require a black box label was lifted based on no evidence of increased ischemic cardiovascular risk. Consequently, the remaining glitazone, pioglitazone (Actos), is not a popular noninsulin hyperglycemic agent in this category because of concerns related to side effects and adverse events (Hickson et al., 2019). Mechanism of action Thiazolidinediones enhance insulin’s effect in skeletal muscle, adipose tissue, and the liver. They are sometimes referred to as insulin sensitizers and work by decreasing insulin resistance. Insulin resistance decreases pancreatic beta-cell function by causing compensatory hyperinsulinemia, causing beta-cell lipotoxicity, and increasing islet cell inflammation (Lebovitz, 2017). Specifically, thiazolidinediones stimulate a group of peroxisome proliferator-activated receptors (PPAR) mainly thiazolidinediones. It is likely related to the activation of the peroxisome proliferator-activated receptors (PPAR) in adipose tissue, increasing deposition, and, in the kidney, retention of salt and water. Edema, fluid retention, and weight gain are problematic with coexisting chronic heart failure (Capoccia & Odegard, 2022). Therefore, the use of thiazolidinediones is contraindicated in patients with New York Heart Association (NYHA) Class III or IV heart failure or any patients with symptomatic heart failure. While small numbers of patients receiving pioglitazone (Actos) have reported an incidence of bladder cancer, the inconsistency of findings and limitations associated with study designs prohibit the use of pioglitazone (Actos) in patients with active or a history of bladder cancer (White, 2022). In addition, pioglitazone (Actos) and rosiglitazone (Avandia) have different effects on lipid profiles. Pioglitazone (Actos) has a higher affinity for PPAR, with more significant improvements in lipid profile (e.g., reduction of triglycerides, increase in high-density lipoprotein cholesterol [HDL-C], and neutral effect on low-density lipoprotein cholesterol Side effects Weight gain is the most common side effect of [LDL-C]). On the other hand, Rosiglitazone (Avandia) raises LDL-C levels with a reduction in triglycerides and an increase in HDL-C (Capoccia & Odegard, 2022). Dosing of thiazolidinediones Available strengths, starting doses, and titrating doses for thiazolidinediones are displayed in Table 3. Rosiglitazone (Avandia) and pioglitazone (Actos) act within one to two hours after administration and are administered once daily, usually in the morning, and have no risk of hypoglycemia when used
Rosiglitazone (Avandia) and pioglitazone (Actos) are two thiazolidinediones that are currently on the market in the U.S. Both have similar glucose-lowering effects with positive effects on pancreatic beta cells.
found in adipose tissue and muscle, liver, and pancreatic cells. Thiazolidinediones increase glucose uptake in muscle tissue by reducing circulating free fatty acid levels. Thiazolidinediones do not exert an effect on the pancreas; thus, circulating insulin levels do not increase. The use of thiazolidinediones decreases insulin levels because as they reduce insulin resistance, glucose decreases, and the pancreas secretes less insulin (Capoccia & Odegard, 2022). Another side effect associated with the use of thiazolidinediones is an increased risk of bone fractures. Over the past 15 years, study findings related to several large, randomized control trials (RCTs) found an increased risk of limb fractures in the first year of treatment that persisted throughout the trials (Capoccia & Odegard, 2022; Lebovitz, 2017). Most data suggest an increased risk of limb fractures in older women. However, men and younger patients may be susceptible as well. Thus, thiazolidinediones should not be used in patients at risk for fractures (Capoccia & Odegard, 2022). There is no evidence of hepatotoxicity when taking rosiglitazone (Avandia) or pioglitazone (Actos). However, because of the association between troglitazone (Rezulin) and liver toxicity, patients treated with thiazolidinediones need to have their liver function checked before initiating therapy and periodically thereafter. In addition, the 2022 Standards of Medical Care by the American Association of Diabetes (ADA) and the consensus report by the ADA and the European Association for the Study of Diabetes (EASD) encourage healthcare providers to balance the effects of using an insulin sensitizer against possible side effects of weight gain, bone fractures, fluid retention, and congestive heart failure (Davies et al., 2022; ElSayed et al., 2023a). alone. The therapeutic effects of thiazolidinediones may not be apparent for several weeks or months following initiating or changing dosages. When taken with other noninsulin antihyperglycemic agents, thiazolidinediones can heighten hypoglycemic effects.
Table 3: Noninsulin Antihyperglycemic Agents: Thiazolidinediones Thiazolidinedione
Available Strengths
Starting Dose
How to Titrate Dose
Dosage Range
Generic Name (Trade Name) Rioglitazone (Avandia) Rosiglitazone (Actos)
• 2 mg • 4 mg
• 2 mg/daily.
• 2 mg every 1–2 weeks.
• 2–8 mg/daily (maximum dose: 8 mg/daily).
• 15 mg • 30 mg • 45 mg
• 15 mg/daily.
• 15 mg every 3–4 weeks.
• 15–45 mg/daily (maximum dose: 45 mg/daily).
● Take this medication at the same time every day. ● Thiazolidinediones may increase blood pressure and worsen heart failure.
Key points for patients taking a thiazolidinediones: ● Thiazolidinediones may cause your body to hold onto fluids—if you gain weight, get short of breath, or get swollen ankles, tell your doctor and nurse. Meglitinides are like sulfonylureas and are referred to as glinides or nonsulfonylurea secretagogues. In the early 1990s, two new hypoglycemia agents, nateglinide (Starlix) and repaglinide
MEGLITINIDES
(Prandin), were shown to have stimulatory effects on insulin secretion.
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