Does hydrochlorothiazide (HCTZ) increase blood sugar levels?

Hydrochlorothiazide and Blood Sugar Effects

Yes, hydrochlorothiazide does increase blood sugar levels, with evidence showing it can cause both hyperglycemia in non-diabetic patients and worsen glycemic control in diabetic patients. 1, 2

Mechanism and Evidence

Hydrochlorothiazide (HCTZ) has well-documented effects on glucose metabolism:

• The FDA drug label explicitly states that "latent diabetes mellitus may become manifest and diabetic patients given thiazides may require adjustment of their insulin dose" 1

• In the ALLHAT study, diabetes incidence after 4 years was 11.8% with chlorthalidone therapy (a thiazide similar to HCTZ) compared to 9.6% with amlodipine and 8.1% with lisinopril 2

• The American Diabetes Association recognizes that thiazide diuretics can exacerbate hyperglycemia, noting that "a person treated with thiazides who develops diabetes years later probably has type 2 diabetes that is exacerbated by the drug" 2

Magnitude of Effect

The hyperglycemic effect varies based on dosage and duration:

• Meta-analysis data shows HCTZ increases fasting plasma glucose by an average of 0.27 mmol/L (4.86 mg/dL) compared to non-thiazide agents or placebo 3

• Dose-dependent relationship:

  • Lower doses (≤25 mg daily): Smaller increases in blood glucose (0.15 mmol/L or 2.7 mg/dL) 3
  • Higher doses (>25 mg daily): Larger increases in blood glucose (0.60 mmol/L or 10.8 mg/dL) 3

• The European Working Party on Hypertension in the Elderly found that after 2 years of treatment, HCTZ increased fasting blood sugar by an average of 9.6 mg/dL compared to a 3.1 mg/dL decrease in the placebo group (p<0.001) 4

Mechanism of Hyperglycemia

The hyperglycemic effect appears to be related to:

• Potassium depletion: Studies show impaired glucose tolerance is most marked in patients who experience decreases in serum potassium 5, 4

• Insulin resistance: Thiazides may reduce peripheral insulin sensitivity 6

Clinical Implications

For patients with or at risk for diabetes:

• Patients with diabetes may require adjustment of their antidiabetic medications when starting HCTZ 1

• Patients at risk for developing diabetes (obesity, family history, metabolic syndrome) should be monitored closely when taking HCTZ 2

• The Joint National Committee (JNC) guidelines note that "some reports have described an increased degree of sexual dysfunction when thiazide diuretics, particularly at high doses, are used" 2

Management Recommendations

When prescribing HCTZ:

• Use the lowest effective dose (12.5-25 mg) to minimize hyperglycemic effects 2, 3

• Monitor blood glucose regularly, especially in patients with diabetes or at risk for diabetes 2

• Consider alternative antihypertensives in patients with diabetes or prediabetes, such as ACE inhibitors or ARBs 2

• If HCTZ is necessary in diabetic patients, closer monitoring of blood glucose and potential adjustment of antidiabetic medications may be required 1

Key Takeaways

1. HCTZ definitively increases blood sugar levels, with effects being dose-dependent
2. The hyperglycemic effect is likely mediated through potassium depletion
3. Lower doses (≤25 mg) have less impact on glucose metabolism
4. Patients with diabetes or at risk for diabetes require careful monitoring when taking HCTZ