The slide shows information and choice of modern medicines for cure of type 2 diabetes mellitus

1. ORAL HYPOGLYCEMIC AGENTS
WITH
COMPLICATIONS
Prepared by
Sanjay Kumar (PhD Scholar)
Minshu Prashant (PhD Scholar)
Dr. B. Ram (Associate Professor)
Department of Dravyaguna
Faculty of Ayurveda
Institute of Medical Sciences, Banaras Hindu University Varanasi

2. WHO define “Diabetes is a chronic, metabolic disease
characterized by elevated levels of blood glucose (or
blood sugar)”, which leads over time to serious damage
to the heart, blood vessels, eyes, kidneys, and nerves.

3. GLOBAL FACTS ON DIABETES
• The number of people with diabetes has risen from 108 million in
1980 to 422 million in 2014.
• The global prevalence of diabetes among adults over 18 years of
age has risen from 4.7% in 1980 to 8.5% in 2014.
• Diabetes prevalence has been rising more rapidly in middle- and
low-income countries.
• Diabetes is a major cause of blindness, kidney failure, heart attacks,
stroke and lower limb amputation.
• In 2015, an estimated 1.6 million deaths were directly caused by
diabetes.
• Almost half of all deaths attributable to high blood glucose occur
before the age of 70 years.
• WHO projects that diabetes will be the seventh leading cause of
death in 2030.

4. • Diabetes might be one of the most talked about diseases across the world and
especially in India
• In India, today have more people with type-2 diabetes (more than 50 million) than
any other Nation.
• According to World Health Organization (WHO) fact sheet on diabetes, an
estimated about 3.4 million deaths are caused due to high blood sugar.
• The WHO also estimates that 80 percent of diabetes deaths occur in low and
middle-income countries and projects that such deaths will double between 2016
to 2030.
• It has been further estimated that the global burden of type-2 diabetes is expected
to increase to 438 million by 2030 from 285 million people recorded in 2010.
• In India, this increase is estimated to be 58%, from 51 million people in 2010 to 87
million in 2030.

5. TYPES OF DIABETES MELLITUS (DM)
• Type 1 DM
• Type 2 DM
• Gestational diabetes mellitus (GDM)

6. TYPE 1 DIABETES MELLITUS
• Due to an absolute insulin deficiency
• Previously called Insulin-Dependent Diabetes Mellitus
(IDDM) or Juvenile-Onset DM
• Originally diagnosed in children and youth but now can be
diagnosed in adults.
• Exogenous insulin must be used for these individuals.
DIAGNOSIS:
Accounts for 5-10% of all diabetes cases
FASTING BLOOD GLUCOSE > 126 mg/dl
RANDOM BLOOD GLUCOSE > 200 mg/dl
ORAL GLUCOSE TOLERANCE TEST > 200 mg/dl
HbA1c > 6.5 %

7. CAUSES OF TYPE 1 DIABETES MELLITUS
• Genetics
• Environment
• Viruses
These can trigger an autoimmune response in which the
body's immune system attacks and destroy the insulin
producing beta cells of the pancreas

8. TYPE 2 DIABETES MELLITUS
• Due to a combination of ineffective insulin and/or
insufficient insulin production.
• Previously called Non-Insulin-Dependent DM
(NIDDM) or Adult-Onset DM.
• Historically linked to abdominal adiposity.
• It used to be seen in only adults but is now seen in
youth.
Accounts for 90-95% of all diabetes cases

9. CAUSES FOR TYPE 2 DIABETES MELLITUS
• Insulin resistance is the primary cause of type
2 DM.
• The pancreas secretes insulin but this insulin is
not 100% effective to helping glucose move
into muscle, fat and liver cells.
• The body “resists” the effect of insulin, and
consequently sugar remains in the blood.

