Oral hypoglycemic agents with complications

Oral hypoglycemic agents with complications

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  ORAL HYPOGLYCEMIC AGENTS WITH COMPLICATIONS Preparedby Sanjay Kumar (PhD Scholar) Minshu Prashant (PhD Scholar) Dr. B. Ram (Associate Professor) Department of Dravyaguna Faculty of Ayurveda Institute of Medical Sciences, Banaras Hindu University Varanasi
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  WHO define “Diabetesis a chronic, metabolic disease characterized by elevated levels of blood glucose (or blood sugar)”, which leads over time to serious damage to the heart, blood vessels, eyes, kidneys, and nerves.
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  GLOBAL FACTS ONDIABETES • The number of people with diabetes has risen from 108 million in 1980 to 422 million in 2014. • The global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014. • Diabetes prevalence has been rising more rapidly in middle- and low-income countries. • Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation. • In 2015, an estimated 1.6 million deaths were directly caused by diabetes. • Almost half of all deaths attributable to high blood glucose occur before the age of 70 years. • WHO projects that diabetes will be the seventh leading cause of death in 2030.
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  • Diabetes mightbe one of the most talked about diseases across the world and especially in India • In India, today have more people with type-2 diabetes (more than 50 million) than any other Nation. • According to World Health Organization (WHO) fact sheet on diabetes, an estimated about 3.4 million deaths are caused due to high blood sugar. • The WHO also estimates that 80 percent of diabetes deaths occur in low and middle-income countries and projects that such deaths will double between 2016 to 2030. • It has been further estimated that the global burden of type-2 diabetes is expected to increase to 438 million by 2030 from 285 million people recorded in 2010. • In India, this increase is estimated to be 58%, from 51 million people in 2010 to 87 million in 2030.
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  TYPES OF DIABETESMELLITUS (DM) • Type 1 DM • Type 2 DM • Gestational diabetes mellitus (GDM)
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  TYPE 1 DIABETESMELLITUS • Due to an absolute insulin deficiency • Previously called Insulin-Dependent Diabetes Mellitus (IDDM) or Juvenile-Onset DM • Originally diagnosed in children and youth but now can be diagnosed in adults. • Exogenous insulin must be used for these individuals. DIAGNOSIS: Accounts for 5-10% of all diabetes cases FASTING BLOOD GLUCOSE > 126 mg/dl RANDOM BLOOD GLUCOSE > 200 mg/dl ORAL GLUCOSE TOLERANCE TEST > 200 mg/dl HbA1c > 6.5 %
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  CAUSES OF TYPE1 DIABETES MELLITUS • Genetics • Environment • Viruses These can trigger an autoimmune response in which the body's immune system attacks and destroy the insulin producing beta cells of the pancreas
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  TYPE 2 DIABETESMELLITUS • Due to a combination of ineffective insulin and/or insufficient insulin production. • Previously called Non-Insulin-Dependent DM (NIDDM) or Adult-Onset DM. • Historically linked to abdominal adiposity. • It used to be seen in only adults but is now seen in youth. Accounts for 90-95% of all diabetes cases
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  CAUSES FOR TYPE2 DIABETES MELLITUS • Insulin resistance is the primary cause of type 2 DM. • The pancreas secretes insulin but this insulin is not 100% effective to helping glucose move into muscle, fat and liver cells. • The body “resists” the effect of insulin, and consequently sugar remains in the blood.
