Diabetes Mellitus Oral Hypoglycemic Agents Dr. A. ghanei endocrinologist
Diabetes Mellitus Oral Hypoglycemic Agents
Dr. A. ghanei
endocrinologist
Non-Insulin Hypoglycemic Agents
Oral¨Biguanides¨Sulfonylureas¨Meglitinides¨Thiazolidinediones¨Alpha Glucosidase inhibitors¨Incretin Enhancers (DPP-IV inhibitors)¨Resin binder
Parenteral¨ Amylin analogs¨ Incretin mimetics
Sulfonylureas : stimulate β cells to produce more insulin
¨ 1st generation– (1)Orinase (tolbutamide)– (3)Tolinase (tolazamide)– (6)Diabinese (chlorpropamide)
¨ 2nd generation– (75)Glucotrol (glipizide)– (150)Glucotrol XL (ex. rel. glipizide)– (150)Micronase, Diabeta (glyburide)– (250)Glynase (micronized glyburide)
¨ 3rd generation– (350)Amaryl (glimepiride)
2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD) was used in treatment of typhoid fever in 1940’s hypoglycemia
Currently > 12,000
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*Hydroxylation of the aromatic ring appears to be the most favored metabolic pathway*Hydroxylated derivatives have much lower hypoglycemic activity
¨ Mechanism of action:– presence of functional pancreatic beta cells is must
– SUs imitate the effects of glucose on beta cells
– SUs bind to SURs at the beta-cell potassium channels >
this closes the channels and blocks potassium ions from
leaving the cell > The membrane then becomes
depolarized and calcium channels open > Calcium ions
enter the cell and trigger the release of insulin > The
increased insulin concentration lowers blood glucose
levels
Mechanism of action
Glimepiride (Amaryl) 1, 2, 4 mg tablets
Glipizide (Glucotrol, Glucotrol XL)
(2.5), 5, 10 mg (XL) tablets
Glyburide (DiaBeta) 1.25, 2.5, 5 mg tablets
Pharmacology - SulfonylureasCompound • 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
Biguanides : improves insulin’s ability to move glucose into cells (esp. muscle)
¨ Metformin- Glucophage®, Fortamet®, Riomet®
*only anti-diabetic drug that has been proven to reduce the complications of diabetes, as evidenced in a large study of overweight patients with diabetes (UKPDS 1998).
- Metformin was first described in the scientific literature in 1957 (Unger et al). - It was first marketed in France in 1979 but did not receive FDA approval for Type 2 diabetes until 1994.
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- mechanism improves insulin sensitivity by increasing peripheral glucose uptake and utilization. - Zhou et al (2001) showed that metformin stimulates the hepatic enzyme AMP-activated protein kinase
Metformin is a widely used monotherapy, and also used in combination with the sulfonylureas in treatment of type 2 diabetes
Biguanides
Metformin is a biguanide that works mainly by: Suppressing excessive hepatic
glucose production Increasing glucose utilization in
peripheral tissues to a lesser degree It may also improve glucose levels by
reducing intestinal glucose absorption
Metformin Glucophage 500, 850, 1000 mg tablets
(Glucophage XR) 500, 750 mg XR tablets
Pharmacology - BiguanidesMechanism Activates AMP-kinase
Action(s) • Hepatic glucose production • Intestinal glucose absorption • Insulin action
Glucose Lowering Effect
• Fasting• 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
Thiazolidinediones (TZD’s) : make cells more sensitive to insulin (esp. fatty cells)
¨ Pioglitazone- Actos®, Avandia®
- binds to and activates (PPARγ).
- PPARγ is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue, cardiac and skeletal muscle, liver and placenta
PPAR - γ
- upon activation of this nuclear receptor by a ligand such as a TZD, PPARγ–ligand complex binds to a specific region of DNA and thereby regulates the transcription of many genes involved in glucose and fatty acid metabolism.