10. Gestational Diabetes
• During pregnancy, women can develop insulin
resistance.
• Affects about 4% of all pregnant women.
• Gestational diabetes usually disappears after
pregnancy.
• Gestational diabetes increases risk for Type 2
diabetes later in life.
GESTATIONAL DIABETES (GD)

11. • Hormones from the placenta may block the
action of the mother's insulin in her body
causing insulin resistance
• The stress of the pregnancy may also cause
insulin resistance
CAUSES OF GESTATIONAL DIABETES

12. OTHER CAUSES FOR DIABETES MELLITUS
• Genetic defects of β-cell function
– Maturity onset diabetes of the young (MODY)
– Mitochondrial DNA mutations
• Genetic defects in insulin processing or insulin action
– Defects in pro-insulin conversion
– Insulin gene mutations
– Insulin receptor mutations
• Exocrine pancreatic defects
– Chronic pancreatitis
– Cystic fibrosis
– Pancreatic neoplasea

13. • Endocrinopathies
• Acromegaly
• Cushing's syndrome
• Hyperthyroidism
• Pheochromocytoma
• Infections
• Cytomegalovirus
• Coxsackievirus B
• Drugs
• Glucocorticoids
• Thyroid hormones
• Statins
• Beta adrenergic agonist

16. Insulin resistance
Hyperinsulinemia
(Normal glucose tolerence)
Impaired insulin secretion
(beta cell failure)
Type 2 DM
Medicines
Hyperglycemia
Obesity
Diseases (HIV)
hyperlipidemia
Sedentary life style
Environmental factorDiet

17. SIGN AND SYMPTOMS OF DIABETES
MELLITUS
• Increased thirst
• Increased hunger
• Polyurea
• Glycosurea
• Dry mouth
• Frequent urination
• weight loss
• Fatigue
• Blurred vision
• Headaches
• Slow-healing sores or cuts (Diabetic foot)
• Itching
• Numbness and tingling of the hands and feet
• Erectile dysfunction (impotency)

18. COMPLICATIONS OF TYPE 2 DIABETES
MELLITUS
I. Acute complications:
– Diabetic Ketoacidosis
– Hypoglycemia
II. Chronic complications:
a. Microvascular
– Retinopathy
– Nephropathy
– Neuropathy
– Diabetic foot
b. Macrovascular
– Cerebrovascular.
– Cardiovascular.
– Peripheral vascular disease.

19. WHO DIABETES DIAGNOSTIC CRITERIA FOR BLOOD SUGAR LEVELS
Blood glucose Normal Prediabetes Diabetes
Random
80 - 159 mg/dl 160 – 199 mg/dl 200 mg/dl or more
Fasting
Below 110 mg/dl 110 to 125 mg/dl
(IFG)
126 mg/dl or more
2 hour post-
prandial Below 140 mg/dl 140 to 199 mg/dl
(IGT)
200 mg/dl or more
HbA1c Below 6.0 % 6.0 to 6.5 % More than 6.5 %

20. ORAL HYPOGLYCEMIC DRUGS
“Agents that are given orally to reduce the
blood glucose levels in diabetic patients are
called oral hypoglycemic agents”.

21. 1. Age – between 35 – 70 years
2. BMI - < 36 kg/m2
3. Random blood glucose(RBG)– 200 – 400mg/dl,
fasting blood glucose(FBG) – >126 mg/dl,
post prandial glucose(PPG) – > 200 mg/dl
4. Insulin requirement - < 40 U /day
5. HbA1c - < 11%
Oral hypoglycemics

22. EXCUSION CRITERIA FOR ORAL
HYPOGLYCEMIC AGENTS
• Treatment with insulin.
• 2 or more hypoglycemic episodes within the
past years.
• Severe cardiovascular, respiratory, hepatic,
renal, gastrointestinal and neurological
disorders.
• Positive hepatitis B & C
Oral hypoglycemics

23. CLASSIFICATION OF ORAL
HYPOGLYCEMIC AGENTS
1. Biguanides – Metformin
2. Sulphonylureas –
First generation -(Tolbutamide, Chlorpropamide);
Second generation – (Glibenglamide, Glipizide,
Gliclazide, Glimiperide)
3. Meglitinides – Repaglinide, Nateglinide
4. Thiazolidinediones – Rosiglitazone, Pioglitazone
5. Alpha glucosidase inhibitors – Acarbose, Miglitol
6. Dipeptidyl peptidase-4 (DPP-4) inhibitors – Sitagliptin
7. Glucagon like peptide (GLP-1) analogue – Exenatide
8. Amylin analogue - Pramlintide

24. BIGUANIDES
Metformin
Decrease hyperglycemia
intestine liver Skeletal muscle
↑ Anaerobic glucose
metabolism
↓ Gluconeogenesis
↓ Glycogenolysis
↓ fatty acid oxidation
↑ Glucose uptake
↑ Glycogenesis
↓ fatty acid oxidation