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  Gestational Diabetes • Duringpregnancy, women can develop insulin resistance. • Affects about 4% of all pregnant women. • Gestational diabetes usually disappears after pregnancy. • Gestational diabetes increases risk for Type 2 diabetes later in life. GESTATIONAL DIABETES (GD)
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  • Hormones fromthe placenta may block the action of the mother's insulin in her body causing insulin resistance • The stress of the pregnancy may also cause insulin resistance CAUSES OF GESTATIONAL DIABETES
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  OTHER CAUSES FORDIABETES MELLITUS • Genetic defects of β-cell function – Maturity onset diabetes of the young (MODY) – Mitochondrial DNA mutations • Genetic defects in insulin processing or insulin action – Defects in pro-insulin conversion – Insulin gene mutations – Insulin receptor mutations • Exocrine pancreatic defects – Chronic pancreatitis – Cystic fibrosis – Pancreatic neoplasea
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  • Endocrinopathies • Acromegaly •Cushing's syndrome • Hyperthyroidism • Pheochromocytoma • Infections • Cytomegalovirus • Coxsackievirus B • Drugs • Glucocorticoids • Thyroid hormones • Statins • Beta adrenergic agonist
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  Insulin resistance Hyperinsulinemia (Normal glucosetolerence) Impaired insulin secretion (beta cell failure) Type 2 DM Medicines Hyperglycemia Obesity Diseases (HIV) hyperlipidemia Sedentary life style Environmental factorDiet
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  SIGN AND SYMPTOMSOF DIABETES MELLITUS • Increased thirst • Increased hunger • Polyurea • Glycosurea • Dry mouth • Frequent urination • weight loss • Fatigue • Blurred vision • Headaches • Slow-healing sores or cuts (Diabetic foot) • Itching • Numbness and tingling of the hands and feet • Erectile dysfunction (impotency)
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  COMPLICATIONS OF TYPE2 DIABETES MELLITUS I. Acute complications: – Diabetic Ketoacidosis – Hypoglycemia II. Chronic complications: a. Microvascular – Retinopathy – Nephropathy – Neuropathy – Diabetic foot b. Macrovascular – Cerebrovascular. – Cardiovascular. – Peripheral vascular disease.
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  WHO DIABETES DIAGNOSTICCRITERIA FOR BLOOD SUGAR LEVELS Blood glucose Normal Prediabetes Diabetes Random 80 - 159 mg/dl 160 – 199 mg/dl 200 mg/dl or more Fasting Below 110 mg/dl 110 to 125 mg/dl (IFG) 126 mg/dl or more 2 hour post- prandial Below 140 mg/dl 140 to 199 mg/dl (IGT) 200 mg/dl or more HbA1c Below 6.0 % 6.0 to 6.5 % More than 6.5 %
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  ORAL HYPOGLYCEMIC DRUGS “Agentsthat are given orally to reduce the blood glucose levels in diabetic patients are called oral hypoglycemic agents”.
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  1. Age –between 35 – 70 years 2. BMI - < 36 kg/m2 3. Random blood glucose(RBG)– 200 – 400mg/dl, fasting blood glucose(FBG) – >126 mg/dl, post prandial glucose(PPG) – > 200 mg/dl 4. Insulin requirement - < 40 U /day 5. HbA1c - < 11% Oral hypoglycemics
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  EXCUSION CRITERIA FORORAL HYPOGLYCEMIC AGENTS • Treatment with insulin. • 2 or more hypoglycemic episodes within the past years. • Severe cardiovascular, respiratory, hepatic, renal, gastrointestinal and neurological disorders. • Positive hepatitis B & C Oral hypoglycemics
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  CLASSIFICATION OF ORAL HYPOGLYCEMICAGENTS 1. Biguanides – Metformin 2. Sulphonylureas – First generation -(Tolbutamide, Chlorpropamide); Second generation – (Glibenglamide, Glipizide, Gliclazide, Glimiperide) 3. Meglitinides – Repaglinide, Nateglinide 4. Thiazolidinediones – Rosiglitazone, Pioglitazone 5. Alpha glucosidase inhibitors – Acarbose, Miglitol 6. Dipeptidyl peptidase-4 (DPP-4) inhibitors – Sitagliptin 7. Glucagon like peptide (GLP-1) analogue – Exenatide 8. Amylin analogue - Pramlintide
