Drug Management of Diabetes Mellitus

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Drug Management of

Diabetes MellitusDr. S .K. Maulik


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Diabetes Mellitus It is a group of metabolic diseases

characterized by hyperglycemia resultingfrom defects in insulin secretion, insulinaction, or both

Two major types : Type 1 and Type 2 There is either ABSOLUTE or RELATIVE

deficiency of insulin

In 2010, the number worldwide isprojected to reach 221 million In Asia and Africa, diabetes rates could

rise two- to threefold


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Criteria for the diagnosis of diabetes mellitusA. Casual plasma glucose concentration 200 mg/dl (11.1 mmol/l), with or without

classic symptomsCasual is defined as any time of day without regard to time since last meal.

The classic symptoms of diabetes include polyuria, polydipsia, and unexplainedweight 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 aglucose 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%.


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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


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Therapeutic strategies

Diabetes management should begin withMedical Nutrition Therapy (MNT)

(A typical days meals and snacks should provide 1,5002,000calories with 50% of the calories from carbohydrate, 20% fromprotein, and 30% from fat)

An exercise regimen to increase insulinsensitivity and promote weight loss should alsobe started.

If the patients glycemic target is not achievedafter 3 to 4 weeks of MNT & exercise regimen,pharmacologic therapy is indicated.


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Pharmacologic management of for Type 1DM is only insulin

Pharmacologic management of Type 2 DM includes both oral glucoselowering agents or/ plus insulin

(As Type 2 DM is a progressive disorder, it ultimatelyrequires multiple therapeutic agents and often insulin)

Pharmacologic (DRUG) management


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Recap of Drugs


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Oral Glucose Lowering Agents, also calledOral Hypoglycemic Agents

Based on their mechanisms of action, oral glucose lowering agentsare subdivided into agents those:

Increase insulin secretion ( Insulin Secretagogues)

Reduce glucose production

Decrease glucose absorption from GIT

Increase insulin sensitivity


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1.Insulin Secretagogues (hypoglycemic agents)

Sulfonylureas MeglitinidesRapaglinide (0.25 - 4 mg tid/ qid)

Nateglinide

1 st . Generation:

Chlorpromamide (100-500 mg od)

2 nd . Generation:

Gliblenclamide (5-15 mg bid ac)

Glimepiride (1-6 mg od)


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These drugs stimulate insulin secretion byinteracting with the ATP sensitive K + channel onthe beta cells of pancreas

1 st generation sulfonylureas have a longer plasma half-life which causes a greater incidence of hypoglycemia

2 nd generation sulfonylureas are generallypreferred, because they cause much lesshypoglycemia due to their shorter half-life

Insulin Secretagogues (Sulfonylureas)


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Sulfonylureas

ADRs : hypoglycemia, weight gain

Contraindications : Type 1 DM, liver or kidneydisease, 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. Thiazides,2. Hydantoins3. Oral contraceptives4. Corticosteroids


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Insulin Secretagogues (meglitinides)

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

They have Fast onset of action (


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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 appetiteThe 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)


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3. -GLOCUSIDASE INHIBITORS

Examples : acarbose and miglitol

M.O.A. : Reduction in glucose absorption by inhibiting theenzyme that breaks complex sugars into simple sugars inthe 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


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4. THIAZOLIDINEDIONES (glitazones)

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

They correct insulin resistance

The first drug of this group, troglitazone, was withdrawn due tohepatotoxicity

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.


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Incretin -mimetic (exenatide)

It has a novel mechanism of action

It mimicks the endogenous incretin, glucagon-like peptide-1 (GLP-1) and thus it stimulatesglucose-dependent insulin release

As opposed to insulin secretagogues, whichmay cause nonglucose-dependent insulinrelease and hypoglycemia

Patients may attain modest weight loss. This drug requires twice daily injections and is

more expensive than high-dose glitazonetherapy.


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DPP-4 inhibitors

The newest oral hypoglycemic agents is

SITAGLIPTIN , a dipeptidyl peptidase IV (DPP-4)inhibitor

DPP-4 degrades numerous biologically activepeptides including the endogenous incretins,GLP-1 and glucose-dependent insulinotropicpeptide (GIP).

Sitagliptin can be used as a monotherapy or incombination with metformin or the glitazones

It is given orally and once daily


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How to treat Type 2 DM


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Efficacy Safety Cost

Determinants of selection of drugs for Type 2 DM


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Efficacy of Oral Hypoglycemic Agents

Sulfonylureas are not much helpful inpatients with moderate glucose intoleranceand pancreatic -cell loss

Thiazolidinediones (glitazones) do not demonstrate much efficacy in patients whodont have much insulin resistance


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The benefits of combination therapy must beweighed against the risk of side effects.

For sulfonylureas, the major side effect hasbeen the frequency and severity of hypoglycemia .

However, for many patients, weight gain is alsounacceptable

Side effects


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Glycemic Control Algorithm for Type 2 Diabetes Mellitus

GoalsHb A1C 6.0%, Fasting BG 100 mg/Dl , 2-hr PP BG 140 mg/dLAvoid hypoglycemia; i.e. glucose


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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


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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%


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I

N

S

U

L

I

N

L

E

V

E

L

Time in hours

AB

C

These are the plasma levels of THREE

different Insulin Preparations

Identify A , B & C

Quiz


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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


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Dosage

Usual Total Daily dose is0.5 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


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Dosage (basal-bolus)

Calculate thetotal daily dose

of insulin (0.5 iu/kg)

2/3 rd beforeBREAKFAST

1/3 rd beforeEVENING MEAL

2/3 rd asintermediate or

long-acting insulin

1/3 rd asshort-actingInsulin

1/3 rd asshort-acting

Insulin

2/3 rd asintermediate or long-acting insulin

Quiz: Calculate thedosage if the total dailyrequirement in a patientof 90kg BW


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Break Fast Dinner

Regular Insulin

NPH InsulinNPH Insulin

Regular Insulin

Bed Time Break Fast LunchDinner

NPH Insulin

Regular Insulin

Regular Insulin

An intermediate- plus a short-acting insulin given together

in morning & evening

An intermediate- or long-acting insulin at bedtimePLUS a short- actinginsulin before each meal

1

2


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Monitoring therapy1. Finger prick blood glucose testing

Reagent strips and measuring instrument Before each meal, before bed Before meal blood glucose should be 70 120 mg/dl After food level should be


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Self-monitoring of blood glucose (individualizedfrequency)

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)


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Essential information for patients What is hypoglycemia and how to treat it

Carry a diabetic card with details of drugsand patient information

Carry glucose (dextrose) or simple sugar (sucrose)

Careful while driving cars and handlingheavy machine


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All of them have Diabetes mellitus

Prescribe the drug of choice for each of them

A. _______

B._______

C.________


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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

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Drug Management of Diabetes Mellitus