Tolbutamide and Lisinopril: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Tolbutamide
Lisinopril
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Tolbutamide is a diabetes pill that lowers your blood sugar, and lisinopril is a blood pressure medicine. When they are taken together, your blood sugar may drop a little lower than usual. That could mean signs of low blood sugar like shakiness, sweating, dizziness, or feeling hungry or confused.
The good news is that this concern is mostly theoretical, and it is easy to manage. Your care team can simply check your sugar a bit more often and adjust your dose if needed. Please don't stop either medicine on your own. Just let your pharmacist or doctor know so they can keep an eye on things and keep you feeling well.
Effect: Possible additive risk of hypoglycemia when the ACE inhibitor lisinopril is combined with the sulfonylurea tolbutamide. Neither drug requires bioactivation here, so the concern is a pharmacodynamic enhancement of glucose lowering, not an altered clearance.
- Direction: Increased hypoglycemic effect.
- Mechanism: Unknown; theoretical.
- Evidence: Weak/theoretical. A self-controlled case series found no increase in serious hypoglycemia with ACE inhibitors plus insulin secretagogues, with glimepiride a possible exception.
- Onset: Unspecified.
- Management: More frequent glucose monitoring during therapy and after ACE inhibitor withdrawal; individualize antidiabetic dosing as needed.
What happens
An increased risk of hypoglycemia
Interaction Deep Dive
Taking ACE inhibitors together with antidiabetic medications can heighten the likelihood of hypoglycemia231. When their combined use cannot be avoided, glucose levels should be checked more often, throughout therapy as well as following discontinuation of the ACE inhibitor4. Modifications to the insulin dose might likewise become necessary23. Findings from a self-controlled case series indicate that pairing ACE inhibitors with insulin secretagogues does not correlate with a rise in serious hypoglycemia events, though glimepiride may represent an exception5.
Why it happens (mechanism)
Unknown
How to manage this interaction
Keep taking both medications as prescribed. This combination can usually be used safely with a little extra attention.
- Check your blood sugar more often, especially when you first start or stop the lisinopril.
- Learn the signs of low blood sugar (shakiness, sweating, dizziness, hunger, confusion) and how to treat it quickly.
- Your tolbutamide dose may need to be adjusted and individualized by your care team based on your readings.
Talk with your pharmacist or prescriber before making any changes, and share your glucose logs so they can tailor your treatment.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) In a self-controlled case series, Medicare claims records from 5 states covering 1999 to 2011 were reviewed for the combined use of ACE inhibitors together with insulin secretagogues (glimepiride, glipizide, glyburide, nateglinide, and repaglinide) or metformin (negative control). The endpoint assessed was hospital presentation for serious hypoglycemia. During the observation period, the counts of serious hypoglycemic events were 8159, 14,353, 11,129, 1595, 2901, and 32,639 for glimepiride, glipizide, glyburide, nateglinide, repaglinide, and metformin, respectively. The confounder-adjusted rate ratio (RR) was not significantly increased with glipizide, glyburide, repaglinide, or metformin, but was slightly increased with glimepiride (RR, 1.23; 95% CI, 1.11 to 1.37) and slightly decreased with nateglinide (RR, 0.73; 95% CI, 0.56 to 0.96). Apart from glimepiride, these findings indicate that concurrent use of an ACE inhibitor and insulin secretagogues was not linked to a greater risk of serious hypoglycemia 5.
Common questions
Can I take Tolbutamide and Lisinopril together?
Taking tolbutamide with lisinopril may slightly increase the chance of low blood sugar, so monitor your glucose more closely and let your care team adjust your dose if needed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Tolbutamide and Lisinopril interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Tolbutamide and Lisinopril interaction managed?
Keep taking both medications as prescribed. This combination can usually be used safely with a little extra attention. Check your blood sugar more often, especially when you first start or stop the lisinopril. Learn the signs of low blood sugar (shakiness, sweating, dizziness, hunger, confusion) and how to treat it quickly. Your tolbutamide dose may need to be adjusted and individualized by your c… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Tolbutamide or Lisinopril need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there anything you'd monitor while I'm on both?
References (5)
- Product Information: Zestril(R) oral tablets, lisinopril oral tablets. AstraZeneca Pharmaceuticals LP (per FDA), Wilmington, DE, 2014. DailyMed
- Product Information: TOUJEO(R) subcutaneous injection, insulin glargine subcutaneous injection. sanofi-aventis (per manufacturer), Bridgewater, NJ, 2015. DailyMed
- Product Information: AFREZZA(R) oral inhalation powder, insulin human oral inhalation powder. MannKind Corporation(TM) (per manufacturer), Danbury, CT, 2014. DailyMed
- Product Information: AMARYL(R) oral tablets, glimepiride oral tablets. Sanofi-Aventis U.S. LLC (per FDA), Bridgewater, NJ, 2013. DailyMed
- Hee Nam Y, Brensinger CM, Bilker WB, et al: Angiotensin-converting enzyme inhibitors used concomitantly with insulin secretagogues and the risk of serious hypoglycemia. Clin Pharmacol Ther 2022; 111(1):218-226. PubMed
Keep reading about Tolbutamide
Keep reading about Lisinopril
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