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  BIGUANIDES Metformin Decrease hyperglycemia intestine liverSkeletal muscle ↑ Anaerobic glucose metabolism ↓ Gluconeogenesis ↓ Glycogenolysis ↓ fatty acid oxidation ↑ Glucose uptake ↑ Glycogenesis ↓ fatty acid oxidation
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  Efficacy – Reduces FBGby 60-70 mg/dl – Reduces HbA1c by 1.5-2.0% – Reduction in: TGs by 16%, LDL by 8%, and increases HDL by 2% – Weight loss of 2-5 kg Adverse effects – GI: bloating, nausea, diarrhea, cramping – Metallic taste in the mouth – Lactic acidosis – Hypoglycemia if used in combination with insulin or sulphonylurea – Headache Contrindications – Renal impairment: Serum Creatinine ≥ 1.5mg/dl for men and ≥1.4mg/dl for women – Cardiac or respiratory insufficiency – lactic acidosis – Severe infection – Liver diseases – Alcohol abuse
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  Drug interactions: – Drugsthat are eliminated through renal tubular secretion can potentially interact with metformin such as digoxin, morphine, procainamide, vancomycin, ranitidine – Furosemide and nifedipine can potentially increase metformin plasma concentrations Dosing: – start with 500mg or 850mg QD or BID
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  SULPHONYLUREA Mechanism of action
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  Pharmacokinetics: • Well absorbedorally • 90% plasma protein bound • Low volume of distribution • Metabolized in liver and excreted through urine Interactions • Clofibrate, phenylbutazone, salicylates, sulfonamides → displace Sulphonylureas from protein binding • Chloramphenicol, MAOIs, phenylbutazone →reduce hepatic Sulphonylurea metabolism • Allopurinol, probenecid →decrease urinary excretion of Sulphonylurea
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  Who is acandidate: • Normal weight type 2 DM patients • Onset of DM after age of 30 year • Initial Blood Glucose < 250mg/dl • Relatively normal renal and hepatic function Who is not a candidate: • Pregnant and lactating women • Ketosis-prone patients Efficacy: • HbA1c ↓1.5%-2% • FBG ↓50-60mg/dl • Dose can be increased every 1-2 weeks for glycemic control Adverse effects: hypoglycemia, weight gain, GI upset
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  SULPHONYLUREA DRUGS First generation Second generation Tolbutamide GlibenclamideGlipizide Gliclazide Glimperide Half life 6 hr 2-4 hr 3-5 hr 8-20 hr 5-7 hr Duration of action 6-8 hr 24 hr 12 hr 12 – 24 hr 24 hr Daily dose required 0.5-3 gm 2.5-15 mg 5-20mg 40-240 mg 1-6 mg No of doses 2-3/day 1-2/day 1-2/day 1-2/day 1-2/day Draw back Prolong hypoglycemia, sweating, rapid breathing, fast heart rate, weight gain Weight gain, hypoglycemia Weight gain, skin changes, hypoglycemia Hypoglycemia, numbness and tigling Lower incidence of hypoglycemia
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  MEGLITINIDES (Repaglinide, Nateglinide) • Non-sulfonylurea •Also bind the ATP –dependent K channel to release insulin secretion. • Used for management of meal-related glucose loads • Less hypoglycemia than with sulphonylurea Efficacy: HbA1c ↓ 0.6%-1% Adverse reaction Low incidence of hypoglycemia (0.3%) Slight weight gain Contraindications Pregnancy, DKA, severe infection
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  Repaglinide Pharmacokinetics: • Metabolized byCyt P450 • Half-life: 1 hr • Excreted in bile • Dose: 0.5-4mg QD, max 16mg/day • Take 30 min before meal, if meal is skipped, skip the dose as well
