Oral hypoglycemic agents in diabetes

Dr. Aditi M. Panditrao 1


Oral Hypoglycemic Agents in Diabetes

Dr. Aditi M. Panditrao04/09/2015


Diabetes Mellitus• Diabetes mellitus is a group of metabolic diseases

characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both

• Hyperglycemia, glycosuria, hyperlipidemia, hyperuricemia

• Fasting plasma glucose >7.0 mmol/l (126mg/dL)• Two-hour plasma glucose ≥ 11.1 mM (200 mg/dL)• HbA1c ≥ 6.5%

• Multi-organ dysfunction syndrome


Global Burden• Nov 2014 – 347 million worldwide

• India – 65.1 million

• 7th leading cause of death in the world by the year 2030

• 90% - Type 2 DM

• 2012 – 1.5 million deaths


Types • Type 1 –

• Immune β-cell destruction or idiopathic, leading to absolute insulin deficiency

• Type 2 – • Insulin resistance with relative insulin deficiency or insulin

secretory defect with insulin resistance• Gestational Diabetes –

• Diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes

• Specific types of diabetes due to other causes – • Neonatal diabetes, maturity-onset diabetes of the young [MODY],

diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced diabetes (such as in the treatment of HIV/AIDS or after organ transplantation


MEALSTARVATION


Pathogenesis of DM type 2

• Beta cell dysfunction• Decreased Sensitivity to stimuli• Decreased number

• Insulin Resistance• Free Fatty Acids


Clinical Features

• Polyuria, polydipsia, polyphagia• Delayed wound healing, sepsis

• Acute complications – Ketoacidosis

• Long term complications – Retinopathy, neuropathy, nephropathy, cardiovascular events


Goals of treatment

• Achieve near normal glycaemia

• Alleviate the symptoms related to hyperglycemia

• Prevent or reduce the acute and chronic complications of diabetes

• Good quality of life, near normal life expectancy

Dr. Aditi M. Panditrao

Modalities of treatment of DM:

• Insulin [Replacement therapy]

• Oral anti-diabetic agents:• Insulin secretagogues• Insulin sensitizing agents• Those which reduce carbohydrate absorption

• Newer agents

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Oral Hypoglycemic Agents

• Insulin Secretagogues• Sulfonylureas (KATP Channel blockers) – • Tolbutamide, Glibenclamide (Glyburide), Glipizide,

Gliclazide, Glimepiride

• Meglitinide/ D-phenylalanine analogues – • Repaglinide, Nateglinide


Oral Hypoglycemic Agents (contd.)

• Overcome Insulin resistance

• Biguanide (AMPK activator)• Metformin

• Thiazolidinediones (PPARγ activator)• Pioglitazone


Oral Hypoglycemic Agents (contd.)

• Miscellaneous antidiabetic drugs• α-Glucosidase inhibitors• Acarbose, Miglitol, Voglibose

• Dopamine-D2 receptor agonist• Bromocriptin

• Sodium-glucose cotransport-2 (SGLT-2) inhibitor• Dapagliflozin


Sulfonylureas• Increase endogenous insulin secretion• Closure of potassium channels in Beta cells• Reduction of serum glucagon levels (Chronic use)• Sensitize tissues to insulin

• First Generation – Tolbutamide, Chlorpropamide, Tolazamide

• Second Generation - Glibenclamide (Glyburide), Glipizide, Gliclazide, Glimepiride


Sulfonylureas: Pharmacology

• Food and hyperglycemia can reduce absorption• Largely bound to protein (90-99%)• Half-lives are short, hypoglycemic effects are evident

for 12-24 hours• Metabolism – Liver• Excretion – Urine • Require functioning pancreas [at least 30%]• Secondary Failure



• Adverse Reactions• Hypoglycemia• Weight gain (1-3 kg)• Nausea and vomiting• Cholestatic jaundice, agranulocytosis, aplastic and

hemolytic anemias• Generalized hypersensitivity reactions

• Contraindications• Pregnancy, Lactation• Renal and Hepatic Impairment



• Drug Interactions –

• Enhance SU action• Displace from protein binding: Phenylbutazone,

sulfinpyrazone, salicylates, sulfonamides• Inhibit metabolism/excretion: Cimetidine ketoconazole,

sulfonamides, warfarin, chloramphenicol, acute alcohol intake • Synergise with or prolong pharmacodynamic action:

Salicylates, propranolol, lithium, theophylline, alcohol



• Drug Interactions –

• Decrease SU action• Induce metabolism: Phenobarbitone, phenytoin,

rifampicin, chronic alcoholism.• Opposite action/suppress insulin release:

Corticosteroids, thiazides, furosemide, oral contraceptives.


