If you decide to go on an anti-diabetic medication you should discuss this important question with your physician: Why has the doctor chosen a certain drug and what are its advantages and disadvantages, including all of the possible side-effects?

Which Anti-Diabetic Medication and Why?

In choosing anti-diabetic medications, I focus on treating Insulin Resistance — the root cause of Type 2 diabetes — first and foremost. Therefore, I primarily utilize those anti-diabetic drugs which help to treat insulin resistance.

Here is a list of commonly prescribed anti-diabetic medications in the U.S.A., listed by their brand as well as generic names, followed by more detailed and specific information about their benefits and side-effects.

List Of Anti-Diabetic Medications  

*Glucagon is a hormone produced by the alpha cells of the pancreas. It increases blood glucose.

Combination Anti-Diabetic Medications

Please note that I discuss only the main clinical points about these anti-diabetic medications, primarily based on my clinical experience. The description may not include every possible side-effect of the drug, for which you may want to consult your physician or surf it on the internet.

Glucophage, Fortamet, Glumetza, Riomet

(Generic: Metformin)

Metformin was released for use in the U.S. in 1994 under the brand name Glucophage, although it had been in use in other parts of the world for many years. Now, Metformin is also available under several other brand names such as Fortamet, Glumetza, and Riomet.

Mechanism of Action

Metformin primarily acts by reducing insulin resistance at the level of the liver. Normally, the liver is actively producing glucose during the night when you are asleep and this phenomenon is exaggerated in Type 2 diabetic patients. Now you understand why you may wake up with high blood glucose even though you didn’t eat anything overnight. Metformin reduces this excess glucose production by the liver and helps to lower your morning blood glucose.

Benefits Of Metformin

• By itself, Metformin does not cause low blood glucose.
• Metformin modestly reduces serum triglycerides.
• It also causes some weight loss.
• Metformin may reduce the risk of pancreatic cancer. It was shown in an excellent study, from University of Texas M.D. Anderson Cancer Center in Houston, researchers observed that patients with Type 2 diabetes who were treated with insulin were 5 times more likely to develop pancreatic cancer compared to those who did not use insulin. On the other hand, patients who were on Metformin had a 62% lower risk for developing pancreatic cancer.¹

Side-Effects Of Metformin

• Nausea, abdominal upset, and diarrhea are fairly common side effects due to Metformin.
• A metallic taste in mouth.
• Deficiency of vitamin B12. In my experience, this is a common side effect. Vitamin B12 deficiency can cause tingling and numbness in the feet and hands, forgetfulness, low blood count , and an increase in homocysteine levels, which is a risk factor for heart disease and stroke. Therefore, it is a good idea to check your vitamin B12 level. If the level is low, start taking vitamin B12.
• A serious but rare side effect of Metformin is lactic acidosis. This can occur if Metformin is used in patients with kidney failure, liver disease, heart failure, emphysema, or shock. Lactic acidosis carries a high mortality rate. Therefore, Metformin should not be used in the above mentioned conditions.

Why Stop Metformin Before a CT san?

You should withhold metformin for twenty-four hours after a procedure involving administration of a dye, such as a coronary angiogram or CT scan. The rational for this precaution is that you may develop kidney failure after these types of procedures. If metformin is continued in the presence of kidney failure, you can develop lactic acidosis. A blood test for kidney function (serum creatinine) should be performed twenty-four hours after the procedure. You can resume metformin if this test is normal.

Actos  (Generic: Pioglitazone)

Actos (pioglitazone) belongs to the class of drugs known as TZD (short for thiazolidinedione) drugs. This anti-diabetic medication was released in the U.S. in 1999.

Mechanism Of Action

Actos (pioglitazone) treats insulin resistance at the level of muscles and fat, which are the two most important sites where insulin resistance takes place.  In addition, it also modestly reduce insulin resistance in the liver, which is the third site of insulin resistance.  As a result of reduction in insulin resistance, your body’s own insulin becomes more efficient in lowering blood glucose.

Actos (pioglitazone) has a slow onset of action. You do not see any significant effect on blood glucose during the first two weeks of therapy. You will see its peak effect at three to four months of treatment.

