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Oral antidiabetic drugs (OADs) are being used in addition to lifestyle recommendations (MNT and physical activity) in type 2 diabetes.
OADs are contraindicated in pregnancy.
Current OADs include insulin secretagogues, insulin sensitizers and alpha-glucosidase inhibitors. Also newly developed “insulinomimetic” drugs, some of which can be used by oral administration, will find a wide application area in the treatment of type2 diabetes.
This group includes sulfonylureas, that increase secretion of insulin from pancreatic β-cells, and glinides, that has a mechanism ofaction similar to sulfonylureas, but shorter duration of action (Table 7.1).
Table 7.1 Insulin secretagogues
Generic name
Trade name
Daily dose
Timing of intake
A. Sulfonylureas (Second generation sulfonylureas)
Two times in a day, with breakfast and dinner One or two times in a day, before or with Glirid, Sanprid 1, 2, 3, 4 mg; Mepiriks 1, 2, 3 mg tb One or two times in a day, in breakfast (and dinner if needed) One or two times in a day, with breakfast(and dinner if needed) B. Glinides (Meglitinides: Short-acting secretagogues)Repaglinide Three times in a day, just before main meals Three times in a day, just before main meals Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy ■ Hypoglycemia■ Weight gain■ Allergy■ Skin rashes■ Alcohol flushing (especially seen with chlorpropamide which is not widely used nowadays because of the long duration of action)■ Hepatotoxicity■ Hematological toxicity (agranulocytosis, bone marrow aplasia) ■ Type 1 diabetes mellitus (differential diagnosis should carefully be performed with LADA)■ Secondary diabetes (pancreatic diseases and other causes)■ Hyperglycemic emergencies (DKA, HHS)■ Pregnancy■ Trauma, stress, operations■ Severe infections■ Sulfonylurea allergy■ Predisposition to severe hypoglycemia■ Liver and kidney failure Numerous drugs used in patients with diabetes can change the effect sulphonylureas with a variety of mechanisms. The dosage ofsulphonylureas may need to be adjusted when using concomitantly with drugs shown in Table 7.2.
Two classes of drugs are used as insulin sensitizers: biguanides and thiazolidinediones (TZD, glitazons). Biguanides increase insulinsensitivity in the liver level and TZDs in the adipose tissue.
Table 7.2 Interactions between sulphonylureas and other drugs
Drugs inducing hypoglycemia
Drugs inducing hyperglycemia
Competitive inhibitors of SUs metabolism: Alcohol, H2-receptor blockers, Anticoagulants Drugs blocking insulin secretion/action: Diuretics, β-blockers, Corticosteroids, Estrogenes, Phenytoine Counterregulatory antagonists of SUs:β-blockers, Sympatholytics Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy Table 7.3 Insulin sensitizers
Generic name
Trade name
Daily dose
Timing of intake
Glucophage, Glukofen, Matofin 500, 850, 1000 mg; Gluformin retard, Glukofen retard 850 mg tb B. Thiazolidinediones (TZDs, Glitazones)(**) Avandia 4 mg; Rosenda, Rosvel, Rositaz 4, 8 mg tb One or two times daily, with meals or regardless of meal intake Actos 15, 30 mg; Dropia, Glifix, Piogtan, (*) Not available in Turkey.
(**) Concerning cardiovascular safety, in Sept. 2010, the other agent of the TZD group, rosiglitazone has been banned by the Ministry of Health, Turkey Gastrointestinal irritation (side effects such as floating and distention are usually temporary)■ Abdominal cramps■ Diarrhea■ Metallic taste in mouth■ Vitamin B12 deficiency (Vitamin B12 replacement may be necessary)■ Lactic acidosis (incidence <1/100.000 patient year)■ Renal dysfunction (serum creatinine >1.4 mg/dL) ■ Hepatic dysfunction■ History of lactic acidosis■ Chronic alcoholism■ CV collapse, acute myocardial infarction■ Ketonemia and ketonuria■ Congestive heart failure■ Chronic (obstructive) pulmonary diseases■ Peripheral vascular diseases■ Major surgical procedures■ Pregnant and lactating women■ Advanced age (according to some authors >80 years)■ Edema ■ Anemia■ Congestive heart failure (especially when used concomitantly with intensive insulin therapy)■ Fluid retention■ Weight gain■ Increase in LDL-cholesterol levels (higher with rosiglitazone)■ Increase in aminotranpherase levels (not with new TZDs)■ This group of drugs is still being questioned in terms of increased risk of cardiovascular events (fatal and non-fatal MI). In 2007, thepublished results of serial meta-analyses, especially related to the rosiglitazone, were inconsistent with each other. ‘RosiglitazoneEvaluated for Cardiovascular Outcome and Regulation of Glycaemia in Diabetes (RECORD)’ study results, declared in June 2009,demonstrated that rosiglitazone was not different from other OADs (sulfonylureas and metformin) in terms of cardiovascular Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy morbidity and mortality. However, concerning cardiovascular safety, the other agent of the TZD group, rosiglitazone has been bannedby the Ministry of Health, Turkey. The decision is given following the advice by the European Union in Sept. 24, 2010. Despite of strictlimitations in use this drug has not been banned by the FDA.
