Drug Management Of Diabetes Mellitus

Drug Management of Diabetes Mellitus Dr. S .K. Maulik

Diabetes Mellitus • It is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both • Two major types : Type 1 and Type 2 • There is either ABSOLUTE or RELATIVE deficiency of insulin • In 2010, the number worldwide is projected to reach 221 million • In Asia and Africa, diabetes rates could rise two- to threefold

Criteria for the diagnosis of diabetes mellitus A.

Casual plasma glucose concentration ≥200 mg/dl (11.1 mmol/l), with or without classic symptoms Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.

OR •

Fasting Plasma Glucose is ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.

OR •

2-h post glucose load is ≥ 200 mg/dl (11.1 mmol/l) during an OGTT. Oral Glucose Tolerance Test should be performed as described by WHO, taking a glucose load of 75 g glucose dissolved in water

HbA1c • It measures the amount of glycosylated hemoglobin in blood • It is not useful for the diagnosis of diabetes mellitus • It is often used for monitoring long-term glycemic control and reflect glycemia for the previous 3 months • Its recommended level for a good glycemic is less than 6.5%.

Therapeutic aims • Glycemic control • Treatment of conditions associated with DM – – – –

Obesity Hypertension Dyslipidemia Ischemic heart disease

• Detection / treatment of DM related complications – – – –

renal cardiovascular retinal and neuropathic

Therapeutic strategies • Diabetes management should begin with Medical Nutrition Therapy (MNT) (A typical day’s meals and snacks should provide 1,500–2,000 calories with 50% of the calories from carbohydrate, 20% from protein, and 30% from fat)

• An exercise regimen to increase insulin sensitivity and promote weight loss should also be started. • If the patient’s glycemic target is not achieved after 3 to 4 weeks of MNT & exercise regimen, pharmacologic therapy is indicated.

Pharmacologic (DRUG) management

• Pharmacologic management of for Type 1DM is only insulin • Pharmacologic management of Type 2 DM includes both oral glucose lowering agents or/ plus insulin (As Type 2 DM is a progressive disorder, it ultimately requires multiple therapeutic agents and often insulin)

Recap of Drugs

Oral Glucose Lowering Agents, also called Oral Hypoglycemic Agents Based on their mechanisms of action, oral glucose lowering agents are subdivided into agents those:

• Increase insulin secretion ( Insulin

Secretagogues)

• Reduce glucose production • Decrease glucose absorption from GIT • Increase insulin sensitivity

1.Insulin Secretagogues (hypoglycemic agents)

Sulfonylureas

Meglitinides

1st. Generation:

Rapaglinide (0.25 - 4 mg tid/ qid)

Chlorpromamide (100-500 mg od)

Nateglinide

2nd. Generation: Gliblenclamide (5-15 mg bid ac) Glimepiride (1-6 mg od)

Insulin Secretagogues (Sulfonylureas)

• These drugs stimulate insulin secretion by interacting with the ATP sensitive K+ channel on the beta cells of pancreas • 1st generation sulfonylureas have a longer plasma half-life which causes a greater incidence of hypoglycemia • 2nd generation sulfonylureas are generally preferred, because they cause much less hypoglycemia due to their shorter half-life

Sulfonylureas • •

ADRs: hypoglycemia, weight gain Contraindications: Type 1 DM, liver or kidney

•

disease, sulfa allergy Clinical advantage: Lean patients, with high blood glucose

•

Drug interactions Drugs which can increase hypoglycemic effects of sulfonylureas • • • •

NSAIDs, Sulfonamides Warfarin Beta -blockers

Drugs which can decrease hypoglycemic effects of sulfonylureas 1. 2. 3. 4.

Thiazides, Hydantoins Oral contraceptives Corticosteroids

Insulin Secretagogues (meglitinides)

• Mechanism of Action: also interact with the ATP-sensitive K+ channel and increase insulin secretion from β-cell of pancreas.

• They have – Fast onset of action (<1h.) – short half-lives (1h.) – short duration of action(4h.)