Benefits Of Actos (Pioglitazone)

• Actos (pioglitazone) does not cause low blood glucose.
• Unlike older drugs such as glyburide or glipizide, Actos (pioglitazone) doesn’t stress your insulin-producing cells. Therefore, you continue to have a good control of diabetes for a long period of time and don’t end up on insulin.
• In addition to controlling blood glucose, Actos (pioglitazone) has beneficial effects on lipids. For example, it lowers serum triglycerides and raises HDL (good) cholesterol.
• Narrowing of the blood vessels (atherosclerosis) is common in diabetics. That is why you are at a high risk for heart attack, stroke, dementia, and leg amputation. Actos (pioglitazone) can reduce this narrowing of the blood vessels. This extraordinary effect is unique to Actos. In an excellent study published in the prestigious Journal of Clinical Endocrinology and Metabolism, researchers observed a reduction in the thickness of the carotid artery wall in diabetic patients treated with pioglitazone.²
• Diabetic patients have a high level of a substance called PAI-1 (Plasminogen Activator Inhibitor-1). This abnormality places you at risk for clot formation. Actos (pioglitazone) decreases the level of PAI-1 and therefore can prevent heart attack and stroke.

Side-effects Of Actos ( Pioglitazone)

• Some people can have ankle swelling and gain weight while on Actos (pioglitazone). This happens primarily due to retention of water. If you already have congestive heart failure (weak heart), Actos can be problematic, as it can worsen your heart failure. Therefore, it is contraindicated in patients with moderate to severe congestive heart failure. Additionally, Actos (pioglitazone) can cause congestive heart failure even if you did not have it before. Therefore, while on Actos (pioglitazone), you should watch out for any signs of congestive heart failure, which includes shortness of breath, ankle swelling, and excessive weight gain.

• A decrease in bone density in some women, which increases the risk of fracture.

• Some individuals may develop macular edema in the eyes.

• Occasional liver toxicity.

Does Actos (pioglitazone) cause an increased risk of urinary bladder cancer?

Some layman press makes it sound like there is a strong association between Actos (pioglitazone) and urinary bladder cancer risk. What is the truth? Let’s look at the study that is at the root of all of this confusion. This study (3) is from Kaiser Permanente Northern California (KPNC) pharmacy database, published in Diabetes Care in 2011. In my opinion, the study was poorly designed. First of all, it is a retrospective study. Like other retrospective studies, it suffers from the investigator’s bias. For example, significantly more people in the Pioglitazone-group were smokers, a very well-known risk factor for urinary bladder cancer. Many more Pioglitazone treated patients were also on insulin and sulfonylurea drugs than the non-Pioglitazone group. Despite all of these biases, the authors themselves concluded the following:

“In this cohort of patients with diabetes, short-term use of pioglitazone was not associated with an increased incidence of bladder cancer, but use for more than 2 years was weakly associated with increased risk.”

Those findings were based on the interim analysis of the data. However, the final results of the study did not show any evidence between Actos and risk for bladder cancer.

Starlix (Generic: Nateglinide)

Prandin (Generic: Repaglinide)

Starlix (nateglinide) and Prandin (repaglinide) act by stimulating the pancreas to produce more insulin. These anti-diabetic medications do not treat insulin resistance, the underlying disease process of Type 2 diabetes.

The action of Starlix (nateglinide) and Prandin (repaglinide) lasts for four to six hours. Therefore, Starlix (nateglinide) or Prandin (repaglinide) should be taken with a meal.

Benefits Of Starlix and Prandin

• Starlix (nateglinide) and Prandin (repaglinide) are short acting drugs taken only with meals. Therefore, the potential for low blood glucose (hypoglycemia) is low. For  instance, if you don’t eat for some reason, you don’t take Prandin (repaglinide) or Starlix (nateglinide). In this way, you won’t risk hypoglycemia. In comparison, if a patient is on a sulfonylurea drug (which has a long duration of action), skipping a meal can lead to an episode of hypoglycemia.

• Prandin (repaglinide) is useful in patients who have kidney failure, because it is not excreted through the kidneys. Therefore, it does not accumulate in the body in patients with kidney failure

Side-effects Of Starlix and Prandin

• Prandin (repaglinide) and Starlix (nateglinide) are usually taken three times a day. Some patients may forget to take them properly.

• Although rare, Prandin (repaglinide) and Starlix (nateglinide) can cause low blood glucose (hypoglycemia.)

