1. Principle of Diabetes management Part 2
Maha M. Alrasheed, PhD
Assistant Professor
Clinical Pharmacy Dept.
12/6/2014
Maha

2. The American Diabetes Association (ADA) released standards of medical care in diabetes for 2014.
Glycemic targets for adults with diabetes (nonpregnant):
A1C <7.0%
Preprandial capillary plasma glucose mg/dL (3.9–7.2 mmol/L)
Peak postprandial capillary plasma glucose <180 mg/dL (<10.0 mmol/L; postprandial glucose measurements should be made 1-2 h after beginning of meal).
Individualize targets based on
Age/life expectancy
Comorbid conditions
Diabetes duration
Hypoglycemia status
Individual patient considerations (more or less stringent targets may be appropriate)
Known CVD/advanced microvascular complications
More or less stringent A1C targets may appropriate for individual patients if achieved without significant hypoglycemia or adverse events.
Refer to source document for full recommendations, including level of evidence rating.
American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care.
2014;37(suppl 1):S14-S80.
January 2014
This slide was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.

3. The American Diabetes Association (ADA) released standards of medical care in diabetes for 2014.
Lowering A1C below or around 7.0% has been shown to reduce microvascular complications and macrovascular disease (if implemented soon after diagnosis).
More or less stringent targets may be appropriate for individual patients if achieved without significant hypoglycemia or adverse events.
Less stringent target (<8%) may be appropriate for patients with:
Severe hypoglycemia history
Limited life expectancy
Advanced microvascular or macrovascular complications
Extensive comorbidities
Patients with long-term diabetes in whom general A1C target is difficult to attain*
More stringent target (<6.5%) may be appropriate for patients with:
Short diabetes duration
Long life expectancy
No significant cardiovascular disease
Targets shown are for nonpregnant adults
*Despite diabetes self-management, appropriate glucose monitoring, effective doses of
antihyperglycemic agents (including insulin)
Refer to source document for full recommendations, including level of evidence rating.
American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care.
2014;37(suppl 1):S14-S80.
January 2014
This slide was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.

4. Type 2 diabetes Hyperglycemia Insulin resistance
Relative impairment in insulin secretion.

5. The Metabolic Syndrome
Genetic factors
Family history
Physical inactivity
High-fat diet
High ethanol intake
Central obesity
Insulin resistance
High TG, low HDL
Small dense LDL
Hypertension
Type 2 diabetes
IGT
Cardiovascular disease
Alberti KGMM et al. Diabet Med. 1998;15: ; Reaven GM. Clinical Diabetes. 1988;37: ; DeFronzo REA et al. Diabetes Care. 1991; ; Bjornthorp P. Ann Med. 1994;24: ; Ford ES. JAMA. 2002;287:

6. Type 2 oral agents
Currently, nine classes of oral agents are approved for the treatment of type 2 diabetes:
α-glucosidase inhibitors
biguanides
meglitinides
peroxisome proliferator–activated receptor γ (PPAR-γ) agonists (which are also commonly identified as thiazolidinediones [TZDs] or glitazones)
DPP-4 inhibitors
dopamine agonists
bile acid sequestrants
sodium-glucose cotransporter 2 inhibitors
sulfonylureas

7. Type 2 treatment
Oral antidiabetic agents are often grouped according to their glucose-lowering mechanism of action.
Biguanides and TZDs are often categorized as insulin sensitizers due to their ability to reduce insulin resistance.
Sulfonylureas and meglitinides are often categorized as insulin secretagogues because they enhance endogenous insulin release.
Three injectable classes, including insulin, GLP-1 receptor agonists, and amylinomimetics, are also available.

