This document discusses the drug management of diabetes mellitus. It begins by classifying the different types of diabetes and criteria for diagnosis. It then discusses the therapeutic aims of glycemic control and treatment of associated conditions. The main therapeutic strategies discussed are medical nutrition therapy, exercise, and pharmacologic therapy including insulin for type 1 diabetes and oral glucose lowering agents or insulin for type 2 diabetes. Finally, it summarizes the mechanisms and examples of common classes of oral glucose lowering drugs including sulfonylureas, meglitinides, biguanides, and alpha-glucosidase inhibitors.

1. Drug Management of
Diabetes Mellitus
Dr. Amol Diwan
SKNMC, Pune

2. Diabetes Mellitus
• Diabetes mellitus is a group of metabolic
diseases characterized by hyperglycemia
resulting from defects in insulin secretion,
insulin action, or both.
• The name 'diabetes mellitus' derives from:
Greek: 'diabetes' – “siphon” or “to pass
through”
Latin: 'mellitus' – “honeyed” or “sweet”**
• Two major types : Type 1 and Type 2
• There is either ABSOLUTE or RELATIVE
deficiency of insulin

3. Classification
• Type 1 diabetes
• Type 2 diabetes
• Other
1. Genetic defects of beta cell function
2. Genetic defects in insulin action
3. Diseases of the exocrine pancreas
4. Endocrinopathies
5. Drug/ chemical - induced
6. Infections
7. Uncommon forms of immune-mediated diabetes
8. Genetic syndromes sometimes associated with
diabetes
• Gestational diabetes mellitus

4. Criteria for the diagnosis of diabetes mellitus
A. Random plasma glucose concentration ≥200 mg/dl (11.1 mmol/l), with or
without classic symptoms
Random is defined as any time of day without regard to time since last meal.
The classic symptoms of diabetes include polyuria, polydipsia, polyphagia and
unexplained weight loss.
OR
B. Fasting Plasma Glucose is ≥ 126 mg/dl (7.0 mmol/l).
Fasting is defined as no caloric intake for at least 8 h.
OR
C. 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
Any of these criteria establishes the diagnosis but needs to be confirmed on a later
day
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%.

5. Prediabetes: IFG, IGT, Increased A1C
Categories of increased risk for diabetes
(prediabetes)*
FPG 100–125 mg/dL: IFG
OR
2-h plasma glucose in the 75-g OGTT
140–199 mg/dL: IGT
OR
A1C 5.7–6.4%
ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S13. Table 3.

6. 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

7. 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.

8. 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)

9. Recap of Drugs

10. Oral Glucose Lowering Agents, also called
Oral Hypoglycemic Agents (OHA)
Based on their mechanisms of action, oral glucose lowering
agents are subdivided into those:
1. Increase insulin secretion ( Insulin Secretagogues)
2. Reduce glucose production
3. Decrease glucose absorption from GIT
4. Increase insulin sensitivity

11. 1.Insulin Secretagogues (hypoglycemic agents)
Sulfonylureas Meglitinides
1st. Generation:
Acetohexamide
Chlorpropamide Rapaglinide (0.25 - 4 mg tid/ qid)
Tolazamide
Nateglinide
Tolbutamide
(rarely used now )
2nd. Generation:
Glibenclamide (Glyburide)
Glipizide
Glicazide
Glimepiride

12. Second generation sulfonylurea
More potent
 have fewer adverse effects
 have fewer drug interactions
 has longer duration (24 h)
 e.g. Glipizide, glyburide (Glibenclamide),
glimepiride
 Contraindicated in hepatic impairement or
renal insufficiency

13. Second generation sulfonylurea
Examples Starting dose Max. daily dose
Glibenclamide 1.25 mg – 2.5 mg 15 mg
(5 mg)
Glipizide 2.5 mg – 5 mg 40
mg (5 mg)
Gliclazide 20 mg – 40 mg 320 mg
(80 mg)
Glimepride 1 - 2 mg 6 – 8 mg

14. Unwanted Effects:
• Hyperinsulinemia & Hypoglycemia:
• More in chlorpropamide & glibenclamide
• Less in tolbutamide.
• More in elderly and patients with renal disease.
• Weight gain due to increase in appetite
• GIT upset.
• Dilutional hyponatremia, water intoxication
(Chlorpropamide) vasopressin effect.
• Disulfiram-like reaction with alcohol (chlorpropamide).
• Tachyphylaxis (secondary failure).