Byetta, Bydureon (Generic: Exenatide)

Victoza (Generic: Liraglutide)

Trulicity (Generic: dulaglutide)

Byetta (exenatide), Victoza (liraglutide) and Trulicity (dulaglutide) are similar drugs. These anti-diabetic medications act by mimicking a chemical in our body known as GLP-1 (glucagon-like peptide-1).

Mechanism Of Action

Byetta (exenatide), Victoza (liraglutide) and Trulicity (dulaglutide) have several actions that include:

• Insulin production from the pancreas in response to food.

• Decrease in glucose output from the liver.

• Slow emptying of the stomach. Consequently, food moves slowly from the stomach to the intestines, where absorption of food into the blood takes place. Thus, there is a slow rise in blood glucose after a meal.

However, these anti-diabetic medications do not treat insulin resistance, the underlying disease process of of Type 2 diabetes.

Benefits Of Byetta (exenatide), Victoza (liraglutide) and Trulicity (dulaglutide)

• These anti-diabetic drugs are particularly helpful to control the sharp rise in glucose after meals.
• Potential weight loss is another benefit.

Side-effects Of Byetta (exenatide), Victoza (liraglutide) and Trulicity (dulaglutide)

• Nausea and vomiting, diarrhea, feeling jittery, dizziness, headache, acid stomach, constipation, and weakness are common side effects.
• Increased risk of acute pancreatitis.
• In animal studies, these anti-diabetic drugs caused thyroid tumors and even cancer, called medullary thyroid cancer (MTC.)

Caution

Because Byetta (exenatide), Victoza (liraglutide) and Trulicity (dulaglutide) slow down stomach emptying, they may reduce the absorption of other orally administered drugs, such as antibiotics and contraceptives. Therefore, take your birth control pills or antibiotics at least one hour before these anti-diabetic medications. In addition, these drugs can interfere with the blood thinner, Coumadin. Therefore, monitor your INR (International Normalized Ratio) more frequently while on these anti-diabetic drugs.

In addition, these anti-diabetic medications can worsen gastroparesis in diabetic patients. What is  gastroparesis? It is a condition that results from the effects of diabetes on the nerves that control the emptying of the stomach. Symptoms of gastroparesis include bloating of stomach after meals.

Januvia (Generic: Sitagliptin)

Onglyza (Generic:Saxagliptin)

Tradjenta (Generic: Linagliptin)

Nesina (Generic: Alogliptin)

These anti-diabetic medications are called DPP-4 inhibitors or “gliptins.” These drugs act by inhibiting an enzyme, called DPP4 (Dipeptidyl peptidase-4.)  As a result, there is an increase in insulin release from the beta-cells of the pancreas in response to food.

In addition, there is a decrease in glucose output from the liver due to a decrease in the Glucagon level.

However, these anti-diabetic medications do not treat insulin resistance, the underlying disease process of Type 2 diabetes.

Benefits Of DPP-4 Inhibitors

• DPP4 inhibitors are particularly helpful in controlling the sharp rise in glucose after meals

Side-effects Of DPP-4 Inhibitors

• Common side effects of these anti-diabetic drugs include upper respiratory tract infections (common colds) and headaches.

• Also there may an increased risk for acute pancreatitis.

Caution about DPP-4-Inhibitors

• DPP-4 inhibitors can cause an increase in the blood level of digoxin. Therefore, if you take digoxin, make sure to have your blood level of digoxin checked on a regular basis. Your dose of digoxin will be adjusted accordingly by your physician.

• The dose of DPP-4 inhibitors needs to be decreased in patients with chronic kidney failure of moderate and severe degree. However Tradjenta (generic: linagliptin) is an exception that its dose does not need to be decreased in patients with chronic kidney disease.

Amaryl (Generic: Glimepiride)

Glucotrol (Generic: Glipizide)

Micronase(Generic: Glyburide)

Diabeta (Generic: Glyburide)

Glynase (Generic: Glyburide)

These anti-diabetic drugs are called sulfonylurea agents. Before 1994, these were the only oral drugs available in the U.S. for the treatment of Type 2 diabetes. These anti-diabetic medications stimulate the pancreas to produce more insulin. Their effect usually lasts for about twenty-four hours. However, in patients with kidney failure, their effect can last up to two to three days.