25. Efficacy
– Reduces FBG by 60-70 mg/dl
– Reduces HbA1c by 1.5-2.0%
– Reduction in: TGs by 16%, LDL by 8%, and increases HDL by 2%
– Weight loss of 2-5 kg
Adverse effects
– GI: bloating, nausea, diarrhea, cramping
– Metallic taste in the mouth
– Lactic acidosis
– Hypoglycemia if used in combination with insulin or sulphonylurea
– Headache
Contrindications
– Renal impairment: Serum Creatinine ≥ 1.5mg/dl for men and ≥1.4mg/dl for
women
– Cardiac or respiratory insufficiency
– lactic acidosis
– Severe infection
– Liver diseases
– Alcohol abuse

26. Drug interactions:
– Drugs that are eliminated through renal
tubular secretion can potentially interact with
metformin such as digoxin, morphine,
procainamide, vancomycin, ranitidine
– Furosemide and nifedipine can potentially
increase metformin plasma concentrations
Dosing:
– start with 500mg or 850mg QD or BID

27. SULPHONYLUREA
Mechanism of action

28. Pharmacokinetics:
• Well absorbed orally
• 90% plasma protein bound
• Low volume of distribution
• Metabolized in liver and excreted through urine
Interactions
• Clofibrate, phenylbutazone, salicylates, sulfonamides →
displace Sulphonylureas from protein binding
• Chloramphenicol, MAOIs, phenylbutazone →reduce hepatic
Sulphonylurea metabolism
• Allopurinol, probenecid →decrease urinary excretion of
Sulphonylurea

29. Who is a candidate:
• Normal weight type 2 DM patients
• Onset of DM after age of 30 year
• Initial Blood Glucose < 250mg/dl
• Relatively normal renal and hepatic function
Who is not a candidate:
• Pregnant and lactating women
• Ketosis-prone patients
Efficacy:
• HbA1c ↓1.5%-2%
• FBG ↓50-60mg/dl
• Dose can be increased every 1-2 weeks for glycemic
control
Adverse effects: hypoglycemia, weight gain, GI upset

30. SULPHONYLUREA DRUGS
First
generation
Second
generation
Tolbutamide Glibenclamide Glipizide Gliclazide Glimperide
Half life 6 hr 2-4 hr 3-5 hr 8-20 hr 5-7 hr
Duration of
action
6-8 hr 24 hr 12 hr 12 – 24 hr 24 hr
Daily dose
required
0.5-3 gm 2.5-15 mg 5-20mg 40-240 mg 1-6 mg
No of doses 2-3/day 1-2/day 1-2/day 1-2/day 1-2/day
Draw back Prolong
hypoglycemia,
sweating, rapid
breathing, fast heart
rate, weight gain
Weight gain,
hypoglycemia
Weight gain,
skin changes,
hypoglycemia
Hypoglycemia,
numbness and
tigling
Lower incidence of
hypoglycemia

31. MEGLITINIDES
(Repaglinide, Nateglinide)
• Non-sulfonylurea
• Also bind the ATP –dependent K channel to release insulin
secretion.
• Used for management of meal-related glucose loads
• Less hypoglycemia than with sulphonylurea
Efficacy:
HbA1c ↓ 0.6%-1%
Adverse reaction
Low incidence of hypoglycemia (0.3%)
Slight weight gain
Contraindications
Pregnancy, DKA, severe infection

32. Repaglinide
Pharmacokinetics:
• Metabolized by Cyt P450
• Half-life: 1 hr
• Excreted in bile
• Dose: 0.5-4mg QD, max 16mg/day
• Take 30 min before meal, if meal is skipped,
skip the dose as well

33. THIAZOLIDINEDIONE
(Rosiglitazone, Pioglitazone)
Mechanism of action
• Thiazolidinedione act by -
activating PPARϒ (peroxisome proliferator-
activated receptors)
• Which is expressed in fat cells but also in
muscles and other cells.
• Reverse insulin resistance by enhancing GLUT-4
expression and translocation

35. Efficacy
• Rosiglitazone
Decreases: FBG by 30-60mg/dl, HbA1c by 0.8-1.5%, TGs
by7-14%
• Pioglitazone
Decreases: FBG by 39-65mg/dl, HbA1c by 1.0-1.6%, TGs by
5-26%
Adverse effect
• Fluid retention
• Weight gain
• Hypoglycemia if combined with other agents
• Liver injury
• Cardiac injury
Contraindication
• In cardiac complications