First-Generation Sulfonylureas

• Tolbutamide• Its half-life is relatively short (6 hr.)• Is the safest sulfonylurea for use in elderly

• Chlorpropamide• Has a long half-life (32 hr.)• Contraindicated in elderly patients

• Tolazamide• Comparable to chlorpropamide in potency but shorter

acting (half life 7 hr.)


Second-Generation Sulfonylureas

• Glyburide• Has few adverse effects other than hypoglycemia.• Contraindicated in the presence of hepatic and renal

insufficiency

• Glipizide• Has the shortest half-life (3 hr.) • Taken 30 mins before meals

• Glimepiride• Has the lowest dose of any sulfonylurea (a single daily

dose of 1 mg)


Meglitinide

• Repaglinide• MOA – same as Sulfonylureas• Very fast onset of action, with a peak effect within

1 hour, the duration of action is 5–8 hr.• Metabolism – Liver, Kidney• Secondary Failure• Is indicated for use in controlling postprandial

glucose excursions• Hypoglycemia is less


D-phenylalanine derivatives• Nateglinide• May have a special role in the treatment of isolated

postprandial hyperglycemia• Dose titration is NOT required• Is ingested just prior to meals, absorbed within 20 min.

And peak concentration of <1 hour• Incidence of hypoglycemia - lowest• It is safe in individuals with very reduced renal function


Biguanides: Metformin

• Decrease hepatic glucose production through activation of the enzyme AMP-activated protein kinase (AMPK)

• Euglycemic conditions (no effect in non diabetics)• Does not stimulate pancreatic β cells• Inhibit Renal gluconeogenesis, slowing of glucose

absorption from the gastrointestinal tract, with increased glucose to lactate conversion by enterocytes, direct stimulation of glycolysis in tissues, increased glucose removal from blood, and reduction of plasma glucagon levels


Metformin (contd.)

• Insulin necessary for action• Metformin has a half-life of 1.5–3 hours, is not bound

to plasma proteins, is not metabolized, and is excreted by the kidneys as the active compound

• Insulin resistance syndrome• Insulin sparing – Weight loss• Side effects – anorexia, nausea-vomiting, abdominal

discomfort, diarrhea, • Contraindicated in alcoholism and anoxic states

(cardiopulmonary dysfunction) because of an increased risk of lactic acidosis


Thiazolidinediones (Tzds)

• Tzds are ligands of peroxisome proliferator-activated receptor gamma (PPAR-γ)

• PPAR is part of the steroid and thyroid superfamily of nuclear receptors involved in lipid and glucose metabolism, and insulin signal transduction.

• Pioglitazone – Bladder Cancer – Ban and reinstatement

• Rosiglitazone – Banned (2010) - MI, CHF, stroke and death


Thiazolidinediones (Tzds)

• Reverse insulin resistance – Euglycemics

• Adipocyte differentiation, uptake of fat and glucose, hepatic gluconeogenesis decreased

• Absorbed within 2 hours of ingestion

• Metabolism – Liver (can be used in renal impairment)

• Side effects – Weight gain, edema, headache, myalgia and mild anaemia. Fractures in older females


Alpha Glucosidase Inhibitors

• Acarbose & Miglitol• Inhibits α-glucosidase - Reduce digestion and

absorption of polysaccharides and disaccharides.• Promotes release of GLP-1• Antihyperglycaemic• Taken before meals. Absorption – low• Side effects: flatulence, diarrhea, and abdominal pain

(undigested carbohydrate is fermented in colon and releases gas), mild to moderate elevations of hepatic transaminases


Bile Acid Sequestrants

• Colesevelam is used for type 2 DM.

• The mechanism of action involves:– An interruption of the enterohepatic circulation

(decrease in hepatic glucose output)– A decrease in farnesoid X receptor (FXR) activation.

• FXR is a nuclear receptor with multiple effects on cholesterol, glucose, and bile acid metabolism.

• Bile acids are natural ligands of the FXR.

• The drug may also impair glucose absorption.


Bile Acid Sequestrants (contd.)

• Three tablets twice a day before lunch and dinner or six tablets prior to the patient’s largest meal

• Absorption – in trace amounts. Distribution only in GI tract

• Excretion – Feces

• Side effects – constipation, dyspepsia, abdominal pain, and nausea.


Bromocriptine

• Dopamine (D2) agonist• Acts on the hypothalamic dopaminergic

control of the circadian rhythm of hormone (GH, prolactin, ACTH, etc.) release and reset it to reduce insulin resistance

• Taken with food in the morning within two hours of awakening


SGLT-2 Inhibitors

• Sodium-Glucose Co-Transporter (SGLT2) is responsible for most renal glucose reabsorption in the kidney.

• SGLT2 Inhibitors reduce the absorption of glucose in the kidney, so reduce the blood sugar.

