Principle of Diabetes management
Part 2
Maha M. Alrasheed, PhD
Assistant Professor
Clinical Pharmacy Dept.
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Type 2 diabetes
• Hyperglycemia
• Insulin resistance
• Relative impairment in insulin secretion.
The Metabolic Syndrome
Genetic factors
Family history
Central obesity
Insulin resistance
High TG, low HDL
Small dense LDL
Hypertension
IGT
Physical inactivity
High-fat diet
High ethanol intake
Type 2
diabetes
Cardiovascular disease
Alberti KGMM et al. Diabet Med. 1998;15:539-553; Reaven GM. Clinical Diabetes. 1988;37:1596-1607;
DeFronzo REA et al. Diabetes Care. 1991;173-194; Bjornthorp P. Ann Med. 1994;24:465-468;
Ford ES. JAMA. 2002;287:356-359
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
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.
II. Oral Antidiabetic Agents
A. Biguanides Metformin ( Glucophage ® or Glucophage XR ®)
1.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
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3. Efficacy :
a.HgbAIC : 1.5-1.7 % as montherapy
b.FBG: 50-70 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
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6. Disadvantages :
may cause lactic acidosis
-Contraindications to therapy:
a.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
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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 250-500mg
Maximum dose : 2550 mg/day or 850 mg TID
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B. Sulfonylureas
1.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)
a.HgbAIC 1.5-1.7%:
b.FBG:
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50-70%
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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
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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)
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7. Drug interactions
a.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
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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
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3. Efficacy : (comparable to metformin and SU)
a.HgbAIC : 1.7 % as montherapy
b.FBG:
61mg/dL
4. Pharmacokinetic
5. Adverse effects
Hypoglycemia
Weight gain
6. Drug interactions
CYP450 3A4 Metabolism , so potential for interactions exist
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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 15-30 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
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D. Thiazolidnediones ( Rosiglitazone – Avandia ® and Pioglitazone – Actos ® )
1.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
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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)
a.HgbAIC : Augment the effect when combined with metformin or SU 0.9-13%
4. Pharmacokinetics
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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)
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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)
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E. Alpha – glucosidase inhibitors ( Acarbose – precose® and Miglitol – Glyset ® )
1.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
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2. clinical applications :
As an adjunct to diet and exercise in type 2 diabetes
In combination.
3. Efficacy :
a.HgAIC
b.FBG
c.PPG
0.5-0.8%
no effect
25-50mg/dL
4.Pharmcokinetics
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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 )
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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 )
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.
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 0.8-1.1%
combination therapy additional 1.5% decrease
FBG: 15-26 mg/dL
Weight : reduced 4-5kg after 80 weeks
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
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 twicedaily exenatide.
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
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
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
F: Dipeptidyl Peptidase-4
Inhibitors(DPP-4 inhibitors)
• Efficacy:
HbA1c: 0.6-0.7
FPG: 15mg/dL
2hrPPG: 45mg/dL
*does not affect body weight or appetite
(compared to GLP-1 mimetics)
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
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
G-Amylin Receptor Agonists
(Amilinomimetics)
Pramlintide: synthetic amylin analog
Used for adjunctive treatment in type 1 and 2
Efficacy:
 HbA1c 0.3-0.6
 Weight loss
G-Amylin Receptor Agonists
(Amilinomimetics)
Adverse effects;
GI symptoms…transient
Severe insulin induced hypoglycemia
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 0.3-0.4
LDL 12-16
TG 23
H. Other agents
Colesevelam
• Clinical application:
As add on therapy in combination with
metformin, SU and insulin
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.
J. Dopamine Agonists
• Efficacy
HbA1c : 0.3% to 0.6%
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.
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
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
Pioglitazone
Duetact
Rosiglitazone
Avandaryl
Alogliptin
Oseni
Pioglitazone
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
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.