■ TZDs may exacerbate orbitopathy in patients with Graves disease.
■ Also they have been reported to lead to an increase in fracture risk in postmenopausal women and elderly men.
Thiazolidinediones should not be used in the following groups of patients; 7.2.4 Contraindications of Thiazolidinediones ■ Cases with high alanine aminotransferase levels (ALT >2.5 X upper limit of normal)■ New York Heart Association Class I-IV congestive heart failure patients■ Chronic severe renal failure■ Pregnancy■ Patients with type 1 diabetes■ Patients at risk for macular edema■ Adolescents and children 7.3 ALPHA GLUCOSIDASE INHIBITORS
This group of drugs delays intestinal absorption of glucose. Particularly they are effective in the treatment of postprandial hyperglycemia. Of the drugs belonging to this group only acarbose is commercially available in Turkey (Table 7.4).
■ Abdominal distention, dyspepsia, diarrhea Table 7.4 Alpha glycosidase inhibitors
Generic name
Trade name
Daily dose
Timing of intake
Acaris, Arokan, Glucobay, Glynose 50, 100 mg tb Three times in a day with the first bite of food One to three times in a day, at the beginning of the meal 7.3.1 Side Effects of Alpha-Glycosidase Inhibitors ■ Reversible increase in liver enzymes■ Rarely can cause iron deficiency anemiaThis group of drugs should not be used in the following cases; 7.3.2 Contraindications of Alpha-Glucosidase Inhibitors ■ Inflammatory bowel diseases■ Chronic gastrointestinal ulcerations■ Malabsorption■ Partial bowel obstruction■ Cirrhosis■ Pregnancy■ Lactation■ Diabetic patients under 18 years old This new group comprises of amylin agonists, incretin mimetic drugs and newly developing agents. In general, their mechanism ofaction depends on increasing endogenous insulin secretion (Table 7.5).
Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy Pramlintide, a synthetic analog of β-cell hormone, amylin is used as a support to insulin treatment in type 1 and type 2 diabetes in theUnited States. It is effective on postprandial glycemia and requires s.c. injection three times a day.
One of the significant defects in type 2 diabetes is the reduction of level and/or effects of incretin hormones (GLP-1 and GIP), and that 7.4.2 Incretin-Based Drugs (Incretin Mimetics) glucagon secretion is not inhibited. The drugs belonging to this group have been developed to mimic incretin hormones or to inhibitdegradation of incretin. They do not cause hypoglycemia because they exert a glucose-dependent effect.
A. Incretinmimetics and GLP-1 Agonists
They mimic the endogenous incretin hormone glucagon-like peptide-1 (GLP-1). Example: GLP-1 receptor (GLP-1R) agonists (Exendin-4:Exenatide, Exenatide LAR, and Liraglutide) are injected s.c.
Exenatide: It is used in the United States since 2005 and in EU countries since 2006. Exenatide, used in patients with type 2 diabetes,became available in our country in 2010. It requires twice daily injections, is more effective in reducing postprandial glycemia, and incontrast to other anti-hyperglycemic drugs and insulin, it provides a weight loss of approximately 2 to 4 kg. It is recommended to beused in combination with metformin, sulfonylureas and TZDs in patients with BMI ≥35 kg/m2. But it should not be used in obese type2 diabetic patients under the age of 18 due to safety concerns. If the patients treated with exenatide could not reach 1% reduction inA1C after one-year treatment and if at least a 3% reduction of body weight is not obtained within 6 months, the therapy should be discontinued.