• Canagliflozin and Dapagliflozin

• The urine will test positive for glucose while on this medication.

• Effectiveness depends on kidney function.

• There is a risk of genital infections and urinary tract infections.


Newer Drugs

• GLP-1 Receptor Agonists• Exenatide - injected subcutaneously within 60 minutes

before a meal• Absorbed equally from arm, abdomen, or thigh• Plasma t1/2 - 2 hrs, duration of action of up to 10 hours• Excretion – Kidney

• Liraglutide – longer acting• Plasma t1/2 – 12 hrs, duration >24 hrs


Newer Drugs (contd.)

• Dipeptidyl Peptidase 4 Inhibitors• Sitagliptin, saxagliptin, and linagliptin• Increase circulating levels of GLP-1 and GIP• Sitagliptan – Oral BA – 85%• Plasma t1/2 – 1-4 hrs, Duration >12 hrs• Metabolism – Liver, Excretion – Kidney• S/E - nasopharyngitis, upper respiratory infections,

headaches, and hypoglycemia, acute pancreatitis• Adjunctive therapy in type 2 diabetics who have failed

to achieve glycemic goals


Newer Drugs (contd.)

• Amylin Analog• Pramlintide – • Synthetic Antihyperglycemic drug• Suppresses glucagon release via undetermined

mechanisms, delays gastric emptying, and has central nervous system mediated anorectic effects• Injected subcutaneously prior to meals. • Plasma t1/2 of 50 minutes. • Metabolism and clearance is primarily by the kidney• Useful in both type 1 and 2 DM• S/E - hypoglycemia and gastrointestinal symptoms,

including nausea, vomiting, and anorexia


Management of DM

• Non-pharmacological• Diet• Exercise

• Pharmacological• Type 1 – Insulin• Type 2 – Oral, Insulin


Status of OHA

• Oral hypoglycemics are indicated only in type 2 diabetes, in addition to diet and exercise.

• They are most effective in patients with—• Age above 40 years at onset of disease.• Obesity at the time of presentation.• Duration of disease < 5 years when starting treatment.• Fasting blood sugar < 200 mg/dl.• Insulin requirement < 40 U/day.• No ketoacidosis or a history of it, or any other

complication.


Treatment of Type 2 Diabetes

Diagnosis

Therapeutic Lifestyle Change

Combination Therapy - Oral Drug with Insulin

Combination Therapy - Oral Drugs Only

Monotherapy


Need for Combination

• Failure to maintain a good response to - owing to a progressive decrease in beta-cell mass

• Reduction in physical activity, decline in lean body mass, or increase in ectopic fat deposition


Sulfonylurea + Biguanide - Glyburide + Metformin - Glucovance Glipizide + Metformin - Metaglip

Thiazolidinedione + Biguanide - Rosiglitazone + Metformin - Avandamet

Fixed Combination Pills

Combination Therapy for Type 2 Diabetes


Recent

• Intravenous Glyburide

• As a treatment for acute stroke, traumatic brain injury and spinal cord injury

• Based on the identification of a non-selective ATP-gated cation channel which is upregulated in neurovascular tissue during these conditions and closed by sulfonylurea agents


Recent

• Resveratrol – • Natural compound found in grape skin• Improves insulin action, increases insulin

stimulated glucose uptake• Activation of gene Sirtuin-1


Recent

• Glucokinase Activators – • Glucokinase – “Glucose Sensors” • Mutations – Diabetes• PIRAGLIATIN

• Salsalate – • NSAID• Reverses Insulin Resistance


References• American Diabetes Association. Strategies for improving care. Sec. 1. In

Standards of Medical Care in Diabetesd2015. Diabetes Care 2015;38(Suppl. 1):S5–S7

• American Diabetes Association. Classification and diagnosis of diabetes. Sec. 2. In Standards of Medical Care in Diabetes—2015. Diabetes Care 2015;38(Suppl. 1):S8–S16

• Kaveeshwar SA, Cornwall J. The current state of diabetes mellitus in India. AMJ 2014, 7, 1, 45-48. http//dx.doi.org/10.4066/AMJ.2014.1979

• Yesudian C, Grepstad M, Visintin E, Ferrario A. The economic burden of diabetes in India: a review of the literature. Globalization and Health. 2014;10(1):80.

• IDF Diabetes Atlas . 6 th edition• Tandon, Nikhil, Raizada, Nishant. The burden of diabetes in India [internet]. 2014

Sep 3; Diapedia 1105045828 rev. no. 8. Available from:http://dx.doi.org/10.14496/dia.1105045828.8

• DeFronzo Annals of Internal Medicine 1999;131:281-303 • Nathan N Engl J Med 2002; 347:1342-1349

Dr. Aditi M. Panditrao 60Thank You!!

Oral hypoglycemic agents in diabetes

Health & Medicine

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