8. II. Oral Antidiabetic Agents
Biguanides Metformin ( Glucophage ® or Glucophage XR ®) A.
Mechanism of action: (Antihyperglycemic agent)
Improve insulin sensitivity ( insulin sensitizer)
Increase tissue uptake and utilization of glucose by muscle
Decrease hepatic production of glucose .
2.Clinical applications:
First line of therapy in type 2 DM with diet and exercise
If patients unable to achieve goals with metformin alone in 3-6 months,
additional insulin or other oral agents should be considered.
Recommended in prediabetic patients
12/6/2014
Maha

9. HgbAIC : 1.5-1.7 % as montherapy
3. Efficacy :
HgbAIC : % as montherapy
b.FBG: mg/dL
4. pharmacokinetics
5. Advantages
Less risk of hypoglycemia due to no insulin release
Benefit on lipids (decrease total cholesterol and TG)
Weight loss, No weight gain
12/6/2014
Maha

10. may cause lactic acidosis
6. Disadvantages :
may cause lactic acidosis
-Contraindications to therapy:
Renal dysfunction
b. Alcoholics
c. Any patient at risk for lactic acidosis
d. People older than 80 years unless normal renal function
GI effects
Titrate dose slowly to minimize side effects
12/6/2014
Maha

11. in case of polymorphism of OCT1 , metformin function will be reduced
7. Drug interactions
Cimetidin , nifedipine , furosemide – all can increase metaformin levels
Organic cation transporter (OCT)1 is involved in the hepatic uptake of metformin….
in case of polymorphism of OCT1 , metformin function will be reduced
8. Dosing principle ( see Oral antidiabetic Agent table )
Initial dose is 500 mg po BID or 850mg Po QD , with meals to decrease
side effects
Titrate dose weekly and increase by mg
Maximum dose : 2550 mg/day or 850 mg TID
12/6/2014
Maha

12. Stimulate insulin release from pancereatic beta cells
B. Sulfonylureas
Mechansim of action
Stimulate insulin release from pancereatic beta cells
2. Clinical applications
- Add on therapy to patients uncontrolled with metformin
- Until metformin and other anti DM agents available, SU was the first line therapy
-Used in combination therapy with insulin , metformin , thiazolidinediones or alpha
glucusidase inhibitors
3. Overall efficacy (as metformin)
HgbAIC %:
b.FBG: %
12/6/2014
Maha

13. Chlorpropamid , tolazamide , and tolbutamide
4. Types :
a. First generation
Chlorpropamid , tolazamide , and tolbutamide
Not used commonly today duo to increase adverse effects , active metabolites ,
some prolonged half – lives , and increase drug interaction
b. Second generation
Glyburide(glibenclamide) , glipizde , glimepiride
Despite being 100 times more potent than first generation, they are
not more clinically effective
Have favorable side effects profile compared to first generation and taken
once or twice daily
12/6/2014
Maha

14. -Renal / hepatic insufficiency patients
5. Adverse effects
Hypoglycemia
-Renal / hepatic insufficiency patients
Elderly or malnourished patients
Concurrent hypoglycemic drugs.
CNS
GI disturbances
Hematologic
Allergic skin reactions / photosensitivity
6. pharmacokinetics of second generations
Glipizide intermediate acting
Glyburide, glimipride long acting (once daily dosing)
12/6/2014
Maha

15. 7. Drug interactions
Increased hypoglycemic effect
Warfarin , azole antifungals , gemfibrozil , clofibrate , sulfonamides , MAOIs,
tricyclic antidepressant , alcohol , cimetidine , aspirin and concomitant agents
for diabetes .
b. Decreased hypoglycemic effect
beta – blockers , CCBs, cholestyramine , Glucocorticoides , phenytoin ,
Oral contraceptives , rifampin , thiazides , niacin
8.Dosing principles
Start at low end of the dosing range , especially in the elderly
Increase dose every 1-2 weeks until maximum dosage
Exceeding the maximum dosage increases side effects, but does not decrease
blood glucose
Current maximum doses now being questioned