• So these agents are taken immediately before each meal • Clinical advantage: Effective in reducing post prandial hyperglycemia and hypoglycemia is rare

• Dose: 0.25 – 4.0 mg (repaglinide) & 60-120 mg (nateglinide) tid / qid • ADR: They should be cautiously used in hepatic & renal dysfunctions

2. BIGUANIDES • •

Metformin is the only drug used Mechanisms of action: – – – –

Reduced hepatic gluconeogenesis Increased glycolysis in peripheral tissues Reduced absorption of glucose from GIT Decreased plasma glucagon level

3. •

The initial starting dose is 500 mg OD/ BID, upto 1000 mg BID ADR: diarrhea, anorexia, nausea, and loss of appetite The major ADR of metformin is lactic acidosis

•

Clinical Advantage: No hypoglycemia and No weight gain Useful in OBESE diabetics with not very high Blood Glucose

•

Metformin is contraindicated in patients with – – – –

renal / liver diseases any form of acidosis, congestive heart failure Use of contrast radiography (should be stopped 48 hrs. before)

3. α-GLOCUSIDASE INHIBITORS

Examples: acarbose and miglitol M.O.A.: Reduction in glucose absorption by inhibiting the enzyme that breaks complex sugars into simple sugars in the intestinal lumen. Dose: start with a low dose (25 mg of acarbose or miglitol) and may be increased over weeks to months ADRs: diarrhea, flatulence, abdominal distention Clinical advantage: Pre-diabetic, obese persons

4. THIAZOLIDINEDIONES (glitazones) •

These drugs bind to the PPAR – y (peroxisome proliferatorsactivated receptor-y) nuclear receptor in adipose tissues

•

They correct insulin resistance

•

The first drug of this group, troglitazone, was withdrawn due to hepatotoxicity

•

For rosiglitazone and pioglitazone, liver function tests are recommended before starting and at regular intervals

•

These drugs are contraindicated in patients with liver disease or congestive heart failure

•

The safety of thiazolidinediones in pregnancy is not established.

Incretin -mimetic (exenatide) • It has a novel mechanism of action • It mimicks the endogenous incretin, glucagonlike peptide-1 (GLP-1) and thus it stimulates glucose-dependent insulin release • As opposed to insulin secretagogues, which may cause non–glucose-dependent insulin release and hypoglycemia • Patients may attain modest weight loss. • This drug requires twice daily injections and is more expensive than high-dose glitazone therapy.

DPP-4 inhibitors • The newest oral hypoglycemic agents is SITAGLIPTIN, a dipeptidyl peptidase IV (DPP-4) inhibitor • DPP-4 degrades numerous biologically active peptides including the endogenous incretins, GLP-1 and glucose-dependent insulinotropic peptide (GIP). • Sitagliptin can be used as a monotherapy or in combination with metformin or the glitazones • It is given orally and once daily

How to treat Type 2 DM

Determinants of selection of drugs for Type 2 DM

Efficacy

Safety

Cost

Efficacy of Oral Hypoglycemic Agents • Sulfonylureas are not much helpful in patients with moderate glucose intolerance and pancreatic β -cell loss • Thiazolidinediones (glitazones) do not demonstrate much efficacy in patients who don’t have much insulin resistance

Side effects • The benefits of combination therapy must be weighed against the risk of side effects. • For sulfonylureas, the major side effect has been the frequency and severity of hypoglycemia. • However, for many patients, weight gain is also unacceptable

Cost Metformin and 2nd. Generation Sulfonylureas are LESS EXPENSIVE

Newer drugs are MORE EXPENSIVE

Glycemic Control Algorithm for Type 2 Diabetes Mellitus Goals Hb A1C ≤ 6.0%, Fasting BG ≤100 mg/Dl, 2-hr PP BG ≤140 mg/dL Avoid hypoglycemia; i.e. glucose <60 mg/dL or <70 mg/dL if IHD

Initial Intervention 1. Diabetes Education

2. Medical Nutrition, Weight Control, Exercise If NOT CONTROLLED 3. Consider Monotherapy (Metformin, if OBESE)

Goals Achieved • Continue Therapy • A1C every 3-6 months

Goals not met after 3 months • Add additional oral agent if A1C ~7%

Goals not met after 3 Months • Add insulin (see Insulin Algorithm) • Consider referral to endocrinologist

Insulin Insulin is essential for patients with: • • • • • •

Type I Diabetes mellitus Type II DM poorly controlled with OHA s Some secondary diabetes Diabetes associated with pregnancy Surgery In some serious concurrent diseases, AMI • Ketoacidosis

