A. Classes of OHA [1]

1. Metformin (Glucophage®)
2. Glitazones: Rosiglitazone, Pioglitazone; (Troglitazone withdrawn from market)
3. Sulfonylureas (insulin secretogogues)
4. Meglitinides (non-sulfonylurea insulin secretogogues): Repaglinide, Nateglinide
5. Alpha-Glycosidase Inhibitors: Acarbose, Miglitol
6. Use alone or in combination with each other and/or with insulin

B. Metformin (Dimethylbiguanide, Glucophage®) [2,3]

1. Biguanide OHA
2. Mechanism
   1. Major effect is decrease in hepatic glucose production by inhibiting gluconeogenesis
   2. Increases glucose uptake in peripheral tissues by ~13%
   3. May increase gastrointestinal glucose utilization
   4. Plasma insulin levels are unchanged or decreased in patients with hyperinsulinemia
   5. Reduction in adipose tissue mass usually leads to weight loss
3. Use and Efficacy
   1. As effective as insulin in patients with Type II DM who have failed sulfonylureas
   2. As effective as sulfonylureas and acarbose as monotherapy, with more weight loss [4]
   3. Efficacy demonstrated only on reduction in Hemoglobin A1c (HbA1c) levels
   4. Minimal hypoglycemic effects and induces weight loss
   5. Metformin alone has beneficial effects on plasma lipids and weight reduction
   6. FINFAT trial found metformin + NPH Insulin led to nearly normal HbA1c levels (~7%) [5]
   7. Synergistic efficacy of metformin with sulfonylureas (complementary mechanisms)
   8. Synergistic efficacy of metformin with troglitazone (HbA1c levels ~8.3%) [6]
   9. Metformin + insulin as effective as insulin + glyburide without weight gain [5]
   10. Metformin use in patients on insulin allows reduction in insulin dose, reduced weight gain, and 10% added reduction in HbA1c [7]
   11. Reduced risk of developing type 2 DM in patients with glucose intolerance by 31% [8]
   12. With clomiphene, restores ovulation in patients with polycystic ovary syndrome (PCOS)
   13. Metformin inferior to clomiphene as monotherapy in PCOS [9]
   14. Metformin is a reasonable first line therapy for gestational DM about as effective as insulin, preferred by patients, and is well tolerated [47]
4. Dosing
   1. Begin with single dose 500mg or 850mg po qd with morning meal
   2. Increase graudally (every 2 weeks) to maximal 850mg tid or 500mg qid
   3. Monitor glucose weekly and hemoglobin A1c monthly
   4. Drug shows effects at 500mg po qd; maximal effects at maximal doses
   5. May be given safely at bedtime alone, combined with NPH insulin and/or sulfonylurea [5]
   6. Glucophage® XR can be taken once daily with dose equivalent to bid-qid metformin [86]
   7. Now available in combination pill (Glucovance®) with glyburide (sulfonylurea) [82]
   8. Glucovance® is available in 1.25/250, 2.5/500, 5/500 glyburide/metformin combinations
5. Side Effects [2,10]
   1. Metallic taste, nausea, diarrhea, anorexia, decreased B12 and folate uptake
   2. Lactic acidosis is uncommon, but increased in patients with renal insufficiency
   3. Lactic acidosis also increased with alcohol ingestion and after intravenous contrast
   4. Avoid use in patients with active hepatic disease, renal insufficiency, alcohol abuse

