1. Update on the Pharmacological Treatments for Diabetes Mellitus
Scott K. Stolte, Pharm.D.
Chair, Department of Pharmacy Practice
Bernard J. Dunn School of Pharmacy
Shenandoah University
This program has been made possible by an education grant from Pfizer Labs.

2. Objectives
At the completion of this program, the participant will be able to:
Identify the mechanisms of action, pharmacology and the other important information for the medications used to treat both types of diabetes.
Apply information about diabetes that has application in the daily practice of pharmacy.
Enhance the understanding of new treatment approaches for diabetes.

3. Background About 18.2 million people with DM
Approximately 33% undiagnosed
6.3% of US adults have DM
Higher prevalence:
Ethnic Groups – AA, NA, Latino
Increased age and weight

4. Background Incidence Impact 625,000 cases diagnosed each year
Leading cause of adult blindness (25x), renal failure (17x), nontraumatic amputation (5x)
5th leading cause of death due to disease
Direct and indirect medical costs > 50 billion

5. Pharmacotherapy Oral Hypoglycemics Insulin Sulfonylureas Meglitinides
Alpha-glucosidase inhibitors
Biguanides
Thiazolidinediones
Insulin

6. Sulfonylureas Pancreatic Actions
Stimulates insulin release from pancreatic β-cells – Primary acute mechanism
Down-regulation of this affect over time
No stimulation of insulin release in chronic therapy – How do they continue to work?
Explanation not clear
Reduced plasma glucose may allow circulating insulin to have pronounced effects on target tissues
Chronic hyperglycemia impairs insulin secretion

7. Sulfonylureas Other pancreatic actions:
Reduce hepatic clearance of insulin
Suppress glucagon release slightly
Stimulate somatostatin release

8. Sulfonylureas Extrapancreatic effects
Responsible for long-term efficacy
Reduce hepatic gluconeogenesis
May increase insulin receptor sensitivity and number
Potentiation of post-receptor insulin effects - Stimulate synthesis of glucose transporters

9. Sulfonylureas
Two categories based on potency, duration of action, and drug interaction/side effect profiles
First Generation
Tolbutamide (ORINASE), Chlorpropamide (DIABINESE) , Tolazamide (TOLINASE) , Acetohexamide (DYMELOR)
Second Generation
Glyburide (DIABETA, GLYNASE), Glipizide (GLUCOTROL), Glimepiride (AMARYL)

10. Sulfonylureas Characteristics Administered orally
Few therapeutic differences among agents
Should be administered 30 min. before breakfast for maximal absorption
Dose can be increased every 1-2 weeks
Metabolized in liver, mainly excreted in urine (glyburide – 50% in feces)

11. Sulfonylureas Drug Onset (h) Half-life (h) Duration (h) Starting Dose
Max. dose/day
Tolbutamide 1
5.6
6-12
1-2g/d in 2 or 3 doses
2-3 g
Acetohexamide 5
10-14
mg/d
1.5 g
Tolazamide
4-6 7
mg/d in 1 or 2 doses
750mg – 1 g
Chlorpropamide 35 72
250 mg/d
500 mg
Glyburide
1.5
2-4
18-24
2.5 mg/d
20 mg
Glyburide, micronized
1.5 mg/d
12 mg
Glipizide
3-7
10-24
5 mg/d
40 mg*
Glimeperide 2
18-28
1-2 mg/day
8 mg
* - Doses above 15 mg/day should be divided and administered twice daily

12. Sulfonylureas Adverse effects Drug Interactions
Hypoglycemia – fairly common
Skin reactions (3%) – rashes, pruritis GI
Rare hematologic reactions
Drug Interactions
Increase in concentration from liver metabolism inhibition or protein binding displacement – fluconazole, warfarin
Decrease in effect by increasing liver metabolism or inhibiting insulin release - rifampin, beta-blockers

