Thiazolidinediones (TZDs), such as pioglitazone and rosiglitazone, are peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists. A well-documented and clinically significant adverse effect of this class is fluid retention. The mechanism involves the upregulation of the epithelial sodium channel (ENaC) in the renal collecting ducts, leading to increased sodium and water reabsorption. This can manifest as peripheral edema, weight gain, and hemodilution. Importantly, this side effect can exacerbate or precipitate congestive heart failure, leading to a boxed warning for this drug class.

A. Bile acid sequestrants primarily cause gastrointestinal side effects, such as constipation and bloating, not systemic fluid retention.

B. GLP-1 agonists are associated with gastrointestinal side effects (nausea, vomiting) and weight loss; they do not cause fluid retention.

D. SGLT2 inhibitors work by promoting urinary glucose excretion, which induces an osmotic diuresis, leading to fluid loss, not retention.

E. Alpha-glucosidase inhibitors act locally in the intestine to delay carbohydrate absorption, causing gastrointestinal side effects like flatulence and diarrhea.

1. American Diabetes Association. (2023). 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2023. Diabetes Care

46(Supplement1)

S140–S157. (See Table 9.2

"Drug-Specific and Patient Factors to Consider When Selecting Antihyperglycemic Treatment

" which lists "Edema/Heart Failure" as a side effect for Thiazolidinediones). https://doi.org/10.2337/dc23-S009

2. Katzung

B. G.

& Vanderah

T. W. (2021). Basic & Clinical Pharmacology (15th ed.). McGraw Hill. In Chapter 41

"Pancreatic Hormones & Antidiabetic Drugs

" under the section "Thiazolidinediones

" it states

"The major adverse effect of the thiazolidinediones is fluid retention

which presents as a mild anemia and peripheral edema."

3. Nesto

R. W.

Bell

D.

Bonow

R. O.

Fonseca

V.

et al. (2003). Thiazolidinedione use

fluid retention

and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Circulation

108(23)

2941-2948. (See "Pathophysiology of Fluid Retention" section

which details the renal mechanism). https://doi.org/10.1161/01.CIR.0000103549.88423.75