone 4 mg in combination with either 1 or 2 mg of glimepiride. 4)Minimal Effort Strategy • Taking bedtime insulin is actually relatively well accepted by patients to whom this consideration is important. • Developing strategies to improve adherence and increase motivation is certainly a longterm goal in this population 5)Postprandial Targeting Strategy • On the basis of epidemiologic studies, it has been suggested that : • PPG is more highly correlated with cardiovascular disease risk than fasting glucose levels. • Furthermore, there are no outcome studies that have demonstrated the superiority of these approaches in patients with T2DM 5)Postprandial Targeting Strategy • Nonpharmacologic techniques that can improve postprandial control include : • lowering the carbohydrate content of meals, • adding fiber, • substituting monounsaturated fats for carbohydrates, • and encouraging physical activity after meals 5)Postprandial Targeting Strategy • The pharmacologic approach includes : • AGIs, • exenatide, Liraglutide • rapid-acting insulin analogues. • Nateglinide and repaglinide