Diabetes Medications PDF

AQULOGO Insulin and Oral Hypoglycemic Agents HUSSEIN HALLAK, PH.D. AL-QUDS UNIVERSITY  Actions Of Insulin On liver: ◦ Inhibits glycogenolysis, gluconeogenesis and ketogenesis ◦ Increases glucose uptake and glycogen synthesis ◦ Increases triglyceride synthesis On muscle: ◦ Increases amino...

AQULOGO Insulin and Oral Hypoglycemic Agents HUSSEIN HALLAK, PH.D. AL-QUDS UNIVERSITY  Actions Of Insulin On liver: ◦ Inhibits glycogenolysis, gluconeogenesis and ketogenesis ◦ Increases glucose uptake and glycogen synthesis ◦ Increases triglyceride synthesis On muscle: ◦ Increases amino acid transport and protein synthesis ◦ Increases glucose uptake and glycogen synthesis Actions Of Insulin On adipose tissue: ◦ Inhibits breakdown of intracellular triglycerides ◦ Promotes intracellular triglyceride storage by stimulating hydrolysis of triglycerides from lipoproteins ◦ Stimulates glucose uptake  What is diabetes? Diabetes mellitus (DM) is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Symptoms of Diabetes: Frequent urination. Feeling very thirsty. Feeling very hungry—even though you are eating. Extreme fatigue. Blurred vision. Cuts/bruises that are slow to heal. Weight loss—even though you are eating more Tingling, pain, or numbness in the hands/feet. Diabetes Mellitus (DM) Etiology: ◦ Increase in insulin resistance and/or ◦ Decrease in insulin production Diagnosis: ◦ Hyperglycemia: random, fasting and after glucose load Drug Interactions Many drugs affect glucose homeostasis - adrenergic antagonists, ethanol, salicylates, sulfonamides, Li+ and many others cause hypoglycemia. Epinephrine, glucocorticoids, oral contraceptives, clonidine, Ca+2 channel blockers, and many others cause hyperglycemia. Type 1: Insulin-dependent Diabetes Mellitus (IDDM) Due to autoimmune destruction of  cells in the pancreas. Very low or undetectable insulin levels. Insulin secretion cannot be stimulated. Occurs mostly in children. Patients are prone to ketoacidosis. Can be treated only with insulin. About 10% of cases. Type 2: Non-insulin Dependent Diabetes Mellitus (NIDDM) Decreased responsiveness of peripheral tissues to insulin. Subnormal insulin levels. Blunted insulin response upon stimulation. Adult onset. Patients are usually overweight. Does not have to be treated with insulin. About 90% of cases.  Therapeutic Overview Type 1 DM: ◦ Insulin ◦ Diet (constant composition and timing) ◦ Exercise (increases insulin-independent glucose uptake) Type 2 DM ◦ Diet (weight reduction) ◦ Exercise (to increase insulin-independent glucose uptake and to reduce weight) ◦ Oral anti-diabetic drugs ◦ Insulin Treatment Objectives The goal of therapy using insulin or other anti- diabetic drugs is to normalize blood glucose after meals and between meals. Blood glucose levels are used as a convenient indicator of all the metabolic abnormalities that occur in DM. Pharmacological Targets Of Drugs Used In The Treatment Of DM Insulin and analogues: Insulin receptor. Sulfonylureas, meglitinides and nateglinide: sulfonylurea receptor associated with ATP sensitive K+ channels in the  cells. Biguanides: multiple, unknown? Thiazolidinediones: PPAR (peroxisome proliferator-activated receptor gamma). -glucosidase inhibitors: - glucosidases. Optimal Glycaemic Control Insulins intermediate or long acting emulate basal insulin secretion short or ultra-short acting emulate meal-stimulated secretion  Types Of Insulin Available Very rapid acting. Insulin lispro: modification of the amino acid sequence of human insulin (residues B28 and B29 changed from pro-Lys to Lys-pro) that promotes absorption by preventing self association (solution with Zn). Insulin aspart: modification of the amino acid sequence of human insulin (residue B28 changed from pro to asp) that promotes absorption by preventing self association (solution with Zn).  Types Of Insulin Available Rapid acting. Regular crystalline insulin: human or porcine wild- type amino acid sequence (solution with Zn). Intermediate acting. NPH : human or porcine, wild-type amino acid sequence (cloudy suspension with protamine in a 1:1 molar ratio with insulin). Lente: human or porcine, wild-type amino acid sequence (cloudy suspension with Zn and acetate).  Types Of Insulin Available Slow acting. Ultralente: human or porcine wild-type sequence (cloudy suspension with Zn and acetate). Glargine: modification of the amino acid sequence of human insulin (residue A21 changed from asp to Gly and two Arg residues added at positions B31 and B32) that makes insulin soluble at acidic pH but precipitates at neutral pH thus slowing down absorption (low pH solution with Zn).  