The major side effect of these drugs is nausea. Post-marketing reports have been reported increased number of cases developedacute pancreatitis in patients using exenatide. However, this issue remains controversial because diabetes itself can also cause pancreatitis. Based on these reports FDA requested for an additional warning to insert to the drug package in 2008, and the physicians have been advised to discontinue the treatment in case of suspicion of pancreatitis (severe abdominal pain, nausea, vomiting, increase in amylase/lipase levels and any radiological sign indicating pancreatitis).
Liraglutide: This drug, available in foreign countries (in 2009 in some EU countries), is effective in similar way with exenatide, andrequires one s.c. injection per day. Indications and side-effects are similar to exenatide.
Exenatide LAR, designed to be given by injection once per week, has similar effects, however, it has not been approved for clinical use yet.
B. Incretin enhancer agents (DPP-4 inhibitors)
This group of agents inhibits the degradation of endogenous incretins (GLP-1 and GIP). Example: Dipeptidyl peptidase-4 (DPP-4)inhibitors (sitagliptin, vildagliptin and saxagliptin) have been developed to be used with oral route. DPP-4 inhibitors can be used concomitantly with sulfonylureas, metformin and TZDs. Generally they are used once (or twice if needed) a day and they are weightneutral like metformin and acarbose. Sitagliptin was brought into use in 2006 in Europe and in USA and at the end of 2008 in our country. Vildagliptin and Saxagliptin have been approved for use in 2009 in Europe and in 2010 in our country.
In clinical trials, no important side effect of these drugs has been reported. But some patients developed flu-like symptoms after sitagliptin was brought to market. Also FDA requested a warning in package insert in September 2009 after several acute pancreatitis cases had been reported.
The effects of various drug groups, when they are used alone, on glycemia and A1C in patients with type 2 diabetes are seen in Table7.6. Initial good responses progressively decrease with the duration of diabetes, and the combinations are considered. The responseto TZD drugs begins after 10 to 12 days, and continues about 1 to 3 weeks after withdrawal of the drug.
Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy Table 7.5 Insulinomimetic drugs
Generic name
Trade name
Daily dose
Timing of intak
Once in a day, regardless of mealintake, s.c. injection Once or twice in a day, regardless of meals (*)Not available in Turkey(**)Insulin doses should be decreased by %50 whereas the amount of carbohydrates to be increased Table 7.6 Glycemic responses to antihyperglycemic drugs in monotherapy of type 2 diabetes
Decrease in FPG (mg/dL)
Decrease in A1C (%)
(*)Repaglinide is more effective than Nateglinide. (**)Not available in Turkey OAD; oral antidiabetic drug, FPG; fasting plasma glucose, A1C; Haemoglobin A1c ‘Feld S. Endocr Pract. 2002;8(Suppl. 1):41-82’, ‘Nathan DM et al. Diabetes Care 2006;29:1963-72.
Monotherapies are replaced by combination therapies in type 2 diabetes as a result of natural course of the disease. Insulin sensitizers are insulin secretagogues are combined in accordance with the pathophysiological basis of the disease. Metformin combinations should be the most preferred combination considering the cost and duration of experience. Metformin is usually combined with sulfonylureas according to the characteristics of patients. Also it is possible to combine insulin sensitizer sub-groups(e.g. rosiglitazone plus metformin). Different combinations of OAD group drugs were produced in order to improve the compliance ofpatient to treatment (Table 7.7).
Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy Table 7.7 Available oral antidiabetic drug combinations
Generic name
Trade name
Daily dose
Timing of intake
Actos plus Met tb (Pioglitazone /Metformin 15/1000 mg) Competact tb (Pioglitazone /Metformin 15/850 mg) (*) Not available in Turkey.
(**) Rosiglitazone/Metformin HCl combination has been banned by the Ministry of Health Turkey due to cardiovascular safety.



APPENDIX A “MARKET VALUE” ON RESERVE: MUSQUEAM INDIAN BAND V. GLASS 1 AND THE IMPLICATIONS FOR PROPERTY ASSESSMENTS While the Canada Supreme Court decision on the market value of leasehold land on the Musqueam reserve was for the purpose of determining leasehold payments, and not assessments for property taxes, it is useful to understand the basis of the court’s decisi

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