PRINCIPLES OF ORAL ANTIDIABETIC AND

07 PRINCIPLES OF ORAL ANTIDIABETIC AND INSULINOMIMETIC DRUG THERAPY 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 type 2 diabetes. 7. 1. INSULIN SECRETAGOGUES This group includes sulfonylureas, that increase secretion of insulin from pancreatic β-cells, and glinides, that has a mechanism of action similar to sulfonylureas, but shorter duration of action (Table 7.1). Table 7.1 Insulin secretagogues A. Sulfonylureas (Second generation sulfonylureas) Glipizide Minidiab 5 mg tb 2.5-40 mg Two times in a day, with breakfast and dinner Glipizide controlled Glucotrol XL 5, 10 mg tb 5-20 mg Once in a day, before release form or with breakfast Gliclazide Diamicron, Betanorm, Oramikron, 80-240 mg One or two times in a day, Glumikron, Glikron 80 mg tb with breakfast (and dinner if needed) Gliclazide modified Diamicron MR, 30-90 mg Once in a day, release form Betanorm MR, Efikas 30 mg tb before or with breakfast Glibenclamide Gliben, Dianorm 5 mg; 1.25-20 mg One or two times in a day, with Diyaben 3.5, 5 mg tb breakfast (and dinner if needed) Glimepiride Amaryl, Diaglin, Diameprid, Glimax, 1-8 mg One or two times in a day, before or with Glirid, Sanprid 1, 2, 3, 4 mg; Mepiriks 1, 2, 3 mg tb breakfast (and dinner if needed) Glibornurid Glutril 25 mg tb 12.5-75 mg One or two times in a day, in breakfast (and dinner if needed) Gliquidone Glurenorm 30 mg tb 15-120 mg One or two times in a day, with breakfast (and dinner if needed) B. Glinides (Meglitinides: Short-acting secretagogues) Repaglinide Novonorm, Novade 0.5, 1, 2 mg tb 0.5-16 mg Three times in a day, just before main meals Nateglinide Starlix, Incuria; Teglix 120 mg tb 60-360 mg Three times in a day, just before main meals 33

34 Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy Turk JEM 2010; 14: Suppl 33-9 7.1.1 Side Effects 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) 7.1.2 Contraindications 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 7.1.3 Drug Interactions Numerous drugs used in patients with diabetes can change the effect sulphonylureas with a variety of mechanisms. The dosage of sulphonylureas may need to be adjusted when using concomitantly with drugs shown in Table 7.2. 7.2 INSULIN SENSITIZERS Two classes of drugs are used as insulin sensitizers: biguanides and thiazolidinediones (TZD, glitazons). Biguanides increase insulin sensitivity in the liver level and TZDs in the adipose tissue. Table 7.2 Interactions between sulphonylureas and other drugs Drugs inducing hypoglycemia Drugs linked to albumin: Aspirin, Fibrates, Trimethoprim Competitive inhibitors of SUs metabolism: Alcohol, H2-receptor blockers, Anticoagulants Drugs inhibiting renal excretion of SUs: Probenecid, Allopurinol Counterregulatory antagonists of SUs: β-blockers, Sympatholytics Drugs inducing hyperglycemia Drugs increasing metabolism of SUs: Barbiturates, Rifampin Drugs antagonizing actions of SUs: β-blockers Drugs blocking insulin secretion/action: Diuretics, β-blockers, Corticosteroids, Estrogenes, Phenytoine SUs; sulfonylureas.

Turk JEM 2010; 14: Suppl 33-9 Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy 35 Table 7.3 Insulin sensitizers A. Biguanides Metformin HCl Glucophage, Glukofen, Matofin 500, 850, 1000 mg; One to three times in a day, Glifor, Diaformin 850, 1000 mg; 500-2550 mg with or after meal Gluformin retard, Glukofen retard 850 mg tb Metformin HCl Glucophage XR 500, 1000 mg tb; extended release Glumetza extended release 1000 mg tb 500-2000 mg Once in a day, with or after meal, preferably dinner B. Thiazolidinediones (TZDs, Glitazones) (**) Rosiglitazone (**) Avandia 4 mg; Rosenda, Rosvel, Rositaz 4, 8 mg tb 2-8 mg One or two times daily, with meals or regardless of meal intake Pioglitazone Actos 15, 30 mg; Dropia, Glifix, Piogtan, 15-45 mg Once in a day, regardless of meal Piondia 15, 30, 45 mg tb intake 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 7.2.1 Side Effects of Metformin 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) 7.2.2 Contraindications of Metformin 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 7.2.3 Side effects of Thiazolidinediones 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, the published results of serial meta-analyses, especially related to the rosiglitazone, were inconsistent with each other. Rosiglitazone Evaluated 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

36 Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy Turk JEM 2010; 14: Suppl 33-9 morbidity and mortality. However, concerning cardiovascular safety, the other agent of the TZD group, rosiglitazone has been banned by the Ministry of Health, Turkey. The decision is given following the advice by the European Union in Sept. 24, 2010. Despite of strict limitations 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 Acarbose Acaris, Arokan, Glucobay, Glynose 50, 100 mg tb 25-300 mg Three times in a day with the first bite of food Miglitol Glyset 50, 100 mg tb 25-300 mg One to three times in a day, at the beginning of the meal Not available in Turkey 7.3.1 Side Effects of Alpha-Glycosidase Inhibitors Reversible increase in liver enzymes Rarely can cause iron deficiency anemia This 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 7.4 INSULINOMIMETIC DRUGS This new group comprises of amylin agonists, incretin mimetic drugs and newly developing agents. In general, their mechanism of action depends on increasing endogenous insulin secretion (Table 7.5).