15. Drugs which decrease hypoglycemic
effect:
• Microsomal inducers.
• Thiazide diuretics
• Corticosteroids.
• Diazoxide.
CONTRAINDICATIONS:
• Pregnancy (use insulin)
• Hepatic or renal insufficiency
• Type I diabetes

16. Insulin Secretagogues
(Sulfonylureas)
• Mechanism of action: These drugs stimulate
insulin secretion by interacting with the ATP
sensitive K+ channel on the beta cells of
pancreas - must have functional beta cells -
• 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

17. Sulfonylureas
1. ADRs: hypoglycemia, weight gain
2. Contraindications: Type 1 DM, liver or kidney
disease, sulfa allergy, pregnancy
3. Clinical advantage: Lean patients with high
blood glucose
3. Drug interactions
Drugs which can increase hypoglycemic effects of sulfonylureas
1. NSAIDs,
2. Sulfonamides
3. Warfarin
4. Beta -blockers
Drugs which can decrease hypoglycemic effects of sulfonylureas
1. Thiazides,
2. Hydantoins
3. Oral contraceptives
4. Corticosteroids

18. Oral Antidiabetic Agents
• Insulin secretagogues
Hypoglycemia, is a side effect
common to almost ALL these drugs
– Sulfonylureas
– Meglitinides
Almost ALL of them are
• Biguanides: Metformin
contraindicated in severe liver, renal
• Thiazolidinediones
andAlpha glucosidase inhibitors should be
• cardiac disease and
used with extreme caution in elderly

19. Insulin Secretagogues (Meglitinides)
Repaglinide / Nateglinide
• 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

20. Meglitinides
• Examples
• Rapaglinide - Starting dose 0.5 mg
3 times before meal
• Max. daily dose 8 mg
• Nateglinide - Starting dose 120 mg
3 times before meal
• Max. daily dose 360 mg

21. Adverse effects of Meglitinides
• Less incidence than sulfonylureas
• Hypoglycemia (if meal is delayed)
• Weight gain
• Drug interactions - Repaglinide has recently been
contraindicated in patients taking gemfibrozil due to the risk of
severe/prolonged hypoglycemia
- Clarithromycin, itraconazole, ketoconazole, MAOIs
- Due to CYP2C8 and CYP3A4 interactions
Contraindications
• Hepatic and renal impairment.

22. 2. BIGUANIDES
1. Metformin is the only drug used
2. 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
4. ADR: Metallic taste in the mouth, diarrhea, anorexia, nausea, and loss of
appetite
The major ADR of metformin is lactic acidosis
5. Clinical Advantage: No hypoglycemia and No weight gain
Useful in OBESE diabetics with not very high Blood Glucose
6. Metformin is contraindicated in patients with
– renal / liver diseases
– Lactic acidosis-any form of acidosis
– congestive heart failure
– Use of contrast radiography (should be stopped 48 hrs. before)
– Long term use interferes with B12 absorption
– Pregnancy

23. BIGUANIDES
• Metformin 500 mg
• Starting dose 500 mg 1-3 doses with
meals
• 1000 mg ER od
• Maximum dose 3000 mg
• Tablets to be taken with or just after meal.

24. 3. α-GLOCUSIDASE INHIBITORS
Examples: acarbose, miglitol and Voglibose
M.O.A.: Reversible inhibitors of intestinal alpha-
glucosidases in intestinal brush border responsible for
degradation of oligosaccharides to monosaccharides.
include sucrase, maltase, dextranase, glycoamylase.
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

25. α-GLOCUSIDASE INHIBITORS
• Acarbose 25/50 mg
• Start with 25 – 50 mg 1 – 3 times with
first bite of meal
• Max dose - 300 mg in divided dose

26. Kinetics of α-glucosidase
inhibitors
• Acarbose
• Given orally, poorly absorbed.
• Metabolized by intestinal bacteria.
• Excreted in stool and urine.
• Miglitol
• well absorbed, no systemic effects.
• Excreted unchanged in urine.
• 6 times more potent inhibitor for sucrase

27. Uses of alpha-glucosidase
inhibitors
• Type II diabetics inadequately controlled
by diet with or without other agents ( SU,
Metformin) alone or combined with insulin
or sulfonylurea.