16. C. Nonsulfonylurea Insulin Secretagogues (Glinides)
Meglitindes ( Repaglinide – Prandin ® and Netaglinide – Starlix ®)
1. Mechanism of action
Non – sulfonylurea moiety of glyburide
Stimulates release of insulin from the pancreatic beta cells.
2. clinical applications :
-As monotherapy an adjunct to diet and exercise to patients with uncontrolled
type 2 diabetes
In combination with metformin or TZD to lower BS in patients who are uncontrolled
by exercise , diet and either agent alone
Unlike sulfonylureas, Rapid Onset and short duration of action , so given with
meals to enhance postprandial glucose utilization
12/6/2014
Maha

17. 3. Efficacy : (comparable to metformin and SU)
HgbAIC : % as montherapy
b.FBG: mg/dL
4. Pharmacokinetic
5. Adverse effects
Hypoglycemia
Weight gain
6. Drug interactions
CYP450 3A4 Metabolism , so potential for interactions exist
12/6/2014
Maha

18. 7.Dosing principles ( see Oral antidiabetic agent table )
If HgbAIC is < 8 % start 0.5 mg repaglinide or 60 mg netaglainide with each meal .
If HgbAIC is > 8 % start 1-2 mg or 120 mg netaglinide with each meal .
Take minutes prior to each meal
Adjust doses at weekly intervals
Instruct patients who skip a meal to skip a dose .
Instruct patient who eat an extra meal to add a dose
12/6/2014
Maha

19. improves cellular response to insulin W/O increasing pancreatic
D. Thiazolidnediones ( Rosiglitazone – Avandia ® and Pioglitazone – Actos ® )
Mechanism of action
improves cellular response to insulin W/O increasing pancreatic
insulin secretion
Decrease insulin resistance (insulin sensitizer)
Decreases hepatic glucose production
●Results in reduction in exogenous insulin dosage when used
in combination .
● May have favorable effect on HDL
12/6/2014
Maha

20. 2. Clinical applications
As an adjunct to diet and exercise
In cimbination with a sulfonylurea , metformin , or insulin
3.Efficay : (intermediate between metformin and Acarbose)
HgbAIC : Augment the effect when combined with metformin or SU %
4. Pharmacokinetics
12/6/2014
Maha

21. Troglitazone pulled from the market secondary to hepatic fatalities
5. Adverse effects
Hepatotoxicity
Troglitazone pulled from the market secondary to hepatic fatalities
Do not start therapy in patients with baseline LFTs> 2.5x
Check LFTs every 2 months for the first year
Monitor nausea vomiting , abdominal pain, fatigue , anorexia ,dark urine
Resumption of ovulation
Exacerbations of CHF (black box warning)
Weight gain (caused by fluid retention or fat accumulation)
12/6/2014
Maha

22. Pioglitazone induce CYP3A4
6. Drug interactions
Pioglitazone induce CYP3A4
7. Dosing principle ( see Oral antidiabetic agent table )
8. Contraindications and Precautions:
Type 1 DM
Type 2 patient using insulin (edema)
Pre existing hepatic disease
NYHA class III and IV HF
Myocardial ischemia(only rosiglitazone) …(results from studies)
Patient at risk of osteoporosis or having osteoporosis
Drug metabolized by CYP3A4
Premenopausal anovulatory women (unwanted pregnancy)
12/6/2014
Maha

23. down polysaccharides and disaccharides into glucose
E. Alpha – glucosidase inhibitors ( Acarbose – precose® and Miglitol – Glyset ® )
Mechanism of action
Competitive reversible inhibition of intestinal alpha – glucosidase which breaks
down polysaccharides and disaccharides into glucose
Delays glucose absorption and lower postprandial hyperglycemia
Dose not enhance insulin secretion
No effect on weight or lipids
12/6/2014
Maha

24. 2. clinical applications :
As an adjunct to diet and exercise in type 2 diabetes
In combination.
3. Efficacy :
a.HgAIC %
b.FBG no effect
c.PPG mg/dL
4.Pharmcokinetics
12/6/2014
Maha

