Sulfonylureas, the first class of oral anti-diabetes drugs developed, have been used since the 1950s. Drugs in the sulfonylurea class work by stimulating the pancreas to produce more insulin. Therefore, they all have the potential to produce hypoglycemia. Sulfonylurea drugs are grouped into "generations" according to when they were first introduced.
All sulfonylurea drugs have
similar effects on blood sugar levels, but they differ in their side effects,
the way they are taken, and interactions with other drugs. The primary side
effects are hypoglycemia and weight gain. Hypoglycemia is the most serious and
potentially life threatening side effect of the sulfonylurea drugs. Hypoglycemia
risk is increased for patients with renal impairment, including elderly patients
with a normal age-related decline in renal function. The elderly are also susceptible
to hypoglycemia because of their tendency to eat erratically or to skip meals.
Other risk factors for hypoglycemia are alcohol intake, poor nutrition, gastrointestinal
diseases, renal impairment, and drug interactions.
Because these drugs stimulate
the pancreas to produce more insulin, the sulfonylurea drugs are used as monotherapy
only in type 2 diabetes or secondary diabetes where the individual has the capacity
to produce some endogenous insulin on his or her own.
This class of drugs includes the benzoic acid derivative repaglinide (Prandin ®) and the d-Phenylalaine derivative nateglinide (Starlix ®). These drugs share many of the pharmacological actions and side effects of the sulfonylureas. They stimulate the pancreas to produce more insulin; however, their effects are decreased with low blood glucose levels. Repaglinide should be used cautiously in patients with impaired liver function. These drugs are taken just before a meal. If the patient skips a meal, he should omit the dose and resume taking it at the next meal.
A group of drugs known as biguanides were in widespread use as anti-diabetes agents until the 1970s. Because of an association between these medications and the development of cases of fatal lactic acidosis, biguanides were banned in the U.S. in 1977. The U.S. Food and Drug Administration (FDA) again approved the use of the biguanide metformin (Glucophage ® and Glucophage ® XL) as safe for treatment of type 2 diabetes in 1994. A combination of metformin and glyburide (Glucovance ®) is also approved for use. The biguanide drugs decrease excess hepatic glucose production and decrease insulin sensitivity. As they do not increase insulin secretion, biguanide agents do not increase the risk of hypoglycemia. Metformin also has positive effects on blood lipids. It lowers total cholesterol, low density lipoproteins (LDLs) and triglycerides, and raises beneficial high density lipoproteins (HDLs). Metformin may cause gastrointestinal distress and diarrhea, which can be lessened by starting on a low dose, gradually increasing the drug as tolerated, and taking the drug with meals. Lactic acidosis is a rare complication. However, due to the possibility of developing this potential fatal complication, metformin should not be used in patients who have impaired liver or renal function. Metformin is contraindicated in patients with congestive heart failure, unstable heart disease, hypoxic lung disease, or advanced age.
In February of 2007 the Federal Drug Administration posted a letter from the manufacturer of rosiglitazone reporting an increased risk of bone fractures in women. In March of 2007, the Federal Drug Administration posted a letter from the manufacturer of pioglitazone reporting an increased risk of bone fractures in women. In May of 2007, the Federal Drug Administration issued a Safety Alert on rosiglitazone noting "data from controlled clinical trials have shown that there is a potentially significant increase in the risk of heart attack and heart-related deaths".
Consider directing your patients to this Rosiglitazone FDA Consumer Update page.
Alpha-glucosidase inhibitors work differently than other oral anti-diabetes drugs. The drugs in this class, acarbose (Precose ®) and miglitol (Glyset ®), slow or impede the breakdown of carbohydrates in the intestinal tract. Acarbose and miglitol must be taken with the first bite of a meal to be effective. In high doses these agents can produce malabsorption syndrome. The most commonly occurring side effects associated with these drugs are dose related gastrointestinal complaints such as abdominal pain, flatulence, and diarrhea. In many cases these side effects may be managed with continued administration of the drug and by starting with a low dose and gradually increasing it. If alpha-glucosidase inhibitors are used with insulin or other oral anti-diabetes drugs that can cause hypoglycemia, hypoglycemic episodes must be treated with sublingual glucose tablets or gel, as the absorption of other carbohydrate sources that are swallowed will be impaired.
Dipeptidyl peptidase-4 inhibitors
This is a new class of drugs which appears to have a number of beneficial effects for the treatment of type 2 diabetes mellitus. It is believed that these drugs stablize certain incretin hormones which are necessary for the management of glucose absorbed through the digestive tract.
Glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP) are incretins secreted by endocrine cells of the small intestine. They are secreted when the endocrine cells sense glucose in the lumen of the small bowel. Incretins travel in the blood to the pancreatic beta cells and up-regulate insulin secretion. In addition, GLP-1 inhibits glucagon secretion, delays stomach emptying and has been shown to increase the number of beta cells.
Dipeptidyl peptidase-4 (DPP-4) is an endogenous enzyme that degrades and inactivates GLP-1 and GIP. Some of the DPP-4 inhibitors have been shown to improve glucose tolerance and insulin response to oral glucose. They seem to increasing insulin secretion, delaying insulin absorption and reducing glucose output from the liver.
Manufacturer prescribing information for sitagliptin phosphate (requires Adobe PDF reader)
Sodium glucose co-transporter-2 inhibitor (SGLT2)
SGLT-2 is a Na+ coupled glucose co-transporter that moves glucose against a concentration gradient using the simultaneous transport of Na+ down a concentration gradient. Meaning, cells of the proximal renal tubule use SGLT2 to reabsorb about 90% of the glucose from the renal tubular filtrate and secrete it back into the blood stream. Inhibiting the action of SGLT2 increases the glucose concentration of the excreted urine by about 50-100 g daily. It can reduce A1c slightly less than 1%.
FDA INVOKANA Label Revision 5/15/2014
Monotherapy, the use of one oral agent, generally reduces HbA1c by approximately 1/2 to 1.5 percent. Combining two or more oral agents may work more effectively than a single medication. Combination therapy may minimize the side effects of one or both medications by allowing lower doses of each. Examples of combination therapies are sulfonylurea with metformin or an alpha-glucosidase inhibitor or glitazone with insulin.