28. Contraindications of α-glucosidase
inhibitors
• Inflammatory bowel disorders (IBD).
• Renal disease.
• Hepatic disease (used with caution).
• Intestinal obstruction.

29. 4. THIAZOLIDINEDIONES (glitazones)
Rosiglitazone and Pioglitazone (Tro / Ciglitazone)
• 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.

30. Glitazones
• Rosiglitazone 4 mg/ 8 mg
• 4 mg once daily morning
• Max Dose - 8 mg
• - Pioglitazone 15 mg / 30 mg
• 15 mg once daily morning
• Max Dose - 45 mg

31. Adverse effects of pioglitazone
• Fluid retention (Edema).
• Weight gain.
• Headache.
• Liver function tests for 1st year of therapy.
• Failure of estrogen-containing oral
contraceptives.
• Clinical benefits are not observed until 6-12
weeks

32. Incretin -mimetic (Exenatide / Liraglutide)
• 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.
Pramlintide : Synthetic amylin that reduces glucagon
secretion and delays gastric emptying [s/c]
Useful in type 1 and type 2 DM

33. DPP- 4 inhibitors
• The newest oral hypoglycemic agents is
Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin
• 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).
• They can be used as a monotherapy or in
combination with metformin or the glitazones
• It is given orally and once daily

34. Dipeptyl- peptidase inhibitors
Sitagliptin
Vildagliptin
Saxagliptin
Septagliptin
Allogliptin

35. Sitagliptin Has a
Weight Neutral Profile
• Monotherapy studies
– No increase in body weight from baseline with sitagliptin
compared with a small decrease in the placebo group
• Add-on to metformin
– A similar decrease in body weight for both treatment groups
• Add-on to pioglitazone
– No significant difference in body weight between treatment
groups
• Noninferiority vs Sulfonylurea
A significant reduction in body weight with sitagliptin versus
weight gain with glipizide
46

36. Clinical uses
• Type 2 DM as an adjunct to diet &
exercise as a monotherapy or in
combination with other antidiabetic drugs.
• Adverse effects: Nausea, abdominal pain,
diarrhea
• Nasopharyngitis

37. Indications for oral antidiabetics:
 NIDDM not controlled by diet and exercise alone
 Maturity onset diabetes > 40yrs age, duration
<5yrs
 BSL < 300mg%
 Use Repaglinide or Nateginide for post-prandial
hyperglycemia
 In obese individuals prefer Metformin or
Glyclazide
a
 One drug combine drugs from each class
if inadequate response Add TZDs
Switch over to insulin

38. Prevention, Prevention, Prevention!
• Refer patients with IGT, IFG, or A1C 5.7–6.4%
to ongoing support program
– Target weight loss = 7% of total body weight
– Minimum of 150 min/week of moderate physical
activity
• Follow-up counseling important for success
• Based on cost-effectiveness of diabetes
prevention, third-party payers should cover such
programs
• In those with pre-diabetes, monitor for
development of diabetes annually
ADA. IV. Prevention/Delay of Type 2 Diabetes. Diabetes Care
2012;35(suppl 1):S16

39. Prevention, Prevention, Prevention!
• Medications shown to delay progression of
IGT/IFG to T2DM
– Metformin (US DPP, NEJM 2002)
– Acarbose (STOP-NIDDM, Lancet 2002)
– Piaglitazone (ACT NOW, presentation 2008)
• Consider metformin for prevention of type 2
diabetes if IGT, IFG, or A1C 5.7–6.4%
– Especially for those with BMI >35 kg/m 2, age <60
years, and women with prior GDM
• None are FDA approved for Diabetes Prevention

40. Easy A1c Correlation
• NOTE: This is an estimate only
• (A1C -2) x 30
– i.e. A1C= 7%; (7-2) x30 = 150mg/dL

41. How to treat Type 2 DM

42. Diagnostic Criteria
Fasting Glucose 2-h OGTT Random Glucose A1c
mg/dL mg/dL mg/dL
Normal <100 <140 <200 <5.7%
Prediabetes 100-125 140-199 5.7-6.4%
(IFG) (IGT)
Diabetes ≥ 126 ≥ 200 ≥ 200 ≥ 6.5%
Note: In the absence of unequivocal hyperglycemia, result(s) should be
confirmed by repeat testing.
ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl
1):S12. Table 2.