13. Meglitinides Repaglinide (PRANDIN) Nateglinide (STARLIX)
Nonsulfonylurea moiety of glyburide
Nateglinide (STARLIX)
Amino acid derivative
Pharmacologic effect is the same as sulfonylureas
Shorter duration of action

14. Repaglinide Absorbed rapidly from the GI tract
Peak serum concentrations obtained within 1 hour
Half-life is about 1 hour
Metabolized mainly by the liver – metabolites are inactive
10% metabolized by the kidney

15. Repaglinide
Starting Dose – 0.5 mg po tid taken immediately before eating each meal
Can increase dose every week
Maximum dose = 4 mg po tid
Main adverse effect is hypoglycemia
Drug Interactions
Metabolized by CYP450 3A4
May interact with inhibitors or inducers of that enzyme
Erythromycin, Azole antifungals, cimetidine, etc.

16. Nateglinide
Starting and maintenance dose – 120 mg po tid 1-30 minutes before meals
Dose should be skipped if meal is skipped
Highly bound to plasma proteins
Clinical significance unknown
Metabolized in the liver by CYP450 2C9 and 3A4
Clinically significant interactions unknown

17. Alpha-Glucosidase Inhibitors
Acarbose (PRECOSE)
Miglitol (GLYSET)
Mechanism of Action
Inhibition of membrane bound intestinal brush border alpha glucosidase enzyme
Membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine
Enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia

18. Acarbose Not absorbed from the GI tract
Will not induce hypoglycemia with monotherapy
Onset – 0.5 hrs.
Half-life – 1 to 2 hrs.
Duration – 4 hrs.
Recommended starting dose – 25 mg/d with first bite of main meal, possibly 25 mg po tid
Max. dose/day – 300 mg

19. Miglitol Dose-dependent absorption from the GI tract
Absorption not related to therapeutic efficacy
Excreted in urine as unchanged drug (95%)
Initial dose – 25 mg po tid with first bite of each main meal, some may need lower dose to minimize GI adverse events
Max. daily dose – 100 mg po tid

20. Adverse Events Mainly GI Skin rash – 4.3% Abdominal pain – 11%
Diarrhea – 29%
Flatulence – 42%
Abdominal pain and diarrhea diminish with continued treatment
AE’s minimized by starting at low dose and utilizing slow dosage titration
Skin rash – 4.3%

21. Other Considerations
Not recommended for patients with inflammatory bowel disease
May alter liver function at high doses
Diet and activity may have to be altered to limit production of gas
Often used in combination with other antidiabetic agents

22. Biguanides Metformin (GLUCOPHAGE) Mechanism of action
Decreases hepatic glucose production – reduces gluconeogenesis
Decreases intestinal absorption of glucose
Improves insulin sensitivity (increases peripheral glucose uptake and utilization)
Does not produce hypoglycemia as monotherapy

23. Metformin Absolute bioavailability is 50-60% - fasting
Not bound to plasma proteins
Excreted unchanged in the urine
Does not undergo hepatic metabolism
Starting dose – 500 mg bid with morning and evening meals
Can be increased at rate of 1 tab/week
Maximum daily dose – 2550 mg/day

24. Metformin Adverse reactions GI
N/V/D, bloating, flatulence, anorexia
Resolve spontaneously with continued treatment
Decreased with gradual dose escalation and administration with food
Asymptomatic subnormal Vit. B12 concentrations-reversed by calcium supp.
Unpleasant metallic taste (3%)

25. Metformin Drug Interactions
Cationic drugs that are excreted by renal tubular secretion
Compete with metformin for excretion
Could increase metformin concentrations
Cimetidine, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin
Theoretical except for cimetidine

26. Metformin Precautions
Lactic acidosis
Rare, but very serious (50% mortality)
Occurs due to metformin accumulation
Plasma levels > 5 mcg/mL
0.03 cases/1000 patient years
Increased risk with significant renal insufficiency, CHF
Hepatic disease increases risk – not often used
Excessive alcohol intake
Metformin should be D/C’d prior to radiocontrast dye and held for 24 hours after administration

