Uha Reddy, MS 3

Oral hypoglycemic agents	Mechanism of action	Molecules Involved	Hypoglycemia
Sulfonylureas First generation · Acetohexamide · Chloropropamide (Diabinese) · Tolbutamide (Orinase) Second generation · Glipizide (Glucotrol) · Glyburide (Diabeta, Micronase, Glynase) · Glimepiride (Amaryl)	Stimulate the release of insulin from pancreatic B-cells (can only be used in patients with some B-cell function) Second generation sulfonylureas can be given in much lower doses than first generation because of their structure.	ATP-dependent potassium channels (on B-cells) contain the sulfonylurea receptor – binding inhibits these channels and alters the resting potential of the cell – this leads to calcium moving into the cell and insulin being secreted	Most common side effect; occurs more often in long-acting sulfs (chloropropamide glyburide and glimepiride)
Meglitinides Repaglinide (Prandin) Nateglinide (Starlix)	Also, stimulate the release of insulin from pancreatic B-cells	Also acts by regulating ATP-dependent K+ channels, but appears to have a different receptor	Most common side effect
Biguanide Metformin (Glucophage)	Decreases hepatic glucose output and increases insulin sensitivity (muscle, liver); Also, anti-lipolytic effect which decreases amount of free fatty acids.	Unknown ? Activation of AMP-activated protein kinase	Less likely to cause hypoglycemia
Thiazolidinediones Rosiglitazone (Avandia) Pioglitazone (Actos)	Increase insulin sensitivity (muscle and liver) and decrease glucose production	Bind and activate peroxisome proliferator-activated receptors (PPARs), which regulates gene expression; Two types: gamma and alpha expressed in different tissues	Less likely to cause hypoglycemia
Alpha-glucosidase inhibitors Acarbose (Precose) Miglitol (Glyset)	Inhibit GI enzymes, alpha-glucosidases, which convert carbs into monosaccharides. This slows and limits the absorption of glucose.	Bind and inhibit alpha-glucosidases.	Less likely to cause hypoglycemia

Oral hypoglycemic agents	Adverse effects	Benefits
Sulfonylureas First generation · Acetohexamide · Chloropropamide (Diabinese) · Tolbutamide (Orinase) Second generation · Glipizide (Glucotrol) · Glyburide (Diabeta, Micronase, Glynase) · Glimepride (Amaryl)	Nausea, skin reactions (including photosensitivity), abnormal LFTs, and poorer outcomes after MI. Chloropropamide: flushing reaction after alcohol ingestion (by inhibiting metabolism of acetaldehyde) and hyponatremia (by increasing vasopressin activity)	Typically lower blood glucose concentrations by ~ 20 percent; Most effective in patients whose weight is normal or slightly increased.
Meglitinides Repaglinide (Prandin) Nateglinide (Starlix)	N – hepatically metabolized with renal excretion (caution in renal insufficiency) R – mostly metabolized in liver May also be assoc. with poorer outcomes after MI	Clinical efficacy similar to sulfs
Biguanide Metformin (Glucophage)	Risk of lactic acidosis (rare): contraindications to metformin therapy due to increased risk of lactic acidosis – renal insufficiency, liver disease, heart failure, past hx of lactic acidosis, hypoxic states, hemodynamic instability. Most common side effects: GI effects such as metallic taste, nausea, diarrhea	Typically lowers blood glucose concentrations by ~ 20 percent as well; Effective in obese and non-obese patients; In obese patients, weight stabilization or weight reduction is often seen; Also, has lipid-lowering effects.
Thiazolidinediones Rosiglitazone (Avandia) Pioglitazone (Actos)	Troglitazone – discontinued b/c of liver dysfx Periodic testing of LFTs recommended Weight gain, fluid retention (sodium reabsorption), heart failure (more so in combo with insulin)	Most effective in combo therapy; P – More favorable lipid profile
Alpha-glucosidase inhibitors Acarbose (Precose) Miglitol (Glyset)	Flatulence and diarrhea A – some association with high aminotransferases	Slows and limits postprandial glucose levels. A – may increase insulin sensitivity

Oral hypoglycemic agents	Pregnancy Category	Reason for Category
Sulfonylureas First generation · Acetohexamide · Chloropropamide (Diabinese) · Tolbutamide (Orinase) Second generation · Glipizide (Glucotrol) · Glyburide (Diabeta, Micronase, Glynase) · Glimepride (Amaryl)	C	Sulfonylureas have been found to be either teratogenic in animals at high doses or been found to cause a mild increase in fetotoxicity at high doses. There have been no adequate, well-controlled studies in pregnant women. However, there have been reports of prolonged severe hypoglycemia (4-10 days) in neonates born to mothers who were taking a sulfonylurea at the time of delivery.
Meglitinides Repaglinide (Prandin) Nateglinide (Starlix)	C	For repaglinide, animal studies have shown skeletal deformities in the offspring of mothers who were taking high doses during gestation and lactation. For nateglinide, animal studies have shown gallbladder agenesis in offspring of mothers taking high doses during gestation.
Biguanide Metformin (Glucophage)	B	Metformin has not shown any teratogenicity in animal studies; and measurement of metformin levels actually suggests a partial placental barrier.
Thiazolidinediones Rosiglitazone (Avandia) Pioglitazone (Actos)	C	Thiazolidinediones have been associated with growth retardation and increased risk of fetal death in animal studies using high doses.
Alpha-glucosidase inhibitors Acarbose (Precose) Miglitol (Glyset)	B	There has been no evidence of teratogenicity in animal studies of alpha-glucosidase inhibitors (acarbose, miglitol).

ACOG Recommendation: The use of oral agents for control of Type II diabetes mellitus during pregnancy should be limited and individualized until data regarding the safety and efficacy of these drugs become available.

FDA Ratings for Drug Use in Pregnancy

A Controlled studies show no risk – Adequate, well-controlled studies in pregnant women have failed to demonstrate risk to the fetus.

B No evidence of risk in humans – Either animal findings show risk (but human findings do not) or if no adequate human studies have been done, animal studies are negative.

C Risk cannot be ruled out – Human studies are lacking and animal studies are either positive for fetal risk or lacking as well. However, potential benefits may justify the potential risk.

D Positive evidence of risk – Investigational or postmarketing data show risk to the fetus. Nevertheless, potential benefits may outweigh the risk.

X Contraindicated in pregnancy – Studies in animals or humans or investigational and postmarketing reports have shown fetal risk which clearly outweighs any possible benefit to the patient.