25. . Increase hepatic transaminases enzymes
5. Adverse effect
● GI
. Increase hepatic transaminases enzymes
Rashes
6. Contraindications : not studied in RF and should not be used in those patients
* Hypoglycemia should be treated with dextrose?
7.Drug interactions
8.Dosing principles:
Titrate dosing :
25 mg QD with the first bite of the main meal for first 7-14 days
25mg BID week 3-4
25mg TID week 5-12
50mg TID ( max dose if wt < 50 kg )
100mg TID ( max it wt > 50 kg )

26. Incretin-Based therapies
Incretin is insulinotropic hormones sereted from neuroendocrine cell in the small intestine in response to CHO ingestion
2 hormones, glucose dependent insulinotropic polypeptide (GIP) and glucagon like peptide 1(GLP-1 )

27. E. GLP-1 Mimetic/Analogs
Two agents, Exenatide, liraglutide
Once daily exenatide….cardio toxicity (QT prolongation) FDA delayed approval?
Used as SC injection
Exenatide may be injected in abdomen, thigh, or upper arm region, but patients are advised to use a different injection site when injecting into the same region.

29. E. GLP-1 Mimetic/Analogs
Clinical application:
Exenatide….used as montherapy
Liraglutide is not recommended as monotherapy by its manufacturer
Both agents approved as add on agents for type 2
Efficacy:
HbA1c: monotherapy %
combination therapy additional 1.5% decrease
FBG: mg/dL
Weight : reduced 4-5kg after 80 weeks

30. E. GLP-1 Mimetic/Analogs
Adverse effects:
GI (titrate dose slowly)
Decrease appetite
Injection site reaction
Acute pancreatitis (rare)
Reduced renal function
A boxed warning about thyroid C-cell tumors is listed in the package insert of liraglutide and extended-release exenatide

31. E. GLP-1 Mimetic/Analogs
Drug Interactions
Exenatide delays gastric emptying; Exenatide can delay the absorption of other medications. If rapid absorption of the medication is necessary, it is best to take the mediation 1 hour before, or at least 3 hours after, the injections of twice-daily exenatide.

32. F: Dipeptidyl Peptidase-4 Inhibitors(DPP-4 inhibitors)
Sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina) are DPP-4 inhibitors currently approved in the United States

33. F: Dipeptidyl Peptidase-4 Inhibitors(DPP-4 inhibitors)
Mechanism of action:
Inhibit degradation of GLP-1 & GIP on entering GI and increase their effect on insulin secretion and glucagon inhibition

34. F: Dipeptidyl Peptidase-4 Inhibitors(DPP-4 inhibitors)
Clinical application
(Sitagliptin) mainly used as add-on therapy in combination withSU, biguanides, TZD, and insulin
Approved as monotherapy

35. F: Dipeptidyl Peptidase-4 Inhibitors(DPP-4 inhibitors)
Efficacy:
HbA1c:
FPG: 15mg/dL
2hrPPG: 45mg/dL
*does not affect body weight or appetite (compared to GLP-1 mimetics)

36. F: Dipeptidyl Peptidase-4 Inhibitors(DPP-4 inhibitors)
Side effects:
Increase risk of infection
Severe hypersenstivity reaction after using sitagliptin
When used with TZD increase edema
Drug interaction:
Sitagliptin not metabolized by CYP, but saxagliptin metablized by CYP3A4/5

37. G-Amylin Receptor Agonists (Amilinomimetics)
Amylin is hormone released from B cells with insulin in response to food
Mechanism of actions:
slow gastric emptying
Suppress glucagon secretion

38. G-Amylin Receptor Agonists (Amilinomimetics)
Pramlintide: synthetic amylin analog
Used for adjunctive treatment in type 1 and 2
Efficacy:
HbA1c
Weight loss