43. Determinants of selection of
drugs for Type 2 DM
Efficacy Safety Cost

44. Choice of Initial Glucose-Lowering
Agent
• The level of hyperglycemia should influence the initial
choice of therapy.
• mild to moderate hyperglycemia [FPG < (200–250 mg/dL)]
often respond well to a single, oral glucose-lowering agent.
• more severe hyperglycemia [FPG > (250 mg/dL)] -stepwise
approach "Combination Therapy"
• Insulin can be used as initial therapy in individuals with
severe hyperglycemia [FPG > (250–300 mg/dL)
• Insulin secretagogues, biguanides, -glucosidase inhibitors,
thiazolidinediones, and insulin are approved for
monotherapy of type 2 DM

45. What is the role of an ideal
oral hypoglycaemic agent?
Conserve islet cell function
- delay the subsequent use of insulin.
Improve patient compliance- single daily dosing.
Reduce the incidence of hypoglycaemic events

46. 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

47. 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
• Renal disease
• Hepatic disease Risk of lactic acidosis
• Pregnancy – OHAs are contraindicated
• Meglitinides are safe at higher levels of serum
Cr than sulfonylureas
• Drug interactions

48. Cost
Metformin and 2nd Generation Sulfonylureas
are LESS EXPENSIVE
Newer drugs are MORE EXPENSIVE

49. Initial Treatment of Type 2
Diabetes
• Diet and exercise are the most effective
treatments for type 2 diabetes !
• Diet for approx 12 weeks
• Then if control is poor (HbA1C > 7%)
– Overweight (BMI > 25) - metformin
– If not controlled then sulphonylureas,
metaglitinides, amino acid derivatives
• Contraindicated in pregnancy and when
breast feeding
• Used in conjunction with diet and exercise

50. Spectrum of Oral Hypoglycaemic
Agents
•Biguanides •Metformin (Biguanides)
•Sulphonylureas •Glybenclemide, Glicliazide
Glipizide, Glimepiride
∀α-Glucosidase • Acarbose , Miglitol, Voglibos
inhibitors • Repaglinide, Nateglinide
•Meglitinide analogues
• Rosiglitazone , Pioglitazone
•Thiazolidinediones • Sitagliptin, Vildagliptin,
DPPV-4 Inhibitors Saxagliptin

51. Combination therapy in the treatment of
Diabetes Mellitus
1. Suphonylurea + Biguanides
2. Sulphonylurea + Insulin
3. Insulin + Biguanides
4. Insulin + Biguanides + Sulphonylurea
5. Non-sulphonylurea + Biguanide + Glitazone
6. Sulphonylurea + Acarbose
7. Metformin + Acarbose
8. Acarbose + Insulin
9. Repaglinide + Pioglitazone/Rosiglitazone (FDA
approved).

52. Guideline for combination therapy
• Obese Type 2 DM - Start first with
biguanides – if fails with maximum dose add
Sulphonylurea or any insulin secretagogue or
glitazone or acarbose
• or minimum amount of insulin.
• Normal weight Type 2 DM - Start with
sulphonylurea if fails with moderate dose of OHA
or
• you may add biguanide/glitazone add insulin in
moderate dose

53. Guideline for combination therapy
• Under-weight Type 2 DM - Start with
insulin then add minimum sulphonylurea
• - Never use biguanides.