C. Glitazones (Thiazolidinediones) [11,12]

1. PPAR gamma agonists, insulin sensitizers
   1. Rosiglitazone (Avandia®) [13]
   2. Pioglitazone (Actos®) [14]
   3. Ciglitazone - in clinical studies
   4. Englitazone - in clinical studies
   5. Troglitazone (Rezulin®) has been removed from the market [15,16]
   6. Pioglitazone or rosiglitazone can substitute for troglitazone [16]
2. Physiological Effects [11]
   1. Increases insulin actions on target tissues and increases glucose transport (disposal)
   2. Main effects appear to be on adipocytes, skeletal muscle, liver
   3. Little or no effect on glucose production (gluconeogenesis) by the liver [6]
   4. Reduces liver fat (including fatty liver) and increases hepatic insulin sensitivity
   5. Increases HDL but may also increase LDL levels (reduces VLDL levels)
   6. Increases insulin sensitivity in muscle cells
   7. Reduces insulin secretion by pancreas
   8. Appear to stimulate fatty acid utilization by muscles and reduce triglyceride levels
   9. Promotes fatty acid storage in adipocytes (increases fat mass)
   10. Also improves endothelial function and reduce smooth muscle cell proliferation
   11. Should be considered in insulin resistance and polycystic ovary syndromes
   12. Reduces fatty acid stores in liver and improves fatty liver histology
   13. No clear clinical benefit in HIV-associated lipodystrophy
3. Molecular Mechanisms of Action
   1. Thiazolidinediones, certain NSAIDs, and natural ligands bind PPAR gamma proteins
   2. PPAR are nuclear peroxisome proliferator-activated receptor proteins
   3. PPAR-thiazolidinedione complex binds to retinoic acid X receptor (RXR)
   4. PPAR-drug-RXR complex forms a potent transcription factor
   5. PPAR-drug-RXR complex is involved in insulin response, adipocyte development
   6. Thiazolidinediones stimulate adipocyte generation as well, so increase body fat
   7. These are the only current agents which (partially) reverse insulin resistance
   8. PPARs play a role in smooth muscle proliferation as well [62]
4. Efficacy in Diabetes
   1. Reduced mean glucose 35-50% (dose dependent)
   2. May be used as monotherapy, or with sulfonylureas or insulin or metformin
   3. HbA1c levels reduced >0.84-1.4% as single agent therapy
   4. Appears slightly less effective on HbA1c levels than sulfonylureas or metformin
   5. Combination with metformin led to average HbA1c levels of <8.3% [18]
   6. Improves metabolic parameters except cholesterol levels [18]
   7. Rosiglitazone plus sulfonylurea additive efficacy in Type 2 DM
   8. Pioglitazone + sulfonylurea leads to improved HbA1c levels and lipid profiles [19]
5. Nonhypoglycemic Effects [20]
   1. Reduction of blood pressure
   2. Reduction of triglycerides and increase HDL (and also LDL) levels
   3. Improvement in fibrinolysis: decrease PAI-1 and fibrinogen levels
   4. Decrease in carotid artery intima-media thickness
   5. Increase LDL levels but increase LDL particle size and reduce LDL oxidation
   6. Reduce microalbuminuria
   7. Induce coronary artery relaxation, improve stroke volume and cardiac index
6. Dosages
   1. Rosiglitazone: 4-8mg po qd or 2-4mg bid
   2. Pioglitazone: 15-45mg po qd
   3. Pioglitazone and rosiglitazone may be used alone or in combination with other agents
7. Side Effects
   1. Generally well tolerated
   2. Weight gain occurs in most patients
   3. Increased peripheral edema and heart failure (1.11-2.0X risk) with rosiglitazone at 1-3.75 years [21,30,44]
   4. Rosiglitazone associated with no increase [2,44,45] or a 1.4X increase [30,33] in risk of myocardial infarction (MI) overall
   5. Rosiglitazone showed 1.4X increased risk of acute MI and 1.29X increased death compared with other oral hypoglycemic agents in age >65 year DM2 patients [46]
   6. Still unclear whether rosiglitazone increases ischemia risk [43] or overall cardiovascular mortality [30,45]
   7. Increased heart failure (1.4X), non-cardiac peripheral edema, weight gain with pioglitazone [17,22,44]
   8. Overall, pioglitazone caused reduction of 18% in combined death, MI, stroke [17]
   9. Total cholesterol levels may increase, but all DM patients on should be on statins
   10. Triglyceride and VLDL levels decrease and HDL levels typically increase
   11. Fat can accumulate with any of these agents
   12. Troglitazone causes transaminase elevations in 2-4% of patients, can cause hepatic failure [23,24] and has been removed from the market [16]
   13. Because of troglitazone, use of other glitazones requires liver function monitoring
   14. However, incidence of hepatitis with other agents is similar to placebo [13,14]
   15. Transaminase levels checked every 2 months up to 12 months
8. Combinations
   1. Rosiglitazone+metformin (Avandamet®) single pill [25]
   2. Rosiglitazone+glimepiride (Avandaryl®) single pill [26]
   3. Pioglitazone+glimepiride (Duetact®) single pill [27]

D. Alpha-Glycosidase Inhibitors [28,29]

1. Mechanism
   1. Competitive inhibitor of intestinal brush border alpha-glucosidase
   2. Thereby reduces breakdown of carbohydrates and absorption of glucose
   3. Acarbose reduces post-prandial plasma glucose and insulin responses
   4. Very little systemic absorption of drug
2. Agents
   1. Acarbose (Precose®) [28]
   2. Miglitol (Glyset®) [29]
3. Use and Efficacy
   1. Improved diabetic control in Type II DM patientsversus placebo
   2. Independent of which other agents (including insulin) the patients were on
   3. Acarbose plus metformin or sulfonylureas is better than single agents alone
   4. Acarbose similar to and additive with sulfonylureas
   5. Similar 1.1-1.3% reduction in HbA1c with acarbose 100mg po tid versus metformin 850mg po bid
   6. Acarbose 100mg tid reduces risk of developing frank DM2 ~25% in patients with impaired glucose tolerance
   7. Miglitol reduced HbA1c from 9.9% to 8.3% (placebo 9.9% to 9.6%) in 6 month study [29]
4. Dosing
   1. Acarbose and miglitol both initiated at 25mg po tid for most patients
   2. Full dose is 50-300mg per day po divided (100mg po tid is maximal dose)
   3. Use in combination with sulfonylureas and/or insulin
   4. Inhibits the absorption of metformin (concern with combination therapy)
5. Side Effects [28,29]
   1. Mainly gastrointestinal due to increased carbohydrate load delivered to colon
   2. Dose-dependent flatulence, cramps, abdominal distension, borborygmi, diarrhea
   3. These symptoms usually lesson over time
   4. May decrease intestinal iron absorption, leading to anemia in some cases
   5. Mild hepatic enzyme elevations are occasionally reported with acarbose
   6. Thusfar miglitol has not shown increases in hepatic enzymes
   7. Slight risk of hypoglycemia when used with insulin or sulfonylureas
   8. Acarbose reduces bioavailability of metformin