36. ALPHA – GLUCOSIDASE INHIBITOR
Acarbose : An inhibitor of intestinal α-
glucosidase enzyme
Mechanism of action : It delays carbohydrate
metabolism, absorption, reducing the
postprandial increase in blood glucose .
Adverse effect: flatulence, loose stools or diarrhea,
abdominal pain and bloating.
Contraindications : in pregnancy, liver disease,
kidney disease, breast feeding women and in
hypersensitivity

37. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS
Vildagliptin, Sitagliptin

38. • Efficacy: DPP-4 inhibitors lowered HbA1c
values by 0.74%, comparable to other anti-
diabetic drugs.
• Side effects: Pancreatitis, nausea, vomiting,
loss of appetite, fast heart rate; or urinating
less than usual or not at all; swelling, weight
gain, feeling short of breath.
• Contraindications: renal impairment,
hypersensitivity, pancreatitis, heart failure.

39. Sitagliptin vs Vildagliptin
Vildagliptin Sitagliptin
HbA1c Decreases 1.1 % Decreases 0.7 %
Side
effect
No skin rashes hypersensitivity

40. GLUCAGON LIKE PEPTIDE (GLP-1) ANALOGUE
(Exenatide, Liraglutide)
Exenatide,
Liraglutide

41. Efficacy : Decrease HbA1c 0.7 – 1.5 %
Side effects: Diarrhea, nausea, vomiting,
headaches, dizziness, increased sweating,
indigestion, constipation, loss of appetite

42. AMYLIN ANALOGUE
(Pramlintide)

43. AMYLIN ANALOGUE
• Efficacy
– Lowers HbA1c – 0.5 %
• Adverse effect
– Hypoglycemia
– Nausea, headache, anorexia
– Abdominal pain

44. Options for monotherapy
Biguanide
(Metformin)
Sulphonylurea
(Glibenclamide,
tolbutamide,
glipizide etc)
Meglitinide
(Repaglinide,
Nateglinide)
Thiazolidinedione
(Rosiglitazone,
Pioglitazone)
Alpha
glucosidase
inhibitors
(Acarbose)
Target population Target population Target population Target population Target population
Over weight/obese
Insulin resistance
Normal weight Elevated PPG Insulin resistance Elevated PPG
Advantages Advantages Advantages Advantages Advantages
No weight gain
↓ risk of
hypoglycemia
Effectiveness at
reducing glycemia
levels,
Low cost
↓ risk of
hypoglycemia,
Short acting
Meal adjusted
dosing
Hyperinsulinemia,
↓ risk of hypoglycemia
↓ risk of
hypoglycemia
Disadvantages Disadvantages Disadvantages Disadvantages Disadvantages
GI side effects
Rare lactic acidosis
Weight gain,
↑ risk of
hypoglycemia
High cost Weight gain
Slow onset of action
Liver toxicity
Cardio-toxicity
High cost
Hypersensitivity reactions
GI side effect,
High cost
If a single agent is inadequate, initiate combination therapy

45. Option for combination therapy
Biguanide
+
Sulphonylurea
or
Thiazolidinedione
or
Alpha glucosidase
inhibitors
Biguanide
+
Meglitinide
Biguanide
+
Thiazolidinedione
Biguanide
+
Alpha glucosidase
inhibitors
Triple combination
therapy
Sulphonylurea
+
Biguanide
+
Thiazolidinedione
or
Sulphonylurea
+
Biguanide
+
Alpha glucosidase
inhibitors

46. REFERENCES
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PLoS Med, 2006, 3(11)
2. American Diabetes Association. Standards of medical care in diabetes – 2017. Diabetes Care.
2017;40(1):1-98.
3. Joslin’s. Diabetes Mellitus. Fourteenth edition, Published by Lippincott Williams and Wilkins,
Page no-449-463.
4. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of
WHO/IDF consultation. World Health Organization. 2006. Page no 21-23.
5. Diabetes Fact Sheet. WHO. March 2014.
6. Gilman AG, Goodman LS, The Pharmacological Basis of Therapeutics. 13th edition, Macmillan,
New York.1985; 1490- 1516.
7. Tripathi K D. Essential of Mediacal Pharmacology. 7th Edition, Jaypee Publication. Page no: 258-
280.