54. Determinants of OAD usage
1)Body Mass Index : Metformin, Gliptins
BMI> 22kg/m2
2)Presence of GI symptoms: Sulpho, Gliptins, Glitazones
3)Renal Dysfunction: Gliptins,Glitazones(+/-),Sulpho (variable)
4) Aging Meglitinides, Gliptins(?)
5) Hepatic Dysfunction Nateglinide, Saxagliptin(?)
6) Compliance Gliptins, Glitazones,
7) Cost Metformin, Sulphas, Glitazones

55. 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

56. Type 2 Diabetes Recommendations
• Metformin + lifestyle changes at diagnosis
providing no contraindication
– Medications are ALWAYS to be used in combination
with healthy meal planning and regular physical
activity (150 minutes per week)
• If marked elevation of A1c /blood glucose and/or
symptomatic consider insulin (+ or – other
agents) from the outset
• If noninsulin monotherapy at maximal tolerated
dose does not achieve /maintain the A1c goal
over 3–6 months, add a second oral agent, a
GLP-1 receptor agonist, or insulin
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl
1):S21

57. Non-Insulin Hypoglycemic Agents
Oral Parenteral
•Biguanides • Amylin analogs
•Sulfonylureas • Incretin mimetics
•Meglitinides
•Thiazolidinediones
•Alpha Glucosidase
inhibitors
•Incretin Enhancers
•(DPP-IV inhibitors)

58. Pharmacology - Biguanides
Class Biguanides
Compound Metformin
Mechanism Activates AMP-kinase
Action(s) • Hepatic glucose production ↓
• Intestinal glucose absorption ↓
• Insulin action ↑
Glucose Lowering • Fasting
Effect • Post Prandial
Advantages • No weight gain
• No hypoglycemia
• Reduction in cardiovascular events and mortality (UKPDS f/u)
Disadvantages • Gastrointestinal side effects (diarrhea, abdominal cramping)
• Lactic acidosis (rare)
• Vitamin B12 deficiency
• Contraindications: reduced kidney function
Cost Low – free at Marsh
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.
Adapted with permission from Silvio Inzucchi, Yale University

59. Pharmacology - Sulfonylureas
Class Sulfonylureas (2nd generation)
Compound • Glibenclamide/Glyburide
• Glipizide
• Gliclazide
• Glimepiride
Mechanism Closes KATP channels on β-cell plasma membranes
Action(s) ↑ Insulin secretion
Advantages • Generally well tolerated
• Reduction in cardiovascular events and mortality (UKPDS f/u)
Disadvantages • Relatively glucose-independent stimulation of insulin
secretion: Hypoglycemia, including episodes necessitating
hospital admission and causing death
• Weight gain
• Primary and secondary failure
Cost Low – free at Marsh
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.
Adapted with permission from Silvio Inzucchi, Yale University.

60. Pharmacology – Meglitinides
Class Meglitinides
Compound • Repaglinide (Prandin®)
• Nateglinide (Starlix®)
Mechanism Closes KATP channels on β-cell plasma membranes
Action(s) Insulin secretion ↑
Advantages Accentuated effects around meal ingestion
Disadvantages • Hypoglycemia, weight gain
• Dosing frequency
Cost Medium
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.
Adapted with permission from Silvio Inzucchi, Yale University.

61. Pharmacology – Thiazolidinediones
(TZD)
Class Thiazolidinediones (Glitazones)
Compound Pioglitazone (Actos®)
Mechanism Activates the nuclear transcription factor PPAR-γ
Action(s) Peripheral insulin sensitivity ↑
Advantages • No hypoglycemia
• HDL cholesterol ↑
• Triglycerides ↓
Disadvantages • Weight gain
• Edema
• Heart failure (CI with stage III and IV)
• Bone fractures
Cost High
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.
Adapted with permission from Silvio Inzucchi, Yale University.

62. Pharmacology – Thiazolidinediones
(TZD)
Class Thiazolidinediones (Glitazones)
Compound Rosiglitazone (Avandia®)
Mechanism Activates the nuclear transcription factor PPAR-γ
Action(s) Peripheral insulin sensitivity ↑
Advantages No hypoglycemia
Disadvantages • LDL cholesterol ↑
• Weight gain
• Edema
• Heart failure (CI with stages III and IV)
• Bone fractures
• Increased cardiovascular events (mixed evidence)
• FDA warnings on cardiovascular safety
Cost High
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.
Adapted with permission from Silvio Inzucchi, Yale University.

