Glitazones

Technically known as thiazolidinediones (TZDs), the glitazones are a family of drugs used sparingly for the treatment of Type 2 diabetes mellitus. Usage was much more common years ago until concerns about side effects grew, some members of the family were banned, and warnings were applied to the drug class. Despite the fear of their adverse effects, glitazones still maintain a role in diabetes care. This article will explore both the reasons for concerns and for continued usage, with glitazone mechanisms of action and cost being factors.

What are glitazones?

Glitazones or TZDs are oral tablets taken to help control blood glucose (blood sugar) levels in Type 2 diabetes patients. Most often, they are not used as monotherapy (the only medication for diabetes), but rather are part of a regimen with antidiabetic agents. They can be added to metformin, sulfonylurea, glucagon-like peptide 1 (GLP-1), or sodium-glucose cotransporter 2 (SGLT-2) therapy. Insulin is typically not used alongside glitazones due to compounding adverse effects, such as weight gain. The glitazone drug class has dwindled to practically just one member, Actos. Rosiglitazone is rarely prescribed, and troglitazone is off the market.

RELATED: What are normal blood sugar levels?

How do glitazones work?

Rather than increasing the bodily supply of insulin, glitazones are effective for glucose control by increasing the body’s sensitivity to insulin, thereby driving glucose into cells and out of the bloodstream. Since insulin resistance (reduced insulin sensitivity) is one of the major problems in Type 2 diabetes, the glitazones’ mechanism of action makes perfect sense. Unlike other diabetic medication options, the mechanism of glitazones does not lend itself to hypoglycemia (low blood sugar) alone, but they can contribute to hypoglycemia in the setting of other medications like sulphonylureas.

Muscle, fat, and liver are all responsive to insulin and can be more responsive in the setting of glitazone therapy. Within these tissues, a glitazone drug attaches to the peroxisome proliferator-activated receptor (PPAR) triggering changes to gene transcription that impact glucose processing. Peroxisome proliferator-activated receptor-gamma (PPARɣ) is present in adipocytes (fat cells). Peroxisome proliferator-activated receptor-alpha (PPARɑ) resides in vascular, muscle, and liver cells. While Actos stimulates both PPARɣ and PPARɑ, Avandia is only a PPARɣ agonist. This likely explains their different bodily effects.

What are glitazones used for?

• Type 2 diabetes

Types of glitazones

Mixed PPARɣ and PPARɑ glitazones

Actos functions as an agonist to PPAR in multiple types of body tissues. At the adipocyte (fat cell) and myocyte (muscle cell), Actos action results in more glucose utilization. At the hepatic (liver) cell, it reduces glucose production to a small degree. Cholesterol benefits can also be realized with Actos. Low-density lipoprotein (LDL) is known as bad cholesterol and typically is unaffected by Actos, while high-density lipoprotein (HDL), the good cholesterol, levels are increased and triglycerides (another type of detrimental lipid) are decreased by this particular glitazone.

Unfortunately, when Actos activates PPAR in other tissues, negative consequences can be seen. In the kidney tubules, sodium and water retention is stimulated by all glitazones. The potential result is fluid retention, causing edema (swelling). Fluid retention is a likely contributor to the tendency for weight gain with Actos, but increased appetite due to brain PPAR activation may contribute, too. 

Actos-derived effects on the heart are not completely understood. Investigation into cardiovascular risk has ultimately shown Actos to potentially be beneficial in reducing the incidence of cardiovascular events such as myocardial infarctions (heart attacks). Any benefit toward ischemic cardiovascular disease, however, is likely offset by an elevated risk of congestive heart failure (CHF) exacerbations due to fluid retention. 

Troglitazone is another duel PPAR ligand (a molecule that binds to either PPARɣ or PPARɑ). Cases of hepatotoxicity (liver damage) and even liver failure were connected to troglitazone, leading it to be removed from the market. Despite having no history of liver toxicity and likely based on troglitazone’s legacy, the other glitazones still require liver monitoring according to the Food and Drug Administration (FDA).

Pure PPARɣ glitazone

Avandia has minimal use these days and is even difficult to obtain. The drug was severely restricted by the FDA in 2010 due to concerns regarding a heightened risk of myocardial infarction and cardiovascular death. The concerns made theoretical sense since Avandia was known to increase LDL levels oftentimes. On further evaluation, a link between Avandia and these negative outcomes was not proven, and the restrictions were eventually lifted. Nonetheless, hesitation to prescribe the drug persists among healthcare providers.

Who can take glitazones?

Can both men and women take glitazones?

The notable gender difference in glitazone usage involves bone health. Glitazones are associated with a small decrease in bone density and an increase in fracture incidence. The increased risk is more significant for women.

Can you take glitazones while pregnant or breastfeeding?

Based on limited available data from clinical trials, caution is advised before usage in pregnancy, and alternatives should be considered during breastfeeding.

Can children take glitazones?

Glitazones are not FDA approved for use in children.

Can seniors take glitazones?

Seniors taking glitazones need to be on guard for adverse effects. Higher rates of side effect risk factors, such as pre-existing low bone density and heart disease, are a reason for greater caution when seniors use a glitazone for diabetic care.

Are glitazones safe?

Black box warnings

The FDA has a black box warning on glitazones, calling attention to their propensity to cause CHF exacerbations. One should look out for shortness of breath, rapid weight gain, and edema (swelling) at possible signs of CHF.

Recalls

No glitazones are currently recalled, but for the most updated information, the FDA’s database can be searched.

Restrictions

The glitazone class of drugs is contraindicated (not to be used) in the setting of prior hypersensitivity allergic reactions to a member of the class, Type 1 diabetes mellitus, diabetic ketoacidosis, New York Heart Association (NYHA) stage 3 or 4 CHF, symptomatic CHF, or acute coronary syndrome. In addition, Avandia is contraindicated if liver enzymes are elevated over 2.5 times normal, and Actos should be avoided if there is active bladder cancer, due to a potentially small but unproven risk of bladder cancer with Actos.

Are glitazones controlled substances?

Glitazones are not listed by the Drug Enforcement Agency (DEA) as controlled substances.

Common glitazone side effects

• Weight gain

• Edema or fluid retention

• Headache or myalgia (muscle ache)

• Upper respiratory infection

• Flatulence

• Ovulation induction (which creates a potential for unplanned pregnancies)

• Shortness of breath

• Dilutional anemia (reduced red cell concentration due to fluid retention)

How much do glitazones cost?

Despite not being new to the market, glitazones can still be costly. A one-month supply of brand-name Actos can cost $750, and a similar supply of generic pioglitazone can be almost $200. These expenses can be lowered by having a SingleCare discount card.