Turk JEM 2010; 14: Suppl 33-9 Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy 37 7.4.1 Amylin Analogs 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 the United 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 inhibit degradation 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 in contrast to other anti-hyperglycemic drugs and insulin, it provides a weight loss of approximately 2 to 4 kg. It is recommended to be used in combination with metformin, sulfonylureas and TZDs in patients with BMI 35 kg/m 2. But it should not be used in obese type 2 diabetic patients under the age of 18 due to safety concerns. If the patients treated with exenatide could not reach 1% reduction in A1C 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 developed acute 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, and requires 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 weight neutral 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. 7.5 GLYCEMIC RESPONSE TO ANTI-HYPERGLYCEMIC DRUGS USED IN MONOTHERAPY The effects of various drug groups, when they are used alone, on glycemia and A1C in patients with type 2 diabetes are seen in Table 7.6. Initial good responses progressively decrease with the duration of diabetes, and the combinations are considered. The response to TZD drugs begins after 10 to 12 days, and continues about 1 to 3 weeks after withdrawal of the drug.

38 Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy Turk JEM 2010; 14: Suppl 33-9 Table 7.5 Insulinomimetic drugs Group Generic name Trade name Daily dose Timing of intak lincretinmimetics Exenatide Byetta 5, 10 μg cartridges Two times a day 5-10 μg Two times in a day, 0-60 minutes before breakfast and dinner, s.c. injection Liraglutide Victoza 6 mg/ml cartridges Once in a day 1.2-1.8 mg Once in a day, regardless of meal intake, s.c. injection Amylin mimetics Pramlintide acetate Symlin vial or cartridge In type 1 diabetes 15-60 μg (2.5-10 u) (**) three times a day, Two-three times a day, regardless in type 2 diabetes 60-120 of meals, s.c. injection. μg (5-20 u) (**) three times a day DPP-4 inhibitors Sitagliptin phosphate monohydrate Januvia 100 mg tb 50-200 mg Once a day, before or with breakfast Vildagliptin Galvus 50 mg tb 50-100 mg Once or twice in a day, regardless of meals Saxagliptin Onglyza 2.5-5 mg tb 0.5-1 mg Once in a day, before or with breakfast 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 (%) Life style modifications 40-60 1.0-2.0 Metformin 50 1.5 Insulin 50-80 1.5-2.5 Sulfonylureas 40-60 1.0-2.0 Glinides 30 1.0-1.5 Thiazolidinediones 25-55 0.5-1.4 Alpha-glycosidase inhibitors 20-30 0.5-0.7 Pramlintide/Exenatide/Liraglutide (**) 20-30 0.5-1.0 DPP-4 inhibitors 20-30 0.5-1.0 Repaglinide is more effective than Nateglinide. (**) Not available in Turkey OAD; oral antidiabetic drug, FPG; fasting plasma glucose, A1C; Haemoglobin A1c 7.6 CURRENTLY AVAILABLE ORAL ANTIDIABETIC DRUG COMBINATIONS 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 of patient to treatment (Table 7.7).

Turk JEM 2010; 14: Suppl 33-9 Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy 39 Table 7.7 Available oral antidiabetic drug combinations Glibenclamide/Metformin HCl Glucovance tb (Glibenclamide/ 2.5/500 mg-20/2000 mg Once or twice a day, with Metformin 1.25/250 mg 2.5/500 mg, 5/500 mg) meals Glipizide/Metformin HCl Metaglip tb (Glipizide/Metformin 2.5/250 mg-10/2000 mg Once or twice a day, with meals 2.5/250 mg, 5/250 mg, 5/500 mg) Rosiglitazone/Metformin HCl (**) Avandamet tb (Rosiglitazone /Metformin 1/500 mg-8/2000 mg Once or twice a day, with meals 1/500 mg, 2/500 mg,4/500 mg Rosiglitazone/Glimepiride Avandaryl tb (Rosiglitazone/ ) 4/1 mg-8/4 mg Once or twice a day, with meals Glimepiride 4/1 mg, 4/2 mg, 8/4 mg Pioglitazone/Metformin HCl Actos plus Met tb (Pioglitazone / Metformin 15/1000 mg) 15/1000 mg-30/2000 mg Once or twice a day, with meals Competact tb (Pioglitazone / Metformin 15/850 mg) Pioglitazone/Glimepiride Dueact tb (Pioglitazone/ 15/2 mg-30/4 mg Once a day, with a main meal Glimepiride 30/2 mg, 30/4 mg) Repaglinide/Metformin PrandiMet tb (Repaglinide/ 2/1000 mg-6/2000 mg 2-3 times a day, just before or at a Metformin 1/500 mg, 2/500 mg) main meal Sitagliptin/Metformin Janumet tb (Sitagliptin/ 50/500 mg - 100/2000 mg Two times daily, with meals Metformin 50/850 mg, 50/1000 mg) Vildagliptin/Metformin Euchres tb (Vildagliptin/ 50/500 mg - 100/2000 mg Two times daily, with meals or Metformin 50/500 mg, 50/1000 mg) after meals. Not available in Turkey. (**) Rosiglitazone/Metformin HCl combination has been banned by the Ministry of Health Turkey due to cardiovascular safety.