63. Pharmacology – Alpha-
Glucosidase Inhibiters
Class α-Glucosidase inhibitors
Compound • Acarbose
• Miglitol
Mechanism Inhibits intestinal α-glucosidase
Action(s) Intestinal carbohydrate digestion and absorption slowed
Advantages • Nonsystemic medication
• Postprandial glucose ↓
Disadvantages • Gastrointestinal side effects (gas, flatulence, diarrhea)
• Dosing frequency
Cost Medium
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.
Adapted with permission from Silvio Inzucchi, Yale University.

64. Pharmacology – Incretin
Enhancers
Class DPP-4 inhibitors (incretin enhancers)
Compound • Sitagliptin (Januvia®)
• Vildagliptin (available in Europe)
• Saxagliptin (Onglza®)
• Linagliptin (Tradjenta®)
Mechanism Inhibits DPP-4 activity, prolongs survival of endogenously released
incretin hormones
Action(s) • Active GLP-1 concentration ↑
• Insulin secretion ↑
• Glucagon secretion ↓
Advantages • No hypoglycemia
• Weight “neutrality”
Disadvantages • Occasional reports of urticaria/angioedema
• Cases of pancreatitis observed
• Long-term safety unknown (cancer ?)
Cost High
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23.
Adapted with permission from Silvio Inzucchi, Yale University.

65. Pharmacology – Incretin Mimetics
Class GLP-1 receptor agonists (incretin mimetics)
Compound • Exenatide (Byetta®)
• Liraglutide (Victoza®)
Mechanism Activates GLP-1 receptors (β-cells/endocrine pancreas;
brain/autonomous nervous system
Action(s) • Insulin secretion ↑ (glucose-dependent)
• Glucagon secretion ↓ (glucose-dependent)
• Slows gastric emptying
• Satiety ↑
Advantages • Weight reduction
• Potential for improved β-cell mass/function
Disadvantages • Gastrointestinal side effects (nausea, vomiting, diarrhea)
• Cases of acute pancreatitis observed
• C-cell hyperplasia/medullary thyroid tumors in animals (liraglutide)
• Injectable
• Long-term safety unknown
Cost High
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23.
Adapted with permission from Silvio Inzucchi, Yale University.

66. Pharmacology – Amylin Analog
Class Antihyperglycemic Synthetic Analog
Compound • Pramlintide (Symilin®)
Mechanism • Amylinomimetic
Action(s) • Glucagon secretion ↓ (glucose-dependent)
• Slows gastric emptying
• Satiety ↑
Advantages • Potential weight loss
Disadvantages • Meal time injections
• Nausea
• Hypoglycemia in combination with insulin
Cost High
Lexi-Drugs Online [Internet]. Hudson (OH) : Lexi-Comp, Inc. 1978-2012[cited 2012
August 1].

67. Pharmacology – Bile Acid
Sequestrants
Class Bile acid sequestrants
Compound Colesevelam (Welchol®)
Mechanism Binds bile acids/cholesterol
Action(s) Bile acids stimulate receptor on liver to produce glucose
Results • Lowers fasting and post prandial glucose
Advantages • No hypoglycemia
• LDL cholesterol ↓
Disadvantages • Constipation
• Triglycerides ↑
• May interfere with absorption of other medications
Cost High
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23.
Adapted with permission from Silvio Inzucchi, Yale University.

68. Typical A1c Reductions
Monotherapy Route of Administration A1c (%) Reduction
Sulfonylurea PO 1.5-2.0
Metformin PO 1.5
Glitazones PO 1.0-1.5
Meglitinides PO 0.5-2.0
α -glucosidase inhibitors PO 0.5-1.0
DPP-4 PO 0.5-0.7
GLP-1 agonists Injectable 0.8-1.5
Amylin analogs Injectable 0.6
Insulin Injectable Open to target
Unger J et al. Postgrad Med 2010; 122: 145-57