27. Metformin Precautions
Renal function
Should be assessed prior to starting metformin and at least yearly thereafter
Not generally used in patients with SrCr above upper limits of normal for age (SrCr > 1.5 for males, 1.4 for females)
Caution with elderly patients
Contraindicated in CHF requiring drug therapy

28. Thiazolidinediones Pioglitazone (ACTOS) Rosiglitazone (AVANDIA)
Mechanism of Action
Improve glycemic control by improving insulin sensitivity
Highly selective and potent agonists for the peroxisome proliferator-activated receptor-gamma (PPARg)
P.A. receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver
Activation of PPARg nuclear receptors regulates transcription of insulin responsive genes involved in the control of glucose production, transport, and utilization
PPARg-responsive genes also participate in the regulation of fatty acid metabolism.
Require insulin to be present for action
May also lower liver glucose production

29. Rosiglitazone Absolute bioavailability – 99% Half-life – 3 to 4 hours
Peak concentration – 1 hr.
Maximal clinical effect in 6-12 weeks
Highly protein bound, mostly albumin
Extensively metabolized, no unchanged drug excreted (mostly CYP2C8, some 2C9)
Excreted in urine (64%) and feces (23%)

30. Rosiglitazone Dose Hepatic Impairment
Monotherapy or in combo. with metformin- 4 mg administered qd or divided bid, dose may be increased to 8 mg/day with inadequate response after 12 weeks
Taken without regard to meals
Hepatic Impairment
Therapy not initiated with evidence of active liver disease or increased ALT (>2.5x upper limit of normal) at baseline
No evidence of induced hepatotoxicity

31. Rosiglitazone Adverse reactions
Edema and anemia – mild to moderate, did not require drug D/C
Drug Interactions – no clinically significant
Precautions
Ovulation - In premenopausal anovulatory patients, treatment may result in resumption of ovulation

32. Pioglitazone Characteristics very similar to rosiglitazone
Therapy should not be initiated if clinical evidence of active liver disease or ALT exceeds 2.5 times the upper limit of normal
No evidence of drug-induced hepatotoxicity
Metabolized by CYP 2C8 and to some degree by CYP3A4
Dose – 15 or 30 mg po qd, maximum 45 mg qd
Without regard to meals
Used in combination with sulfonylureas, metformin, insulin

33. Pioglitazine Drug Interactions
Oral Contraceptives – troglitazine reduced plasma concs. of ethinyl estradiol and norethindrone by 30%
Due to 3A4 metabolism
May lead to loss of contraception
Pioglitazone not investigated
Ketoconazole – inhibits metabolism, monitor closely
Other potential 3A4 interactions – no studies

34. Insulin Composed of two peptide chains Molecular Mass – 5734 Daltons
A chain – 21 AA’s
B chain – 30 AA’s
Molecular Mass – 5734 Daltons

35. Insulin
Actions
Increases glucose uptake by tissues (brain does not require insulin)
Increases liver glycogen production
Decreases glycogen breakdown
Increases fatty acid synthesis
Inhibits breakdown of fatty acids to ketone bodies
Promotes incorporation of AA’s into proteins

36. Insulin Traditionally categorized by:
Strength
Onset and duration of action (PK)
Species source
Purity
Most important consideration now is PK
Most US patients on U-100 insulin
Most use biosynthetic “human” insulin, may see some porcine or bovine used
All US insulin is purified