E. Sulfonylureas
[Figure] "General Structure of Sulfonylureas"

1. Mechanism of Action
   1. Stimulate basal insulin secretion through actual sulfonylurea receptors
   2. SUR1 is the sulfonylurea receptor
   3. SUR1 is a component of the ß-cell inward rectifying potassium channel [48]
   4. Sulfonylureas block SUR1 and increase K+ currents, enhancing insulin secretion
   5. Sulfonylureas also reduce hepatic glucose production
   6. Potentiate insulin's effect on glucose transport in peripheral tissues
   7. Possibly up-regulate insulin receptors
   8. Can cause frank hypoglycemia due to potentiation of insulin secretion
2. Use
   1. Useful in Type II DM when endogenous insulin is still produced
   2. These agents are now second or third line therapies after metformin or acarbose
   3. Combination therapy with insulin is preferred to insulin monotherapy in Type 2 DM
   4. Begin with low dose and increase after 1-2 weeks
   5. Main problems are post-prandial hyperglcyemia, hypoglycemia, lack of efficacy
   6. May be combined with insulin or with metformin to potentiate their effects
3. Second Generation Sulfonylureas [32]
   1. Less polar, larger side chains, 100X higher potency over 1st generation
   2. So dose of drug is lower, but action may not be affected significantly
   3. Duration of action intermediate to tolbutamide and chlorpropamide
   4. Less protein bound, so fewer drug interactions (less drug given, too)
   5. Glyburide (Micronase®, DiaBeta®): 2.5-20mg qd usually in bid divided doses
   6. Glyburide + metformin combination (Glucovance®; see above) [10]
   7. Glipizide (Glucotrol®): 5-40mg/day sustained release (XL) form is cheap and qd only
   8. Glimepiride (Amaryl®): usual dose is 4mg po qd; start 1mg po qd; max 8mg po qd
4. Efficacy
   1. Nearly as effective as metformin and acarbose in terms of HbA1c reductions
   2. However, most patients on sulfonylureas gain weight
   3. Increased incidence of hypoglycemia with these agents compared with other oral agents

F. Meglitinides [34,35,36]

1. Bind and inhibit (closes) ATP sensitive K+ channels on pancreatic ß-cells
   1. Unlike sulfonylureas, stimulate immediate insulin secretion after meal
   2. Primarily functions in the presence of glucose
   3. This reduces the risk for hypoglycemia
2. Reduce HbA1c when used alone by 0.9-1.9%
3. About as effective as sulfonylureas but does not cause weight gain
4. Main side effect is hypoglycemia, less common than with sulfonylureas
5. When used with metformin, reduces glucose more than single therapy
6. Repaglinide (Prandin®) - initial dose 0.5mg before each meal (up to 4 meals per day) [35]
7. Nateglinide (Starlix®) - initial dose is 60-120mg po before each meal (up to 3 times daily) [36]

G. Incretin Therapy (DPP-IV Inhibitors) [37,42]

1. Biology of Glucagon-like Peptide 1 (GLP-1)
   1. GLP1 is released from gastrointestinal tract when food is ingested
   2. GLP1 stimulates insulin and reduces glucagon secretion; preserves ß-cell mass
   3. GLP1 is catabolized by DPP-IV
2. DPP-IV inhibitors
   1. Orally available agents which block GLP-1 breakdown
   2. Similar actions to GLP1 and analogs, but do not promote weight loss
3. Agents
   1. Vildagliptin (Galvus®)
   2. Sitagliptin (Januvia®)
4. Vildagliptin (Galvus®)
   1. Oral DPP-4 inhibitor with 0.8% HbA1c reduction when added to metformin
   2. Very well tolerated without significant nausea
   3. Prevents weight gain but does not appear to induce weight loss
   4. Dose is 100mg po qd or 50mg po bid
5. Sitagliptin (Januvia®) [38,39]
   1. Oral DPP-4 inhibitor with 0.6-0.9% HbA1c reduction alone, slightly higher in combination
   2. Prevents weight gain, and showed 1.5kg weight loss compared with placebo
   3. Well tolerated, even in patients with reduced renal function
   4. Improved ß-cell function and reduced insulin and glucose levels
   5. Dose is 100mg po qd
   6. Sitagliptin/Metformin (Janumet®) 50/500mg bid or 50/1000mg bid [41]

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