Properties Of Several Human Insulin Preparations Type Onset Peak Duration Lispro 0.3h 0.5-1.5h 2-5h Regular 0.5-0.7h 1.5-4h 5-8h NPH 1-2h 6-12h 18-24h Glargine 2-5h 5-24h 18-24h Insulin Regimens Intensive, basal plus bolus “Conventional”, doses before breakfast & dinner  A Typical “Intensive” Regimen Short-acting boluses Plasma Insulin Intermediate Intermediate acting acting 06:00 12:00 18:00 24:00 hr B L D  Another “Intensive” Regimen Short-acting boluses Plasma Insulin Long acting 06:00 12:00 18:00 24:00 hr B L D  Advantages of Intensive Regimens Better glycemic control → better outcomes More flexible Greater hypoglycemia risk More demanding on patient Intensive treatment for whom? Type I, motivated & able Some Type II, motivated & able Pregnant  A Typical BD Regimen 70% Intermediate + 30% Short-acting Plasma Insulin ⅔ daily dose ⅓ daily dose 06:00 12:00 18:00 24:00 hr B L D  Some Examples Of Insulin Therapy Regular insulin (SQ) 30-45 min. Before a meal. Insulin lispro (SQ) 5-15 min. Before a meal. Regular (or lispro) + intermediate acting insulin before breakfast and before supper. Some premixed formulations ( 70% NPH/30% regular, 50%NPH/50% regular, 75% NPH/25% lispro or 50% NPH/50% lispro) are available. Regular (or lispro) before all meals and ultralente (or glargine) before breakfast or before bedtime.  Other Insulin Uses IV infusion of regular insulin for ketoacidosis, during surgery or during childbirth. Continuous subcutaneous insulin infusion (using portable pumps) therapy with regular or lispro is also possible and useful in some cases.  Other Considerations: Years ago only porcine and bovine insulin were available for therapy. Porcine insulin is still available. It differs from human insulin by only one amino acid. Bovine insulin is no longer being manufactured. Human insulin has become the standard form of therapy during the last decade. Adverse Reactions To Insulin Therapy Hypoglycemia: when awake or sleeping. Caused mostly by overdose or failure to eat. Insulin allergy and resistance. Insulin Dose Selection Guided by patient need (Blood Glucose & HbA1c) For Type I, typically about 0.5 units/kg lean body mass/day Initially conservative doses, then adjust Glucagon rescue: emergency injection of glucagon in case of severe diabetic hypoglycemia IM/SC/IV GLUCAGON CAUSES THE LIVER TO CONVERT STORED GLYCOGEN INTO GLUCOSE, WHICH IS RELEASED INTO THE BLOODSTREAM Oral Anti-diabetic Drugs: BIGUANIDES Metformin Buformin and Phenformin (not in all countries) General properties: Reduce hepatic gluconeogenesis and hepatic glucose output Increase glycolysis and glucose uptake in peripheral tissues Reduce glucose absorption Reduce glucagon levels  Metformin ◦ Do not induce hypoglycemia Side effects ◦ Gastrointestinal effects ◦ Lactic acidosis--do not use in people predisposed to this condition like renal, liver or heart disease (susceptible to lactic acidosis) ◦ Use with Caution in patients with Hepatic or Renal impairment ◦ Liver is the site of action ◦ Not metabolized, 100% renal excretion GLUCOPHAGE given twice daily with meals while GLUCOPHAGE XR given once daily with the evening meal United Kingdom Prospective Diabetes Study Metformin should be included in type 2 DM patients, if tolerated and not contraindicated, as it is the only oral anti-hyperglycemic medication proven to reduce the risk of total mortality and CV death.  Oral Anti-diabetic Drugs: SULFONYLUREAS General properties: They increase insulin secretion by decreasing K+ efflux. They increase insulin receptors and responsiveness in peripheral tissues. They reduce glucagon levels. SULFONYLUREAS Types First generation (less potent) ◦ Tolbutamide (duration = 6-12 h) ◦ Chlorpropamide (duration = 60 h) Second generation (more potent) ◦ Glypizide (duration = 10-24 h) ◦ Glyburide (duration = 10-24 h) ◦ Glimepiride (Amaryl®) Types ◦ The recommended starting dose of glimepiride is 1 or 2 milligrams (mg), once a day with breakfast or first main meal. ◦ If you are at increased risk for hypoglycemia (elderly patients or those with kidney impairment), you should start on 1 mg, once daily. ◦ After reaching a daily dose of 2 mg, further dose increases can be made. The maximum recommended dose is 8 mg, once daily. Side effects ◦ Cause Weight gain ◦ Hypoglycemia ◦ Hyponatremia, alcohol-induced flushes Secretagogues: Glinides Agents in Class: Repaglinide Mechanism of action: stimulate a rapid but short-lived release of insulin that lasts for 1-2 hours, therefore should be used to target postprandial glucose levels Efficacy: similar to SU’s for repaglinide; A1C lowering (0.5- 0.8%) Nonglycemic effect: weight gain similar to SU AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008 Secretagogues: Glinides Adverse effect: ◦ Much less hypoglycemia than SU Used with caution in patients with hepatic impairment Repaglinide has minimal renal clearance→ can be used with renal impairment Available combination: repaglinide with metformin AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Initiation and Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008  Oral Anti-diabetic Drugs 5-THIAZOLIDINEDIONES General properties: Agonists for PPAR, they increase insulin sensitivity in target tissues. Types: Pioglitazone, Rosiglitazone. Side effects: Fluid retention (so heart failure contraindicated) Weight gain (Study shows 43% ↑ in Heat attack?) Liver toxicity? (the first generation drug troglitazone caused hepatotoxicity, may not be much of a problem with the newer drugs, but monitoring liver enzymes is recommended).  