Pharmacotherapy of

Diabetes Mellitus

RVS Chaitanya Koppala

Diabetes• Diabetes is a group of metabolic disorders

characterized by chronic hyperglycemia associated with disturbances of carbohydrate, fat and protein metabolism due to absolute or relative deficiency in insulin secretion and/or action

• Diabetes causes long term damage, dysfunction & failure of various organs

Diagnosis of diabetes

• Fasting Plasma Glucose ≥ 126 mg / dl

• Symptoms of DM and a random blood glucose level of ≥ 200 mg/dl

• Oral glucose tolerance test– 2 hr after 75 gm glucose load ≥ 200 mg / dl

Classification of DiabetesProposed by ADA - 1997.

• Type I: – Absolute Insulin Deficiency due to islet cell

destruction • Either immune mediated or idiopathic

• Type II: – Relative insulin deficiency due to impaired -cell

function – Marked ↑ peripheral insulin resistance

• Type III: Other Specific types• Type IV: Gestational Diabetes

Other specific typesA) Genetic defects of Beta cell function (MODY syndromes)

B) Genetic defects in Insulin action (Lipo atrophic Diabetes)

C) Diseases of the Exocrine Pancreas (pancreatitis)

D) Secondary to Endocrinopathies (Acromegaly, Cushings syndrome)

E) Drugs / Chemical induced (Steriods, thiazides)

F) Infections (Congenital Rubella )

G) Uncommon form of Immune Mediated Diabetes. (Anti insulin receptor antibodies)

H) Other Genetic Syndromes associated with Diabetes (Down’s syndromes, Turners syndromes, Klinefelters syndrome)

Type 2 Diabetes

β cells : insulin 65-70 %

cells : glucagon 25 %

δcells : somatostatin 10 %

PP (or F cells): pancreatic polypeptide 2 %

Insulin

• Glucose transporters –

• GLUT 1 Non insulin mediated glucose

uptake• GLUT 3 • GLUT 2 – Beta cell – Glucose sensors

• GLUT 4 – Insulin mediated glucose uptake in

muscle & Adipose tissue

Cell at rest

Secretion of insulin > 70 mg/ml

GLUT 2

• Direct stimulation• Plasma glucose or Amino Acids , ketones

• Hormonal regulation• Gastrointestinal hormones (GIP, CCK) directly

stimulate β cells • Neural regulation

• Parasympathetic stimulates insulin release through IP3/ DAG

• Sympathetic NS inhibits insulin release through 2 receptor activation

Regulation of insulin secretion

Carbohydrate metabolism

• Over all action of insulin is to ↓ glucose level in blood – ↑ Transport of glucose inside the cell– ↑ Peripheral utilization of glucose – ↑ Glycogen synthesis– ↓ Glycogenolysis – ↓ Neoglucogenesis

Lipid metabolism

• ↓ Lipolysis • ↑ Lipogenesis • ↓ Ketogenesis • ↑ Clearance of VLDL & chylomicrons from

blood through enzyme Vascular Endothelial Lipoprotein Lipase

Protein metabolism

• Protein synthesis • ↑ entry of amino acids in cells

Electrolyte metabolism • ↑ transport of K+, Ca++, inorganic phosphates

Other actions • Vascular actions:

– Vasodilation ? Activation of endothelial NO production

• Anti-inflammatory action– Especially in vasculature

• Decreased fibrinolysis • Growth• Steroidogenesis

Mechanism of action of insulin

Conventional insulin preparations Type Onset

(Hr)Peak (Hr)

DOA (Hr)

Short acting Regular insulin Semilente

0.5 -1 1

2-4 3-6

6-8 12-16

Intermediate acting

Lente Isophane(NPH) 1-2 8-10 20-24

Long acting Ultra lente Protamine Zinc Insulin (PZI)

4-6 14-18 24-36

Newer Insulin analogs

Type Onset Peak (Hr)

DOA (Hr)

Rapid acting

Lispro Aspart Glulisine

5-15 min 10-15 min5-15 min

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3-53-55-6

Long acting Glargine Detemir

1-2 hrs 2-3 hrs

No peak 6-8 hr

24 hr 24 hr

Action Profiles of Insulins

0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Plasmainsulinlevels

Regular 6–8 hours

NPH 12–16 hours

Ultralente 18–20 hours

Hrs

Aspart, glulisine, lispro 4–5 hours

Glargine ~24 hours

Detemir ~14 hours

Danne T et al. Diabetes Care. 2003;26:3087-3092

Indications of insulin in type II DM

• Primary or secondary failure of oral hypoglycemics

• Pregnancy• Perioperative period • Steroid therapy• Fasting > 300 mg HbA1c • Unintentional wt loss with or with out ketosis• Type 2 with DKA ( severe beta cell dysfunction)

Pathogenesis of DKA Insulin deficiency Absolute / relative

Counter hormone excess↓ Anabolism ↑ catabolism

↓Peripheral utilization of Glucose

Hyperglycemia

Heavy Glucosuria (osmotic diuresis)

Loss of water & electrolytes

↑ Glycogenolysis ↑ Glycolysis ↑Gluconeogenesis

Dehydration

+

Hyperosmolarity

↓ Fluid intake

Pathogenesis of DKA (How ketoacidosis occurs)

