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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. Thiazides,
2. Hydantoins
3. Oral contraceptives
4. 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 proliferators-


activated 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, glucagon-
like 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 not met after 3 months


Goals Achieved
• Continue Therapy
• A1C every 3-6 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%
Quiz
I
N
A
S
U
B
C
L
I
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
Calculate the dosage if the total daily
total daily dose requirement in a patient
of insulin (0.5 iu/kg) of 90kg BW

2/3 rd before 1/3 rd before


BREAKFAST EVENING MEAL

2/3 rd as 1/3 rd as 2/3 rd as 1/3 rd as


intermediate or short-acting intermediate or short-acting
long-acting insulin Insulin long-acting insulin Insulin
1 An intermediate- plus a short-
acting insulin given together
Regular Insulin
Regular Insulin in morning & evening

NPH Insulin
NPH Insulin

Break Fast Dinner

2
An intermediate- or long-
acting insulin at bedtime
PLUS a short- acting
insulin before each meal Regular Insulin
Regular Insulin

NPH Insulin

Dinner
Lunch
Break Fast
Bed Time
Monitoring therapy
1. 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 <180 mg/dl

3. Urine glucose testing


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

5. 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

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