Antidiabetic Drugs - Oral Agents

Antidiabetic Drugs Dr. Entisar Al-Mukhtar
Oral Agents:
They are useful for type 2 DM that cannot be managed by diet alone.
Patients who have developed diabetes after age 40 and have had diabetes less than 5 years are most likely to respond well to oral glucose-lowering agents.
ORAL AGENTS
Acarbose PRECOSE
Glimepiride AMARYL
Glipizide GLUCOTROL
Glyburide DIA_ETA, GLYNASE PRESTAB
Metformin FORTAMET, GLUCOPHAGE
Miglitol GLYSET
Nateglinide STARLIX
Pioglitazone ACTOS
Repaglinide PRANDIN
Rosiglitazone AVANDIA
Saxagliptin ONGLYZA
Sitagliptin JANUVIA
Tolbutamide
TOLBUTAMIDE
Canagliflozin INVOKANA
Bromocriptine CYCLOSET
Colesevelam WELCHOL
Dapagliflozin FARXIGA
Notes: long-standing DM may require a combination of oral agents with or without insulin.
Oral glucose-lowering agents include:
(1) Insulin secretagogues
(2) Insulin sensitizers
(3) ?- Glucosidase inhibitors
(4) Dipeptidyl peptidase-IV inhibitors
(5) Sodium–glucose cotransporter 2 inhibitors
(6) Others.
1. Insulin secretagogues
(Sulfonylureas & Glinides)
They promote insulin release from pancreas, so their action depend on functioning pancreatic ? cells.
A. Sulfonylureas (SUs)
Include the 1st generation (Tolbutamide) & 2nd generation drugs (Glyburide "Glibenclamide", Glipizide & Glimepiride).
MOA:
1) Block ATP-sensitive K+ channels, resulting in depolarization & Ca2+ influx, & insulin exocytosis.
2) Reduce hepatic production of glucose & increase peripheral sensitivity to insulin.

kinetics:
• Bind to serum proteins, excreted in the urine and feces.
• Duration of action is the shortest for tolbtamide (6-12 hours), while that of 2nd generation is ranged from 12 to 24 hours.
Adverse effects:
• Weight gain, hyperinsulinemia & hypoglycemia.
• Used with caution in patients with hepatic or renal insufficiency.
• Glyburide is metabolized to active compounds, thus glipizide or glimepiride are safer options in renal dysfunction and in elderly.
• Glyburide has minimal transfer across the placenta, and it may be an alternative to insulin for DM during pregnancy.

Drug interaction:
1- Atypical antipsychotic, Corticosteroids, Diuretics, Niacin, Phenothiazines &
Sympathomimetics reduce SUs effects.
2- Azole antifungals, Beta-blockers, Chloramphenicol, Clarithromycin, Monoamine oxidase inhibitors, Probenecid, Salicylates & Sulfonamides potentiate SUs effects.
B. Glinides
Repaglinide & Nateglinide.
MOA:
• Bind to a distinct site on the SUs receptor of ATP-sensitive potassium channels.
• In contrast to SUs, glinides have a rapid onset & a short duration of action.
Effective in the early release of insulin occurs after a meal & are categorized as postprandial glucose regulators. Glinides should be taken prior to a meal.
• glinides should not be used in combination with SUs due to overlapping mechanisms of action which increase the risk of serious hypoglycemia.
Adverse effects:
• Incidence of hypoglycemia & weight gain is lower than that with SUs.
• Repaglinide effect may be enhanced by ketoconazole, itraconazole, fluconazole, erythromycin & clarithromycin, whereas decreased by barbiturates, carbamazepine & rifampin.
• Concurrent use of repaglinide with gemfibrozil (lipid-lowering drug) is contraindicated because the later inhibits hepatic metabolism resulting in severe hypoglycemia.
• Used cautiously in patients with hepatic impairment.
2. Insulin sensitizers (Biguanides & Thiazolidinediones)
They improve target-cell response to insulin without increasing insulin secretion.
A. Biguanides: Metformin
• The only currently available biguanide.
• It increases glucose uptake & use by target tissues, decreasing IR.
MOA:
1. Main mechanism is reduction of hepatic gluconeogenesis (Note: In type 2 DM excess glucose produced by the liver is a major source of hyperglycemia, accounting for fasting hyperglycemia).
2. Slows intestinal absorption of sugars, improving peripheral glucose uptake & utilization.
• Weight loss due to appetite loss.
• The ADA recommends metformin as the initial drug of choice for type 2 DM.
• Used alone or in combination with other oral agent or insulin.
• Hypoglycemia may occur when metformin is taken with insulin or insulin secretagogues (dose adjustment may be required).

kinetics: Not bound to serum proteins and not metabolized.

Adverse effects:
• Largely are gastrointestinal.
• Metformin is contraindicated in presence of renal dysfunction due to the risk of lactic acidosis.
• It should be discontinued in cases of acute MI, exacerbation of HF, sepsis , or other disorders that can cause acute renal failure.
• Used cautiously in old patients (< 80 years) & in those with a history of HF or alcohol abuse.
• Should be temporarily discontinued in patients undergoing diagnosis requiring IV radiographic contrast agents.
• Rarely, potentially fatal lactic acidosis has occurred.
• Long-term use may interfere with vitamin B12 absorption.

