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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2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid

O

OH

NH

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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