Can any antiretroviral (Anti-Retroviral) drugs cause Diabetes Insipidus?

Antiretroviral Drugs and Diabetes Insipidus

No, antiretroviral drugs do not cause diabetes insipidus (DI) as a recognized class effect, but the specific combination of tenofovir plus didanosine has been documented to cause nephrogenic diabetes insipidus through proximal tubular dysfunction. This is a critical distinction from diabetes mellitus (hyperglycemia), which is a well-established complication of antiretroviral therapy, particularly with protease inhibitors.

Key Distinction: Diabetes Insipidus vs. Diabetes Mellitus

The available guidelines focus extensively on diabetes mellitus (hyperglycemia) as a metabolic complication of antiretroviral therapy, not diabetes insipidus 1, 2. These are entirely different conditions:

• Diabetes mellitus: Characterized by hyperglycemia, insulin resistance, and is commonly associated with protease inhibitors and certain NRTIs 1
• Diabetes insipidus: Characterized by inability to concentrate urine, leading to polyuria and polydipsia, which is not a recognized class effect of antiretrovirals

Documented Cases of Diabetes Insipidus

Tenofovir + Didanosine Combination

The only well-documented antiretroviral-related cause of diabetes insipidus is the combination of tenofovir disoproxil fumarate with didanosine, which causes nephrogenic diabetes insipidus through Fanconi syndrome and proximal tubular dysfunction 3.

• Patients present with polydipsia, polyuria, weight loss, anorexia, and wasting 3
• This is an uncommon but well-documented complication requiring continued monitoring for renal toxicity 3
• The mechanism involves direct renal tubular toxicity, not a metabolic effect 3

Other Rare Causes

• Central diabetes insipidus in HIV patients is typically related to opportunistic infections (toxoplasmosis, cryptococcal meningitis, CMV encephalitis) affecting the hypothalamus/pituitary, not the antiretroviral drugs themselves 4
• Drug-induced nephrogenic DI from other medications (lithium, foscarnet, clozapine) is documented, but antiretrovirals are not listed among common causes 5

Clinical Pitfalls to Avoid

Do not confuse the polyuria/polydipsia symptoms of hyperglycemia (diabetes mellitus) with diabetes insipidus. The guidelines repeatedly mention monitoring for "polydipsia, polyphagia, and polyuria" as warning signs of hyperglycemia, not diabetes insipidus 1, 2, 6.

• Hyperglycemia from protease inhibitors or integrase inhibitors (dolutegravir) presents with similar urinary symptoms but is fundamentally different 1, 2, 6
• Check fasting glucose and hemoglobin A1c to distinguish diabetes mellitus from diabetes insipidus 1, 2
• If true diabetes insipidus is suspected (normal glucose, dilute urine, high serum osmolality), consider the tenofovir-didanosine combination or CNS opportunistic infections 3, 4

Monitoring Recommendations

If using tenofovir with didanosine (now rarely prescribed):

• Monitor renal function closely for proximal tubular dysfunction 3
• Assess for signs of Fanconi syndrome (hypophosphatemia, glycosuria, proteinuria) 3
• Discontinue the offending combination if nephrogenic diabetes insipidus develops 3

For routine antiretroviral therapy monitoring (focused on diabetes mellitus, not insipidus):

• Fasting glucose at baseline and within 4-6 weeks of starting therapy 1
• Fasting glucose every 3-4 months during the first year of protease inhibitor therapy 1, 2
• Hemoglobin A1c every 6 months for patients with diabetes mellitus 1