39. G-Amylin Receptor Agonists (Amilinomimetics)
Adverse effects; GI symptoms…transient Severe insulin induced hypoglycemia

40. H.Other agents Colesevelam
In 2008 FDA approved a new indication of colesevalem (bile acid sequestrant) to be used as add-on therapy in type 2 DM
Adverse effects- GI
Efficacy: A1c
LDL
TG 23

41. H. Other agents Colesevelam
Clinical application:
As add on therapy in combination with metformin, SU and insulin

42. J. Dopamine Agonists
Bromocriptine mesylate (Cycloset) is currently approved for the treatment of type 2 DM.
Mechanism of action
Bromocriptine is a dopamine agonist, but the exact mechanism of how bromocriptine improves glycemic control is unknown.

43. J. Dopamine Agonists
Efficacy
HbA1c : 0.3% to 0.6%

44. Potential Future Medications
Selective Sodium-Dependent Glucose Cotransporter-2 Inhibitors (SGLT-2 Inhibitors)
SGLT-2 inhibitors work in the kidney to block the reabsorption of some glucose. Normally, all glucose is reabsorbed back into the systemic circulation from the kidney at normal glucose levels: about 10% through the SGLT-1 receptor, and 90% through the SGLT-2 receptor.

45. Selective Sodium-Dependent Glucose Cotransporter-2 Inhibitors (SGLT-2 Inhibitors)
Safety data have shown a slightly higher rate of genitourinary yeast infections.
SGLT-1 is involved with glucose absorption in the gut, and inhibition of SGLT-1 has been historically thought to cause GI toxicity, but this is unclear and dual inhibitors may be marketed.
Canagliflozin (Invokana) is currently the farthest in development, but several are being developed. Dapagliflozin has been rejected by the FDA several times due to concerns about cancer

47. Medication
Combined With
Trade Name
Metformin and/or metformin extended release
Pioglitazone
Rosiglitazone
Sitagliptin
Saxagliptin
Linagliptin
Alogliptin
Glyburide
Glipizide
Repaglinide
Actosplus Met
Avandamet
Janumet
Kombiglyze
Jentadueto
Kazano
Glucovance
Metaglip
Prandimet
Glimepiride
Duetact
Avandaryl
Oseni

48. Impact of early insulin therapy
Short-term insulin therapy improves insulin resistance - ↓ glucotoxicity and lipotoxicity
Short-term insulin therapy induces “Beta cell rest” which improves subsequent insulin secretion
Insulin therapy potentially decreases cardiovascular risk

50. The American Diabetes Association (ADA) released standards of medical care in diabetes for 2014.
Diabetes treatment goals for younger adults are appropriate for older adults who are functional and cognitively intact, and expected to live long enough to reap benefits.
Glycemic targets may be relaxed for some older adults based on individual criteria; avoid hyperglycemic complications.
Treat cardiovascular risk factors considering time frame of benefit and individual patient characteristics.
Hypertension treatment is indicated in many older adults; lipid and aspirin therapy may benefit patients whose life expectancy is equal to timeframe of primary or secondary prevention trials.
Individualize screening for complications, being mindful of complications that may lead to functional impairment.
Refer to source document for full recommendations, including level of evidence rating.
American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care.
2014;37(suppl 1):S14-S80.
Any pharmacologic agents discussed are approved for use in the United States by the U.S. Food and Drug Administration (FDA) unless otherwise noted. Consult individual prescribing information for approved uses outside of the United States.
January 2014
This slide was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.

51. Prevention strategies for type 2 DM
Prevention strategies for type 2 DM are established. Lifestyle changes, dietary restriction of fat, aerobic exercise for 30 minutes five times a week, and weight loss form the backbone of successful prevention.
No medication is currently FDA approved for prevention of diabetes, although several, including metformin, acarbose, pioglitazone, and rosiglitazone, have clinical trials demonstrating a delay of diabetes onset.