Type 2 Oral Diabetes Medications Side Effects, Differences, and Effectiveness

  • Pharmacy Author:
    Omudhome Ogbru, PharmD

    Dr. Ogbru received his Doctorate in Pharmacy from the University of the Pacific School of Pharmacy in 1995. He completed a Pharmacy Practice Residency at the University of Arizona/University Medical Center in 1996. He was a Professor of Pharmacy Practice and a Regional Clerkship Coordinator for the University of the Pacific School of Pharmacy from 1996-99.

  • Medical and Pharmacy Editor: Jay W. Marks, MD
    Jay W. Marks, MD

    Jay W. Marks, MD

    Jay W. Marks, MD, is a board-certified internist and gastroenterologist. He graduated from Yale University School of Medicine and trained in internal medicine and gastroenterology at UCLA/Cedars-Sinai Medical Center in Los Angeles.

What are oral diabetes medications?

Oral diabetes are medications used to improve blood sugar (glucose) control in patients with type 2 diabetes.

What are the types of oral diabetes medications?

Currently, there are nine drug classes of oral diabetes medications approved for the treatment of type 2 diabetes.

  1. α-glucosidase inhibitors
  2. Biguanides
  3. Sulfonylureas
  4. Meglitinides
  5. Thiazolidinediones
  6. DPP-4 inhibitors
  7. Sodium-glucose cotransporter (SGLT)-2 inhibitors
  8. Dopamine agonists
  9. Bile acid sequestrants

These medications differ in the way they function in the body to reduce blood glucose.

Biguanides

Metformin (Glucophage) is the only biguanide available in the United States and is generally the first choice for oral treatment of type 2 diabetes mellitus. Metformin improves

  • the body's response to natural insulin,
  • decreases the absorption of glucose from the intestines, and
  • reduces the production of glucose by the liver.

Sulfonylureas

Sulfonylureas are the oldest classes of oral diabetes medications. Sulfonylureas work primarily by stimulating the release of insulin. Insulin is the hormone responsible for regulating blood glucose by increasing the uptake of blood glucose by tissues and increasing storage of glucose in the liver.

Meglitinides

Meglitinides and sulfonylureas have a similar mechanism of action. Meglitinides are short acting glucose lowering medications. They stimulate the secretion of insulin from the pancreas.

Thiazolidinediones

Thiazolidinediones enhance insulin sensitivity meaning that the effect of a given amount of insulin is greater. Thiazolidinediones also are referred to as peroxisome proliferator-activated receptor ? or PPAR-? agonists.

α-glucosidase inhibitors

α-glucosidase inhibitors delay the digestion and absorption of starch or carbohydrates by inhibiting enzymes in the small intestine which help breakdown these molecules. The starches and carbohydrates are broken down into glucose, which then is absorbed from the intestine and increases the level in the blood.

DPP-4 inhibitors

DPP-4 inhibitors help lower blood glucose by increasing the production of insulin from the pancreas and reducing the release of glucose from the liver.

SGLT2 inhibitors

SGLT2 inhibitors or sodium-glucose cotransporter 2 inhibitors are the newest class of oral diabetes medications. They work by reducing absorption of glucose from the fluid that is filtered from blood by the kidney, causing more glucose to be eliminated in the urine. These medications increase urinary glucose excretion and consequently lower blood sugar levels.

Bile acid sequestrants

Currently the only bile acid sequestrant approved for the oral treatment of type 2 diabetes is colesevelam (Welchol). Bile acid sequestrants function primarily in the intestines where they bind to and decrease the reabsorption of bile acid. The exact mechanism by which these agents lower blood glucose is not known.

Dopamine agonists

Bromocriptine (Cycloset) is a dopamine agonist approved for the treatment of type 2 diabetes. The exact mechanism whereby bromocriptine lowers blood glucose is not known.

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Early Signs and Symptoms of Type 2 Diabetes

Early signs and symptoms of type 2 diabetes may include

  • increased urination,
  • weight loss,
  • fatigue,
  • nausea,
  • vomiting, and
  • vaginal infections.

What are examples of oral diabetes medications available in the US?

α-glucosidase inhibitors

Sulfonylureas

Sulfonylureas are grouped into two classes, first and second generation agents.

First generation sulfonylureas include

Second generation sulfonylureas are

Biguanides

The only biguanide available in the United States is metformin (Glucophage, Glucophage XR, Riomet).

Thiazolidinediones

Thiazolidinediones or TZDs include

Meglitinides

DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors)

SGLT-2 inhibitors

Bile acid sequestrants

Currently the only bile acid sequestrant approved for the oral treatment of type 2 diabetes is colesevelam (Welchol).

Dopamine agonists

Bromocriptine mesylate (Cycloset) is a dopamine agonist.

What are examples of combination oral diabetes medications?

Combination oral diabetes drugs include

What are the side effects of oral diabetes medications?

The nine classes of oral diabetes drugs differ in their side effect profile. The main side effects of each class are as listed.