However, these anti-diabetic medications do not treat insulin resistance, the underlying disease process of Type 2 diabetes.

Benefits of Sulfonylurea drugs

These anti-diabetic drugs start working immediately and are very effective in lowering blood glucose in the short term.

Side-effects Of Sulfonylurea drugs

Low blood Sugar (hypoglycemia)

Precose (Generic: Acarbose)

Glyset (Generic: Miglitol)

Precose (acarbose) and Glyset (miglitol) act by decreasing glucose absorption from the intestine after eating a meal. These drugs are particularly useful if you tend to have high blood glucose levels after your meals. However, these are weak drugs to control blood glucose levels.

However, these anti-diabetic medications do not treat insulin resistance, the underlying disease process of Type 2 diabetes.

Benefits of Precose (acarbose) and Glyset (miglitol)

• Precose (acarbose) and Glyset (miglitol), by themselves, do not cause low blood glucose levels (hypoglycemia).

• Precose (acarbose) and Glyset (miglitol) can help to control post-meal rises in blood glucose levels.

Side-effects of Precose (acarbose) and Glyset (miglitol)

While on these diabetic medications, patients frequently experience gastrointestinal side effects, such as flatulence, diarrhea, and abdominal pain. Even liver toxicity can develop, especially with larger doses.

Caution about Precose (acarbose) and Glyset (miglitol)

Liver function tests should be done every two to three months if you are on Precose (acarbose) or Glyset (miglitol).

Invokana (Canagliflozin)

Farxiga (Dapagliflozin)

Jardiance (Empagliflozin)

These drugs work through your kidneys through a similar mechanism of action. They inhibit sodium-glucose co-transporter2 (SGLT2) in the kidneys. That’s why Invokana (Canagliflozin), Farxiga (Dapagliflozin), and Jardiance (Empagliflozin) are popularly called SGLT-2 inhibitors. As a result, excess glucose is dumped through your urine.

However, these anti-diabetic medications do not treat insulin resistance, the underlying disease of Type 2 diabetes.

Benefits of Invokana (Canagliflozin), Farxiga (Dapagliflozin), and Jardiance (Empagliflozin)

In addition to lowering of blood glucose, these anti-diabetic medications also work as a diuretic and get rid of excess water. It is a beneficial effect in those Type 2 diabetics who have a weak heart.

Side-effects of Invokana (Canagliflozin), Farxiga (Dapagliflozin), and Jardiance (Empagliflozin)

These anti-diabetic medications may cause the following side-effects:

• Dehydration
• Low blood pressure
• Increase in potassium level in the blood (which can be life-threatening)
• Kidney dysfunction
• Increase in LDL cholesterol
• Urinary tract infections
• Genital fungal infections
• Ketosis

How About Insulin For Type 2 Diabetics?

In my opinion, insulin is not a good choice for most Type 2 diabetic patients. Why? Because insulin therapy may do more harm than good. In fact, most Type 2 diabetic patients suffer from excess insulin due to insulin resistance. Injecting more insulin may control their blood glucose but it does not treat the root-cause which is insulin resistance. In addition, a large amount of insulin is not good for the body and has serious side-effects including weight gain, water retention, low blood sugar, and high risk for heart disease, stroke and cancer.

If you want to learn about various insulins, please click here: Treatment of Type 1 diabetes 

 In Summary

A wide range of anti-diabetic drugs are available to treat Type 2 diabetes. Each class of anti-diabetic medications have a different mode of action. In addition, they also have different side-effects. Hence, you and your physician should carefully choose the diabetic medications which are right for your situation. However, these anti-diabetes drugs should be part of a comprehensive plan to treat Type 2 diabetes.

New Scientific Treatment of Type 2 Diabetes

Complications of Type 2 Diabetes – How To Prevent

Diagnosis of Type 2 Diabetes

Low Blood Sugar

Insulin Resistance Syndrome

References

1. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009 Aug;137(2):482-8
2. Koshiyama H, Shimono D, et al. Inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 2001; 86(7):3452–6.
3. Lewis JD¹, Ferrara A, Peng T, Hedderson M, Bilker WB, Quesenberry CP Jr, Vaughn DJ, Nessel L, Selby J, Strom BL. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. 2011 Apr;34(4):916-22.