Types of insulin • Rapid-acting: Insulin aspart,- lispro, - glulisine (1-2h. onset / 4-6h. duration of action)

• Short-acting: Regular Insulin, inhaled insulin (2-4h. onset / 6-12h. duration of action)

• Intermediate-acting: NPH Insulin, Lente insulin (3-8h. onset / 12-20h. duration of action)

• Long-acting: Insulin glargine, Insulin detimer (6-12 onset / 16-30h. duration of action)

• Pre-mixed insulins: NPH 70%+ Insulin aspart 30%

I N S U L

Quiz

A B

I

C

N

L E V E L

Time in hours

These are the plasma levels of THREE different Insulin Preparations

Identify A , B & C

ADRs of insulin • • •

Hypoglycemia Lypodystrophy at the site of injection (atrophy or hypertrophy) Insulin allergy

How to dose insulin • Sliding Scale Insulin It is the most frequent insulin regimen in hospitalized patients

Otherwise, use

• Basal-

bolus insulin

Dosage • Usual Total Daily dose is 0.5 i.u. per kg BW • Higher doses are needed for those who: – have concurrent disease, AMI – have very high blood glucose levels – have ketoacidosis – are taking corticosteroids

Dosage (basal-bolus) Quiz: Calculate the dosage if the total daily requirement in a patient of 90kg BW

Calculate the total daily dose of insulin (0.5 iu/kg)

2/3 rd before BREAKFAST

2/3 rd as intermediate or long-acting insulin

1/3 rd before EVENING MEAL

1/3 rd as short-acting Insulin

2/3 rd as intermediate or long-acting insulin

1/3 rd as short-acting Insulin

1 Regular Insulin

An intermediate- plus a shortacting insulin given together in morning & evening

Regular Insulin

NPH Insulin NPH Insulin

Break Fast

Dinner

2 An intermediate- or longacting insulin at bedtime PLUS a short- acting insulin before each meal

Regular Insulin

Regular Insulin

NPH Insulin

Bed Time

Break Fast

Lunch

Dinner

Monitoring therapy 1.

Finger prick blood glucose testing Reagent strips and measuring instrument – – –

3.

Before each meal, before bed Before meal blood glucose should be 70 – 120 mg/dl After food level should be <180 mg/dl

Urine glucose testing – – – –

5.

Less accurate than blood glucose Renal threshold may vary Useful in stable patients Useful in patients who can’t do finger-prick

HbA1C measurement – –

Useful for measure of the degree of glycemia in the past 4-6 weeks Good control if < 6 %

• Self-monitoring of blood glucose (individualized frequency)

• HbAIC testing (2-4 times/year) • Medical nutrition therapy and education (annual) • Eye examination (annual) • Foot examination (1-2 times/year) • Screening for diabetic nephropathy (annual) • Blood pressure measurement (quarterly) • Lipid profile (annual)

Essential information for patients

• What is hypoglycemia and how to treat it • Carry a diabetic card with details of drugs and patient information • Carry glucose (dextrose) or simple sugar (sucrose) • Careful while driving cars and handling heavy machine

All of them have Diabetes mellitus

Prescribe the drug of choice for each of them

A. _______

C.________ B._______

Diabetic Ketoacidosis • Altered sensorium, high blood sugar, urinary ketones • It is an emergency and the treatment is:

• Large IV fluid: • Isotonic saline: 1.0 L in 1st 30 min.,1.0 L in next 2hrs., & 0.5L q 4 hr. (depends on degree of dehydration) • Continue until BG is ~ 180 mg/ dl. • Then switch to 10% dextrose • Adjust infusion rate according to CVP and urine output

Treatment of DKA (contd.) 1. Regular insulin: • • •

6.0 iu stat iv and 0.1 iu/kg/h iv till BG 180mg/dl BG level should be monitored every hour If BG does not fall in 2h., and infusion lines are OK, double the insulin dose

•

NaHCO3: if pH of arterial blood is <7.0 (50ml. of 1.26% i.v.)

• Potassium: if <6.0, consider i.v. Frequent assessment of blood sugar, pH, K+, ECG, General Condition