Side effects of thiazolidinediones

Thiazolidinediones may cause

Side effects of DPP-4 inhibitors

Although DPP-4 inhibitors are generally well tolerated, they may cause

Side effects of biguanides (metformin [Glucophage])

The most common side effects of metformin include

These side effects usually are mild and tend to decrease in severity over time despite continuation of treatment.

Other reported side effects of metformin include

Although rare, metformin may cause lactic acidosis, a serious condition that occurs due to the accumulation of acid in the body.

Side effects of sulfonylureas

Sulfonylureas most commonly cause hypoglycemia (low blood glucose) and weight gain. Less common side effects are

Side effects of meglitinides

The most common side effects of meglitinides are hypoglycemia and weight gain. The risk for hypoglycemia and weight gain appears to be low in comparison to sulfonylureas.

Side effects of α-glucosidase

α-glucosidase inhibitors most commonly cause

Side effects of SGLT-2 inhibitors

The most common side effects associated with SGLT-2 inhibitors include

Other reported side effects

Side effects of bile acid sequestrants

The most common side effects of bile acid sequestrants include:

Colesevelam also may cause an increase in triglyceride levels.

Side effects of bromocriptine mesylate (Cycloset)

Side effects associated with bromocriptine therapy include:\

What drugs interact with oral diabetes medications?

Drug interactions with oral diabetes drugs vary based on individual diabetes drug classes. However, drugs which cause blood glucose levels to increase may diminish the effectiveness of any oral diabetes drug therapy. Examples of drugs which increase blood glucose include

Metformin drug interactions

Metformin is eliminated from the body via the kidneys in a process known as renal tubular secretion. Drugs which are also eliminated via this same pathway may compete with metformin for elimination when administered concomitantly and increase the risk of metformin associated side effects due to an increase in blood levels of metformin. Examples of such drugs include

Due to the risk of lactic acidosis metformin containing products must be temporarily discontinued prior to the administration of radiopaque contrast dyes. Metformin should be held for at least 48 hours after contrast dye administration and should not be restarted until the patient's kidney function returns back to normal.

Other drug interactions with oral diabetes medications

  • Sulfonylureas are broken down (metabolized) by a set of liver enzymes. Medications which inhibit or induce the activity of these enzymes may impact their blood levels.
  • Gemfibrozil (Lopid) strongly inhibits the breakdown of repaglinide and consequently may cause prolonged hypoglycemia.
  • Thiazolidinediones may interact with drugs that are strong inhibitors or inducers of liver certain enzymes known as CYP3A4, CYP2C8, or CYP2C9. The dose of pioglitazone must be limited to 15 mg when administered in combination with gemfibrozil (Lopid), a strong inhibitor of these pathways.
  • DPP-4 inhibitors are metabolized extensively by liver enzymes. Therefore, drug-drug interactions are possible with agents that alter the function of these enzymes.
  • The effectiveness of meglitinides may be reduced when administered with carbohydrate digesting enzymes such as amylase, pancreatin, or pancrelipase.
  • Bile acid sequestrants have many drug interactions. Bile acid sequestrants decrease the absorption of levothyroxine (Synthroid), glyburide (DiaBeta, Micronase), and birth control pills when administered together. Additionally, they may also decrease the absorption of other drugs such as warfarin (Coumadin), digoxin (Lanoxin), and fat-soluble vitamins (Vitamins A, D, E, and K). Therefore, these agents should be administered at least 4 hours before the dose of colesevelam.
  • Bromocriptine is metabolized by CYP3A4 liver enzymes. Drugs which alter the activity of these enzymes may change bromocriptine levels in the blood and consequently cause adverse effects. Bromocriptine may also interact with some antipsychotics and ergot based migraine medications.

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What formulations of oral diabetes medications are available?

  • All oral diabetes drugs are available in tablet forms.
  • Glipizide and metformin are available as extended-release tablets.
  • Metformin also is available in an oral liquid form.
  • Colesevelam is available as an oral powder for suspension.

What about taking oral diabetes medications during pregnancy or while breastfeeding?

Use of oral diabetes drugs during pregnancy is controversial. For most women, the first step to maintaining optimal blood glucose control during pregnancy is to make appropriate lifestyle and dietary changes. Insulin therapy is the preferred treatment of pregnant women with gestational diabetes or type 2 diabetes who fail to achieve adequate blood glucose control with dietary or lifestyle (for example, exercise, weight reduction) changes alone.

With the exception of glyburide, all sulfonylureas are classified as FDA pregnancy risk category C (risk not ruled out).

  • Meglitinides, TZDs also are classified as FDA pregnancy risk category C.
  • Glyburide, metformin, DPP-4 inhibitors, α-glucosidase inhibitors, colesevelam, and bromocriptine are categorized as pregnancy risk category B (no risk in animal studies).
  • To prevent fetal harm, use of oral diabetes medications should be avoided during pregnancy if possible.

Oral diabetes drugs can enter the breast milk and can cause hypoglycemia in the newborn. Therefore, careful risk and benefit analysis should be made for each mother and her infant before a decision is made. Use of oral diabetes medications in nursing mothers should be avoided if possible.

REFERENCE: FDA Prescribing Information.

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Reviewed on 12/5/2017
References
REFERENCE: FDA Prescribing Information.

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