37. Onset, Peak and Duration of Human Insulin Preps
Insulin Type
Onset (h)
Peak (h)
Effective Duration (h)
Rapid-acting
Lispro (Humalog)
0.25
2-4
Aspart (Novolog)
0.6-1
3-5
Rapid Acting
Glulisine (Apidra)
0.25 – 0.5
1-2
3-4
Short-acting Regular
0.5-1
2-3
4-6
Intermediate Acting NPH
4-10
10-16
Intermediate Acting Lente
4-12
12-18
Long Acting
Ultralente
6-10
Minimal
14-24
Detemir (Levemir) ??
6-8
12-24
Insulin Glargine(Lantus)
1-2 hours
None
24-28

38. Insulin Formulations
Insulin lispro and aspart made by altering insulin AA structure
NPH (neutral, protamine, Hagedorn) insulin made by adding protamine and zinc to neutral regular insulin
Lente and ultralente made by adding acetate buffers and zinc
Regular, lispro, aspart, and glargine are clear and colorless in vial
Glargine precipitates at physiologic pH

39. Insulin Considerations
Regardless of type, potency is the same
1 unit lowers BG by mg/dL in normal, healthy subjects
Regular insulin, Velosulin (R insulin with added buffers), Humalog, and probably Novolog can be used in insulin pumps
Insulin suspensions (intermediate and long-acting) must be administered subQ, not IV

40. Type 1 Diabetes Insulin Exubera - dosing Do not switch from SQ insulin
based on units-to-dose
Based on weight – then titrate
1 mg capsule = ~ 3 u SQ insulin
3 mg capsule = ~8 u SQ insulin
1mg + 1mg + 1mg ≠ 3 mg
Adjusting dose…
Change dose in 1 mg increments
Weight (pounds)
Pre-prandial dose
Total daily dose
66-87
1 mg
3 mg
88-132
1 mg + 1 mg
6 mg
9 mg
3 mg + 1 mg
12 mg
3 mg + 1 mg + 1 mg
15 mg
3 mg + 3 mg
18 mg
309 +
3 mg + 3 mg + 1 mg
21 mg

41. Type 1 Diabetes Insulin Contraindications – Exubera
Smokers or smoked within 6 months
Discontinue immediately if resume smoking
Lung disease – asthma, COPD
FEV1 < 70% predicted
?? Bronchodilator use – can increase absorption
Monitoring – Exubera
Spirometry – baseline, then at 6 months, then yearly
If  20% decrease in FEV1, repeat; if still  20% decrease in FEV1  discontinue

42. Average Daily Insulin Requirements
Diabetes Type
Dose (u/kg ABW)
Type 1
Initial Dose
Honeymoon Phase
Split-dose therapy
With ketosis or acute illness
Type 2
With insulin resistance

43. Terms Honeymoon Phase Type 1 DM patients
Occurs soon after initial diagnosis
Insulin requirements low
Patient should still use insulin:
To minimize insulin antibody production
To lessen probability of insulin resistance

44. Terms Split-Dose Therapy Single daily injections not routinely used
Doses are divided based on:
Intensiveness of therapy
Type of insulin used for treatment
Regimens try to mimic activity of functioning pancreas

45. Insulin Adverse Events
Hypoglycemia
Weight gain
Insulin Resistance
Injection site effects

46. Exenatide Incretin mimetic
Byetta – biosynthetic form of an incretin, GLP-1 (GLP = glucagon like peptide)
Mechanism of action
Mimics glucose dependent insulin secretion – first phase response
Enhances glucose dependent insulin secretion by pancreatic beta cells
Suppresses inappropriately elevated glucagon secretion during postprandial period
Slows gastric emptying
Administered via SC injection

47. Pramlintide Acetate Symlin Amylin mimetic Slows gastric emptying
Co-located with insulin in secretory granules
Secreted with insulin in response to food intake
Slows gastric emptying
Suppresses inappropriate glucagon secretion
Centrally-mediated appetite modulation
Administered via SC injection

48. Sitagliptin Januvia DPP-4 Inhibitor (dipeptidyl peptidase-4)
Block the breakdown of incretin via inhibition of DPP-4
Thus, produces similar effects to incretin mimetics

49. Questions?