69. Fasting vs. Postprandial Effect
Mostly targets FASTING Mostly targets POSPRANDIAL
hyperglycemia hyperglycemia
Insulin (long and intermediate Insulin (regular, rapid-action)
action)
Colesevelam α-glucosidase inhibitors
Sulfonylureas Meglitinides
TZD Pramlinitide
Metformin DPP-4 inhibitors
GLP-1 agonist

70. Considerations When Selecting Therapy
• How long has the patient had diabetes (duration
of disease – preservation of β-cell function)?
• Which blood glucose level is not at target
(fasting, postprandial, or both)?
• Patient preference for route of administration
(oral, injection)?
• The degree of A1c lowering effect required to
achieve goal?
• Side effect profile and the patients tolerability?
• Co – existing conditions ( CVD, osteoporosis,
obesity, etc)?

71. Drug Pearls
Medication PRO CON
Metformin Low cost, A1c lowering, + CV Renal or hepatic impairment
effects, weight loss, PCOS
Sulfonylurea Low cost, A1c lowering Hypoglycemia, treatment failure
Meglitinides Erratic meals, renal insufficiency Hypoglycemia, treatment failure
Pioglitazone Insulin resistance, decrease in Edema, wt gain, CI with HF
adipose tissue, TG reduction class III and IV
α -glucosidase inhibitors Patients with constipation Long duration of T2DM, patients
with GI problems
DPP-4 Well tolerated ? long term safety
GLP-1 agonists Obese patients GI side effects
Amylin analogs Poor PPG control despite GI side effects
insulin therapy
Insulin Flexible treatment (basal, basal Hypoglycemia, weight gain
bolus, etc)

72. Dyslipidemic Agents
• Statin therapy should be added to lifestyle
therapy, regardless of baseline lipid levels
– with overt CVD
– without CVD >40 years who have one or more other
CVD risk factors
• For patients at lower risk (without overt CVD,
<40 years, etc.)
– Consider statin therapy in addition to lifestyle therapy
if LDL cholesterol remains >100 mg/dL
– In those with multiple CVD risk factors
ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl
1):S30-31

73. 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 (Perioperative)
• In some serious concurrent diseases,
AMI
• Ketoacidosis
• Along with glucose to treat hyperkalemia

74. Chemistry of insulin:
• Polypeptide hormone MW 5808.
• Contains 51 amino acids arranged in
• two chains A (21) & B (30) linked by two disulphide
bridges.
• B cells of pancreatic islets synthesize insulin from a
precursor called proinsulin.
• Proinsulin is hydrolyzed into insulin & C-peptide.
• Insulin and C-peptide are secreted in equimolar amounts
in response to all insulin secretagogues.
• Proinsulin might have mild hypoglycemic action but C-
peptide is inactive.
• One milligram contains 28 units.

75. 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 detemir
( Myristoylated insulin )
(6-12 onset / 16-30h. duration of action)
• Pre-mixed insulins: NPH 70%+ Insulin aspart 30%

76. Ultra-short
rapid-acting insulins
• Insulin lispro, insulin aspart, insulin
glulisine (injection)
• Do not aggregate or form complexes
• Fast onset of action (5-15 min)
• Short duration of action (3-5 h)
• Reach peak level 30-90 min after injection.

77. Short acting insulins
regular insulins
• Regular huminsulin R
• Recombinant DNA technology
• Clear solutions at neutral pH.
• Hexameric analogue.
• Onset of action 30-45 min (s.c.).
• Peak 2-4 h.
• Duration 6-8 h.

78. Short acting insulins
regular insulins
• I.V. emergency.
• – Management of ketoacidosis
• – After surgery
• – During acute infection
•  2-3 times/day.
•  Control postprandial hyperglycemia &
• ketoacidosis.
•  Pregnancy

79. Intermediate acting insulins
• Isophane (NPH), a neutral protamine
hagedorn in phosphate buffer is
combination of protamine & crystalline
zinc insulin (1: 6 molecules). proteolysis
release insulin.
• Turbid suspension at neutral pH
• Given S.C. only
• Onset of action 1-2 h.
• Insulin mixtures 75/25 - 70/30 - 50/50
(NPH/regular)

