Drug therapy in Diabetes

Aims  of management
►    To achieve near normal glycaemia
-    Short term- to prevent symptoms of hyper & hypo
-    Long term- to prevent complications
►    Good quality of life, near normal life expectancy



Types of Insulin
►      Short acting -      Soluble / Neutral insulin
                       Insulin aspart
                     Insulin lispro
►     Intermediate acting - Isophane
►     Long acting - Insulin Zinc suspension
                  new insulin analogue - Glargine
                                 Detemir 
►      Biphasic- mixture of short and intermediate
                     Biphasic lispro
                     Biphasic Isophane


Types of Insulin

Insulin	Lispro Aspart	Neutral/ regular	Isophane	ultratard	Glargine
Onset	10-20′	30′	1h	4h	2-4h
Peak	1h	1-3h	4-6h	6-18h	peak less
Duration	3-5h	4-8h	8-14h	24h	20-24h

Soluble insulin / neutral /clear
►    Names - Human actrapid/ Humulin S
►    Species- Bovine, porcine, human
►    Following s/c injection
        Onset of action – 30 min
           Peak- 1-3 hours
           Duration- 4-8 hours
►    Only insulin suitable for intravenous route –plasma half life < 5 min, required continuous infusion
►    Used in diabetes Ketoacidosis


Sites of injections - Subcutaneous
►    Thighs
►    Upper buttocks
►    Abdomen
►    Arms
Important to rotate the site
Rate of absorption may be significantly different – faster from arm and abdomen than from thigh and buttock


Routes of Administration
►    Subcutaneous for long term regular use
►    Intravenous infusion in acute conditions- diabetes Ketoacidosis, Perioperative period, Hyperosmolar Nonketotic state  ONLY NEUTRAL/ CLEAR INSULIN CAN BE USED
►    Continuous subcutaneous insulin infusion via pump – neutral
►    Intraperitoneal – Peritoneal dialysis patients
►    Inhaled insulin- experimental


Untoward effect of insulin
►    Hypoglycaemia
►    Weight gain- anabolic hormone
►    Lipohypertrophy- injection to same site
►    Insulin oedema
►    Transient deterioration in retinopathy
►    Insulin neuritis – actively regenerating neurone, uncommon
►    Postural hypotension



Recurrent Hypo
►    ? Required dose adjustment
►    ? Right insulin/ injection technique
►    ? Meal/ fasting related
►    ? Injections sites
►    ? Exercise
►    Unexplained - ?autonomic neuropathy


Sick day rules
    never stop insulin
    monitor more frequently
    maintain your hydration
    Check for ketones
    Know when & how to call for help


Oral Medications to Treat Type 2 Diabetes
Major Classes of Medications
    sensitize   the body to insulin +/- control hepatic glucose production

    stimulate the pancreas to make more insulin

    slow the absorption of starches

Thiazolidinediones
Biguanides


Sulfonylureas
Meglitinides


Alpha-glucosidase
 inhibitors



Thiazolidinediones
►    ↓ insulin resistance by making muscle and adipose cells more sensitive to insulin. They also suppress hepatic glucose production.
►    Efficacy
    ↓ fasting plasma glucose ~1.9-2.2 mmol/L
    Reduce A1C ~0.5-1.0%
    6 weeks for maximum effect
►    Other Effects
    Weight gain, oedema
    Hypoglycemia (if taken with insulin or agents that stimulate insulin release)
    Contraindicated in patients with abnormal LFT or CHF
    Improves HDL cholesterol and plasma triglycerides; usually LDL neutral
►    Medications in this Class: pioglitazone (Actos), rosiglitazone (Avandia), [troglitazone (Rezulin) - taken off market due to liver toxicity]


Biguanides
►    Biguanides ↓ hepatic glucose production and increase insulin-mediated peripheral glucose uptake.
►    Efficacy
    Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L)
    Reduce A1C 1.0-2.0%
►    Other Effects
    Diarrhea and abdominal discomfort
    Lactic acidosis if improperly prescribed
    Cause small decrease in LDL cholesterol level and triglycerides
    No specific effect on blood pressure
    No weight gain, with possible modest weight loss
    Contraindicated in patients with impaired renal function
    Medications in this Class: metformin (Glucophage), metformin hydrochloride extended release (Glucophage XR)


Sulfonylureas
►    Sulfonylureas increase endogenous insulin secretion
►    Efficacy
    Decrease fasting plasma glucose 3.3-3.9 mmol/L
    Reduce A1C by 1.0-2.0%
►    Other Effects
    Hypoglycemia
    Weight gain
    No specific effect on plasma lipids or blood pressure
    Generally the least expensive class of medication
►    Medications in this Class:
    First generation : chlorpropamide , tolazamide, acetohexamide , tolbutamide
    Second generation : glyburide , glimepiride , glipizide


Meglitinides
►    stimulate insulin secretion (rapidly and for a short duration) in the presence of glucose.
►    Efficacy
    ↓ peak postprandial glucose
    ↓ plasma glucose 3.3-3.9 mmol/L
    ↓ HbA1C 1.0-2.0%
►    Other Effects
    Hypoglycemia (may be less than with sulfonylureas if patient has a variable eating schedule)
    Weight gain
    No significant effect on plasma lipid levels
    Safe at higher levels of serum Cr than sulfonylureas
►    Medications in this Class: repaglinide , nateglinide


Alpha-glucosidase Inhibitors
►    Alpha-glucosidase inhibitors block the enzymes that digest starches in the small intestine
►    Efficacy
    ↓ peak postprandial glucose 2.2-2.8 mmol/L
    ↓ fasting plasma glucose 1.4-1.7 mmol/L
    Decrease A1C 0.5-1.0%
►    Other Effects
    Flatulence or abdominal discomfort
    No specific effect on lipids or blood pressure
    No weight gain
    Contraindicated in patients with inflammatory bowel disease or cirrhosis
►    Medications in this Class: acarbose , miglitol 




Combination Therapy  for Type 2 Diabetes
Sulfonylurea + Biguanide
    Glyburide  +  Metformin     -  Glucovance
    Glipizide  +  Metformin     -  Metaglip

Thiazolidinedione + Biguanide
   Rosiglitazone + Metformin  -  Avandamet


Chart


Clinic Checklists
►    Glycaemic control- home monitoring, HbA1c, inj site, hypo
►    Diet, exercise, Smoking, alcohol
►    BP
►    Weight
►    Macrovascular- CVA, IHD
►    Microvascular- Retinopathy, microalbuminuria, neuropathy
►    Foot
►    Lipid profile, renal function, TSH


Special circumstances
►    Intercurrent illness
►    Peri-operative period
►    Pregnancy
►    Childhood and adolescents
►    Others- travelling across time zones
                Exercise
                Alcohol
            Driving


Dr K S Myint
Specialist Registrar