Other Useful Drugs: -GLUCOSIDASE Inhibitors: General properties: Reduce intestinal absorption of carbohydrates by inhibiting glucosidases Types: Acarbose, Miglitol Side effects: Flatulence, diarrhea and abdominal pain Hepatic toxicity?  Old approach for Oral Agents Exercise, diet, weight reduction (failure after 3 months: review compliance) Metformin) (failure after 3 months: review compliance) Metformin + Sulphonylurea (failure after 3 months: review compliance) Insulin Acarbose and thiazolidinediones added on, at present  Summary Of Pharmacological Targets And Actions Of Drugs Used In The Treatment Of DM Insulin and analogues: insulin receptor. Stimulate Insulin secretion: Sulfonylureas. sulfonylurea receptor associated with ATP-sensitive K+ channels in the  cells. Agents that mimic insulin actions (biguanides). Multiple, targets, mechanisms of action not well understood. Agents that increase insulin sensitivity (thiazolidinediones) target PPAR Agents that reduce carbohydrate absorption (- glucosidase inhibitors) target -glucosidases. Gila Monster (Heloderma suspectum ) “lizard spit”  GLP-1 Modulates Numerous Functions in Humans GLP-1: Secreted upon the ingestion of food Promotes satiety and reduces appetite Alpha cells:  Postprandial glucagon secretion Liver:  Glucagon reduces Beta cells: hepatic glucose output Enhances glucose-dependent (glycogenolysis) insulin secretion Stomach: Helps regulate gastric emptying Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169  Release and action of Glucagon Like Peptide-1 (GLP-1) Intestinal Resistant to DPP-4 Mixed Meal GLP-1 Inactivation Release - Exenatide - twice daily Half-life of GLP-1 GLP-1 (7-36) - once weekly Active Is 80% of pool) peptidase-4 (DPP-4) GLP-1(9-36) enzyme activity Inactive - Vildagliptin (Galvus®) Mentlein et al. in Eur J Biochem. 214(3):829-35, 1993 Eng J, et al. J Biol Chem 1992; 267:7402-7405 Exenatide (Byetta®) agonist at the glucagon-like peptide (GLP-1) receptor. Twice-daily SC injection Liraglutide (Victoza®) daily SC injection, FDA approved for chronic weight management in patients with obesity or who are overweight with a BMI ≥27 kg/m2 and have a weight related comorbid condition Dulaglutide (Trulicity®) only type 2 diabetes medicine approved to reduce risk of major adverse cardiovascular events, weekly SC injection Semaglutide Semaglutide The first weight loss treatment to get FDA approval to reduce the risk of cardiovascular death, heart attack and stroke in adult patients with cardiovascular disease who have obesity or are overweight 2024 Sales $4.6 billion over 2023. Obesity sales 147% increase during the year, reflecting massive demand FDA NEWS RELEASE (Sept. 2019) FDA approves first oral GLP-1 treatment for type 2 diabetes RYBELSUS ® (SEMAGLUTIDE) ORAL TABLETS TO IMPROVE CONTROL OF BLOOD SUGAR IN ADULT PATIENTS WITH TYPE 2 DIABETES, ALONG WITH DIET AND EXERCISE.  Permeability Enhancer (SNAC) Sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC) Mechanisms: Open epithelial tight junctions (para- cellular route) Mildly perturb the mucosal surface (transcellular permeation enhancement) Non-covalent complexation with the payload Optimal amount of SNAC to enhance absorption of oral semaglutide is 300 mg. Body Weight–Related Efficacy End Points  GLP-1 Agonists Approved as an adjunctive-therapy for adult patients with type 2 diabetes who are using metformin or a combination of metformin and a sulfonylurea High incidence of nausea Side effect of weight-loss (approximately 2 kg) DPP 4 Inhibitors Sitagliptin (Januvia®) Vildagliptin (Galvus®) Saxagliptin (Onglyza®) Linagliptin (Tradjenta®) Most Common Adverse effect: ◦ nasopharyngitis and headache.  Vildagliptin Oral: type 2 diabetes mellitus treatment Dipeptidyl-peptidase-4 inhibitor Eucreas® 50 mg/850 mg film-coated tablets contains 50 mg of vildagliptin and 850 mg of metformin hydrochloride  Vildagliptin + Metformin Sustained A1C Reduction over 1 Year Vilda/MET (extension, ITT n = 42) PBO/MET (extension, ITT n = 29) 8.4 Vilda/MET (core, ITT n = 56) PBO/MET (core, ITT n = 51) 8.0 P