↑ FFA to liver

↑ Acetyl coA

↓ Alkali reserve

↑ Lipolysis

↑ Acetoacetyl coA

Acetoacetate -Hydroxy butrate Acetone

Hyperketonemia

Acidosis

Treatment of DKA

• Fluid therapy • Rapid acting regular insulin • Potassium replacement• Bicarbonate replacement• Phosphate replacement• Antibiotics • Treatment of precipitating cause• General measures

Fluid therapy • Adequate tissue perfusion is necessary insulin

action • Normal saline is fluid of choice for initial

rehydration – 1 litre in first hour – Next 1 L in next 2 hours – 2 litres in next 4 hours – 2 litres in next 8 hours

• i.e 4 to 6 litres in 24 hours • When BSL reaches 300 mg% fluid should be

changed to 5 % dextrose with concurrent insulin

Insulin in DKA • Regular/ short acting insulin IV treatment of

choice • Loading dose = 0.1-0.2 U/kg IV bolus • Then 0.1 U /kg/hr IV by continuous infusion• Rate doubled if no significant fall in BSL in 2 hr• 2-3 U/hr after BSL reaches 300mg%• If patient becomes fully conscious encouraged

to take oral food & SC insulin started

Potassium replacement

• In initial stage of treatment potassium not administered because in DKA it remains normal or ↑

• In presence of insulin infusion Sr potassium ↓ hence 10 mEq/L potassium can be added with 3rd bottle of normal saline

• Sr K+ < 3.3 mEq/L : 20 -30 mEq/hr

Bicarbonates & phosphates

• Bicarbonates – If blood pH > 7.1 no need of sodium bicarbonate – In presence of severe acidosis 50 mEq of sodium

bicarbonate added to IV fluid • Phosphates

– Non availability of ideal preparation– Replacement not very essential unless < 1 mEq/L– potassium phosphate 5-10 m mol/hr

Insulin resistance • State in which normal amount of insulin

produces subnormal amount of insulin response – ↓ insulin receptors – ↓ affinity for receptors

• May be acute or chronic • Requirement of > 200 Units of insulin per day

in absence of stress • Common in type II diabetics & obese

Oral antidiabetic drugs

• Sulfonylureas:• Meglitinides: • Biguanides :• Thiazolidinediones:• -glucosidase inhibitors:

Sulfonylureas I Generation

– Tolbutamide– Chlorpropamide

II Generation– Glipizide– Gliclazide– Glibenclamide (Glyburide) – Glimepiride

Adverse effects

• Hypoglycemia:• GI disturbances: Nausea, vomiting, metallic

taste, diarrhoea & flatulence • Weight gain • Hypersensitivity • Not safe in pregnancy • Chlorpropamide:

– cholestatic jaundice, dilutional hyponatremia, antabuse reaction

Contraindications 1. Allergy to SU

2. Renal failure:

3. Significant hepatic dysfunction

4. Severe infections, stress, trauma, major surgery

5. Pregnancy (except Glibenclamide)

6. T1DM

METFORMIN - INDICATIONS• Obese Type 2 Diabetes.

• Secondary Sulfonylurea Failure state.

• To reduce Insulin requirements.

• Can be combined with Sulfonylureas, Glitazones, Insulin.

Thiazolidinediones (Glitazones) Rosiglitazone & pioglitazone Selective agonists of PPAR

Bind to nuclear PPAR

Activate insulin responsive genes - regulate carbohydrate & lipid metabolism

Sensitize the peripheral tissues to insulin

↓blood glucose by

↑ Glucose transport into muscle & adipose tissue

Inhibit hepatic gluconeogenesis

Promote lipogenesis

• Pioglitazone: – 15 to 45 mg once daily orally

• Rosiglitazone: – 4 to 8 mg once daily orally

• Pt who benefit most are type II DM with substantial amount of insulin resistance

• Monotherapy – Hypoglycemia rare • Add-on Therapy – readjust dosage.• Takes one month to act

Alpha glucosidase inhibitors

• Acarbose • Miglitol • Voglibose

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Voglibose

• Advantages over Acarbose and Miglitol– 20-30 times more potent then acarbose– Does not affect digoxin bioavailability unlike

acarbose– No dosage adjustment required in renal

impairment patients unlike miglitol– Superior tolerability– Dose: 0.2 to 5 mg

Newer drugs for Type II DM

• GLP-1 Analogues – Exenatide– Liraglutide

• DPP-IV Inhibitors– Sitagliptin– Vildagliptin– Alogliptin

• Amylin analog:Pramlintide

Principles of treatment of Type 2 DM

Grade Diabetes Mellitus as mild, moderate or severe NB: (150 -200 ---mild ) HbA1c < 8 ( 200-250 --- Moderate) HbA1c 8 - 9 ( more than 250 severe) HbA1c 9 - 10For severe DM start on insulin if there is wt loss &

ketosisFor mild & moderate DM use metformin if obese &

sulfonylureas if not obese

If diabetes not controlled 

Look for SU failure       Occult infection – TB – UTI      Drug history and compliance     Food history – hypoglycaemia

and compliance  

 cardiac problem – avoid glitazones if in failure avoid metformin Renal problem – avoid metformin

 

Liver problem – avoid glitazone and metformin In general

patients with complication

Short acting SU or insulin 

Be ware of other drugs         - Diuretics

         - Corticosteroid

         - Other hormones

         - ACE inhibitors