Other uses:
Treatment of polycystic ovary syndrome (PCOS). It lower IR in women with PCOS that can result in ovulation and, possibly pregnancy.

B. Thiazolidinediones (TZDs) (glitazones)
• No risk of hyperinsulinemia.
• Include glitazones pioglitazone & Rosiglitazone.
MOA:
• Act as agonists on peroxisome proliferator–activated receptor-? (PPAR?), a nuclear hormone receptor, thus, increase sensitivity to insulin in adipose tissue, liver & skeletal muscle.
• Hyperglycemia, hyperinsulinemia, hypertriglyceridemia & elevated HbA1c levels all are improved.
• Rosiglitazone increases LDL cholesterol & triglycerides, whereas pioglitazone decreases triglycerides.
• Both drugs increase HDL levels.
• TZDs are used as monotherapy or in combination with other oral agents or insulin (insulin dose should be lowered).
• Pioglitazone is recommends as a 2nd or 3rd line alternative for patients who fail or have contraindications to metformin therapy.
• Rosiglitazone is not recommended because of the cardiac adverse effects.

kinetics:
• Some metabolites of pioglitazone have activity.
• The majority of the active pioglitazone & its metabolites are excreted in the bile, whereas rosiglitazone metabolites are primarily excreted in the urine.
• No dose adjustment is required in renal impairment.
• TZDs should be avoided in nursing mothers.

Adverse effects:
• Liver function monitoring is recommended because liver toxicity was reported with the use of these drugs.
• Weight gain possibly because TZDs may increase SC fat & cause fluid retention (can worsen HF), thus TZDs should be avoided in patients with severe HF.
• Osteopenia & increased fracture risk may occur with TZDs use.
• Pioglitazone may increase bladder CA risk.
• Risk of MI & death from CV causes restrict rosiglitazone use.
• After a further review of safety data, the restrictions on rosiglitazone use were subsequently lifted.
Other uses: PCOS.

3. ?- Glucosidase inhibitors : Acarbose & Miglitol
MOA:
• They reversibly inhibit ?-glucosidase enzymes (in the intestinal brush border), if these drugs taken at the start of a meal they delay carbohydrates break down into glucose & other simple sugars, thus lowerhng postprandial glucose levels.
• Acarbose also inhibits pancreatic ?-amylase, thereby interfere with the breakdown of starch to oligosaccharides.
• Do not cause hypoglycemia, but their combination with insulin secretagogues or insulin, may cause hypoglycemia which should be treated with glucose rather than sucrose ( because sucrase is also inhibited).

kinetics:
• Acarbose is poorly absorbed, metabolized by intestinal bacteria & some of its metabolites are absorbed & excreted in the urine.
• Miglitol is very well absorbed but has no systemic effects, excreted unchanged by the kidney.



Adverse effects:
• Flatulence, diarrhea & abdominal cramping.
• Should not be used in the presence of inflammatory bowel disease, colonic ulceration, or intestinal obstruction.

4. Dipeptidyl peptidase - IV (DPP-4) inhibitors:
Alogliptin, Linagliptin, Saxagliptin & Sitagliptin

MOA: Inhibit DPP-4 enzyme preventing the inactivation of incretin hormones such as glucagon-like peptide-1 (GLP-1), increasing insulin release in response to meals & reduce inappropriate secretion of glucagon.
• Used as monotherapy or combined with SU, metformin, TZDs or insulin.
• Unlike incretin mimetics, these drugs do not cause satiety, or fullness, and are weight neutral.

kinetics:
• All DPP-4 inhibitors except linagliptin (eliminated via the enterohepatic system) require dosage adjustments in renal dysfunction (note: alogliptin and sitagliptin are excreted unchanged, whereas saxagliptin is metabolized into an active metabolite).
Adverse effects:
• Nasopharyngitis, headache & pancreatitis.
• Ritonavir, atazanavir, itraconazole, and clarithromycin, may inhibit saxagliptin metabolism.

5. Sodium–Glucose Cotransporter 2 (SGLT2) inhibitors: Canagliflozin &
Dapagliflozin
MOA:
• Inhibit SGLT2 (which reabsorbs filtered glucose in the kidney), decreasing glucose reabsorption & increasing its excretion.
• Also sodium reabsorption is decreased resulting in osmotic dieresis, that may reduce systolic BP, though, SGLT2 inhibitors are not indicated for HT treatment.
kinetics:
• Given once daily in the morning, canagliflozin should be taken before the first meal of the day.
• Both drugs are metabolized to inactive metabolites.
• Canagliflozin is primarily excreted via the feces,& about one-third of a dose is renally eliminated.
• These agents should be avoided in patients with renal dysfunction.

Adverse effects:
• Genital mycotic infections in female (e.g., vulvovaginal candidiasis), UTIs, and urinary frequency.
• Hypotension, occurred, in elderly or patients on diuretics (evaluate volume status before treatment).
6. Other agents: Bromocriptine and colesevelam (bile acid sequestrant) cause modest reductions in HbA1c by unknown mechanism.
• Their clinical use for treatment of type 2 DM is limited by their modest efficacy, adverse effects, and pill burden.