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  THIAZOLIDINEDIONE (Rosiglitazone, Pioglitazone) Mechanism ofaction • Thiazolidinedione act by - activating PPARϒ (peroxisome proliferator- activated receptors) • Which is expressed in fat cells but also in muscles and other cells. • Reverse insulin resistance by enhancing GLUT-4 expression and translocation
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  Efficacy • Rosiglitazone Decreases: FBGby 30-60mg/dl, HbA1c by 0.8-1.5%, TGs by7-14% • Pioglitazone Decreases: FBG by 39-65mg/dl, HbA1c by 1.0-1.6%, TGs by 5-26% Adverse effect • Fluid retention • Weight gain • Hypoglycemia if combined with other agents • Liver injury • Cardiac injury Contraindication • In cardiac complications
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  ALPHA – GLUCOSIDASEINHIBITOR Acarbose : An inhibitor of intestinal α- glucosidase enzyme Mechanism of action : It delays carbohydrate metabolism, absorption, reducing the postprandial increase in blood glucose . Adverse effect: flatulence, loose stools or diarrhea, abdominal pain and bloating. Contraindications : in pregnancy, liver disease, kidney disease, breast feeding women and in hypersensitivity
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  DIPEPTIDYL PEPTIDASE-4 (DPP-4)INHIBITORS Vildagliptin, Sitagliptin
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  • Efficacy: DPP-4inhibitors lowered HbA1c values by 0.74%, comparable to other anti- diabetic drugs. • Side effects: Pancreatitis, nausea, vomiting, loss of appetite, fast heart rate; or urinating less than usual or not at all; swelling, weight gain, feeling short of breath. • Contraindications: renal impairment, hypersensitivity, pancreatitis, heart failure.
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  Sitagliptin vs Vildagliptin VildagliptinSitagliptin HbA1c Decreases 1.1 % Decreases 0.7 % Side effect No skin rashes hypersensitivity
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  GLUCAGON LIKE PEPTIDE(GLP-1) ANALOGUE (Exenatide, Liraglutide) Exenatide, Liraglutide
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  Efficacy : DecreaseHbA1c 0.7 – 1.5 % Side effects: Diarrhea, nausea, vomiting, headaches, dizziness, increased sweating, indigestion, constipation, loss of appetite
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  AMYLIN ANALOGUE (Pramlintide)
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  AMYLIN ANALOGUE • Efficacy –Lowers HbA1c – 0.5 % • Adverse effect – Hypoglycemia – Nausea, headache, anorexia – Abdominal pain
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  Options for monotherapy Biguanide (Metformin) Sulphonylurea (Glibenclamide, tolbutamide, glipizideetc) Meglitinide (Repaglinide, Nateglinide) Thiazolidinedione (Rosiglitazone, Pioglitazone) Alpha glucosidase inhibitors (Acarbose) Target population Target population Target population Target population Target population Over weight/obese Insulin resistance Normal weight Elevated PPG Insulin resistance Elevated PPG Advantages Advantages Advantages Advantages Advantages No weight gain ↓ risk of hypoglycemia Effectiveness at reducing glycemia levels, Low cost ↓ risk of hypoglycemia, Short acting Meal adjusted dosing Hyperinsulinemia, ↓ risk of hypoglycemia ↓ risk of hypoglycemia Disadvantages Disadvantages Disadvantages Disadvantages Disadvantages GI side effects Rare lactic acidosis Weight gain, ↑ risk of hypoglycemia High cost Weight gain Slow onset of action Liver toxicity Cardio-toxicity High cost Hypersensitivity reactions GI side effect, High cost If a single agent is inadequate, initiate combination therapy
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  Option for combinationtherapy Biguanide + Sulphonylurea or Thiazolidinedione or Alpha glucosidase inhibitors Biguanide + Meglitinide Biguanide + Thiazolidinedione Biguanide + Alpha glucosidase inhibitors Triple combination therapy Sulphonylurea + Biguanide + Thiazolidinedione or Sulphonylurea + Biguanide + Alpha glucosidase inhibitors
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