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5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione
- Marketed in USA in August of 1999
Pioglitazone (Actos) 15, 30, 45 mg tablets
Rosiglitazone (Avandia) 2, 4, 8 mg tablets
Pharmacology – Thiazolidinediones (TZD)Compound Rosiglitazone (Avandia®)
Mechanism Activates the nuclear transcription factor PPAR-
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
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.Adapted with permission from Silvio Inzucchi, Yale University.
Αlpha – glycosidase inhibitors :Block enzymes that help digest starches slowing the rise in BS.
¨ AGI’s
- Precose ® (acarbose),
- Glyset ® (miglitol)
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1-(2-Hydroxy-ethyl)-2-hydroxymethyl-piperidine-3,4,5-triol
Pharmacology – Alpha-Glucosidase Inhibiters
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
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.Adapted with permission from Silvio Inzucchi, Yale University.
Meglitinides : Stimulate more insulin production ; dependant upon level of glucose present
¨ Meglitinides- Prandin ® (repaglinide)
- Starlix ® (nateglinide)
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OHO
NH
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2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid
O
OH
NH
O
2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid
Meglitinides Examples: repaglinide, nataglinide It is a benzoic acid derivative and a short-acting
insulin releaser. It stimulates the release of insulin from the
pancreatic beta cells by closing ATP-sensitive potassium channels.
It has no significant effect on plasma lipid levels Rapid onset and short duration of action make
multiple daily doses necessary (take it immediately before each meal!).
Pharmacology – 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
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22.Adapted with permission from Silvio Inzucchi, Yale University.
Diabetes – Oral MedicationsSummary
5 Classes :
¨ Sulfonylureas stimulate β cells
¨ Biguanides improves insulin’s ability to move glucose ¨ Thiazolidinediones cells more sensitive to insulin
¨ Alpha-glycosidase inhibitors Block enzymes that help digest starches
¨ Meglitinides stimulate β cells (dependant upon glucose conc.)
Pharmacology – 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
medicationsADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23.
Adapted with permission from Silvio Inzucchi, Yale University.
Drug PearlsMedication PRO CON
Metformin Low cost, A1c lowering, + CV effects, weight loss, PCOS
Renal or hepatic impairment
Sulfonylurea Low cost, A1c lowering
Hypoglycemia, treatment failure
Meglitinides Erratic meals, renal insufficiency
Hypoglycemia, treatment failure
Pioglitazone Insulin resistance, decrease in adipose tissue, TG reduction
Edema, wt gain, CI with HF 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
Typical A1c ReductionsMonotherapy Route of
AdministrationA1c (%) 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
Insulin Injectable Open to target
Unger J et al. Postgrad Med 2010; 122: 145-57
Fasting vs. Postprandial EffectMostly targets
FASTING hyperglycemia
Mostly targets POSPRANDIAL hyperglycemia
Insulin (long and intermediate action)
Insulin (regular, rapid-action)
Colesevelam α-glucosidase inhibitors
Metformin Meglitinides
Pramlinitide
DPP-4 inhibitors
GLP-1 agonist
PHARMACOLOGIC MANAGEMENT
The stepwise approach described in the 1998 CDA Clinical Practice Guidelines implied that it was acceptable to wait for up to 8 to 16 months before implementing aggressive therapy to treat hyperglycemia.
It is now recommended that the management regimens of patients with type 2 diabetes be tailored to the individual patient, aiming for glycemic targets as close to normal as possible and, in most people, as early as possible.
Multiple therapies may be required to achieve optimal glycemic control in type 2 diabetes.
The choice of antihyperglycemic agent(s) should be based on the individual patient.
Target A1C should be attainable within 6 to 12 months.
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 onset
¨ 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
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)?
¨ The degree of A1c lowering effect required to achieve goal?
¨ Side effect profile and the patients tolerability?¨ Co – existing conditions ( CVD, osteoporosis, obesity,
etc)?¨ Patient preference for route of administration (oral,
injection)?
QUESTIONS