80. Intermediate acting insulins
• Lente insulin
• Mixture of 30% semilente insulin (amorphous precipitate
of insulin with zinc in acetate buffer) + 70% ultralente
insulin (poorly soluble crystal of zinc insulin)
• Turbid suspension at neutral pH
• Given S.C.
• onset of action (1-3 h)
• Peak serum level 4-8 h.
• Duration of action 13-20 h.
• Lente and NPH insulins are equivalent in activity.
• Lente and NPH are Not used in emergencies (diabetic
ketoacidosis).
• Require several hours to reach therapeutic levels

81. Long acting insulin
Insulin glargine (lantus)
• Slow onset of action 2 h.
• Clear solution
• Forms precipitate (depot) at injection site.
• absorbed less rapidly than NPH & Lente insulin.
• Given s.c.- Maximum effect after 4-5 h
• produce broad plasma concentration plateau (low continous
insulin level).
• Prolonged duration of action (24 h)- suitable Once daily
• Should not be mixed with other insulin
• Advantages over intermediate-acting insulins:
• Constant circulating insulin over 24 hr with no pronounced
peak.
• More safe than NPH & Lente insulins ( reduced risk of
hypoglycemia).

82. ADRs of insulin
• Hypoglycemia
• Lypodystrophy at the site of injection (atrophy or hypertrophy)
• Weight gain
• Hypersensitivity reactions.
• Insulin resistance
• Hypokalemia
How to dose insulin
• Sliding Scale Insulin
It is the most frequent insulin regimen in hospitalized patients
Otherwise, use
• Basal- bolus insulin

83. The Basal/Bolus Insulin Concept
• Basal Insulin
– Suppresses glucose production between meals and overnight
– Nearly constant levels
– 50% of daily needs
• Bolus Insulin (Mealtime or Prandial)
– Limits hyperglycemia after meals
– Immediate rise and sharp peak at 1 hour
– 10% to 20% of total daily insulin requirement at each meal
Ideally, for insulin replacement therapy, each
component should come from a different
insulin with a specific profile

84. 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

85. Dosage (basal-bolus)
Calculate the
total daily dose
of insulin (0.5 iu/kg)
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

86. 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
2. 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
3. HbA1C measurement
– Useful for measure of the degree of glycemia in the past 4-6 weeks
– Good control if < 6 %

87. Increasing the dose of insulin
• Any dietary error to be excluded and then the dose of
insulin should be increased by 2-4 units.
• Examples:
• If breakfast and pre-lunch BG and/or urine glucose is
high- add short acting insulin before breakfast
• If post lunch and pre-dinner BG or urine is high –
then increase morning dose of intermediate acting insulin
by 2-4 units
• If post dinner and late night BG or urine sugar is high,
add short acting insulin 2-4 units before dinner
• If fasting BG or urine sugar is high then increase pre-
dinner intermediate acting insulin.

88. • 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)

89. 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

90. Diabetic management “pearls”
• When mixing insulins, draw up the regular insulin
first
• Allow mild hyperglycemia for the patient undergoing
surgery—treat with short acting insulins
• For elective surgery, schedule patient early in day to
avoid prolonged fasting

91. “Pearls”
• Use U-100 syringes for U-100 vials
• In patients with insulin pumps, use regular insulin or
insulin aspart. Generally will deliver one unit per
hour w/bolus insulin before meals
• Tight glycemic control can reduce the complications
of diabetes.
• Use ACE inhibitors to delay nephropathy
• Limit dietary intake of protein

92. “Pearls”
• Glitazones must suspect hepatotoxicity
• Metformin cautiously with liver and renal
impairment Concern that with
hepatotoxicity, because risks of lactic
acidosis are increased.
• Rotate sites of injection of insulin to avoid
development of lipodystrophy
• Absorption of injected insulin in abdomen
is not uniform with injections in arms or
legs

93. Lypoatrophy and
Hyperlypotrophy

94. Injection Sites
.. .. Arms
Stomach Buttocks
Thighs
Site rotation is essential

95. Storage of insulin
• Before use Store in fridge (2-8oC)
• In-use vials Out of fridge to max 25oC (4-6
weeks)
• In-use pens and cartridges Out of fridge at max
25oC (4 weeks)

96. Thank You