What does the research show about ace inhibitors?

ACE inhibitors

Pooled trials found ACE inhibitors lowered blood pressure about 8/5 mm Hg and lowered deaths in heart failure, after a heart attack and in high-risk adults. Ramipril did not prevent diabetes. Cough is the most frequent side effect, at 13.5% against 8.5% on placebo. The label carries a boxed warning about harm to the fetus.

Add to Bio HackChecked 2026-11-13

Status: Prescription drugs in the US. Lisinopril is FDA-approved for high blood pressure in adults and children 6 and older, as add-on therapy for heart failure, and after a heart attack. Approved uses differ by drug across the class. The lisinopril label carries an FDA boxed warning for harm to the fetus.
Also called: lisinopril, Zestril, Prinivil, Qbrelis, enalapril, Vasotec, Epaned, ramipril, Altace, benazepril, Lotensin, captopril, perindopril, quinapril, angiotensin converting enzyme inhibitor, ACE inhibitor, ACEi
Taken for: high blood pressure, heart failure, recovery after a heart attack, heart attack and stroke prevention, kidney protection in diabetes, kidney disease with protein in the urine, migraine prevention

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help6

StrongShown to lower blood pressure about 8/5 mm Hg in adults with high blood pressure, with no difference found between drugs in the class.
StrongShown to lower deaths by about 20 to 23% and hospital readmissions for heart failure by about a third in people with heart failure or a weakened left ventricle.
ModerateShown to lower deaths in the first 30 days after a heart attack, 7.1% against 7.6%, and more in long-term trials of people with a weakened left ventricle.
ModerateShown to lower heart attack, stroke or cardiovascular death from 12.8% to 10.7% over about 4.5 years in adults with vascular disease and no heart failure.
ModerateShown to slow kidney function loss in people with diabetic kidney disease and in non-diabetic kidney disease with protein in the urine.
LimitedOne small crossover trial found lisinopril lowered days with migraine by 21% against placebo in adults with 2 to 6 attacks a month.Very common

Reported risks14

StrongShown to raise cough, reported by 13.5% on an ACE inhibitor against 8.5% on placebo across 22 trials.Very common
ModerateShown to raise high potassium, low blood pressure and kidney failure when an ACE inhibitor is combined with an ARB or aliskiren, with no fewer deaths.Very common
ModerateShown to raise low blood pressure and dizziness, most often in heart failure and soon after a heart attack.Common
ModerateShown to raise blood potassium, above 5.7 mEq/L in 2.2% of people treated for high blood pressure and 4.8% treated for heart failure.Common
ModerateShown to raise creatinine in some people, with kidney dysfunction in 2.4% on lisinopril against 1.1% of controls after a heart attack.Common
ModerateShown to raise angioedema, swelling of the face, tongue or throat, to 0.30% against 0.07% on placebo. The label reports a higher rate in Black patients.Uncommon
LimitedLinked to hospital admission for high potassium and to sudden death in adults over 65 on an ACE inhibitor or ARB given this antibiotic.Uncommon
LimitedFDA states that drugs acting on the renin-angiotensin system can cause injury and death to the developing fetus.How often is not known
LimitedThe label warns of a syndrome that starts with jaundice or hepatitis and can progress to liver failure and death. It gives no rate.How often is not known
LimitedLinked to more acute kidney injury when an NSAID is taken with both a diuretic and an ACE inhibitor or ARB, about 31% higher in one cohort.How often is not known
LimitedThe label warns that potassium-sparing diuretics, potassium supplements and potassium salt substitutes raise the risk of high blood potassium on an ACE inhibitor.How often is not known
LimitedLinked to lithium toxicity, with hospital admission about 7.6 times as likely in the month after an older adult on lithium started an ACE inhibitor.How often is not known
LimitedThe label warns that an ACE inhibitor taken with insulin or oral diabetes drugs may lower blood sugar further. It gives no rate.How often is not known
LimitedLinked to slightly more lung cancer than ARBs in observational studies, 1.6 against 1.2 cases per 1,000 person-years. Pooled trials found no rise in cancer overall.How often is not known

What people take it for, and what was found

Shown to help6

Strong

Lowering blood pressure

Shown to lower blood pressure about 8/5 mm Hg in adults with high blood pressure, with no difference found between drugs in the class.

The numbers and sources

Effect: Across 92 placebo-controlled trials of 14 ACE inhibitors, doses of half the maximum or more lowered trough blood pressure by about 8 mm Hg systolic and 5 mm Hg diastolic. One eighth to one quarter of the maximum dose gave 60 to 70% of that effect, and doses above the maximum did not lower blood pressure further. No one ACE inhibitor lowered blood pressure more than another [1]. A separate analysis of 354 trials found thiazides, beta-blockers, ACE inhibitors, ARBs and calcium channel blockers produced similar reductions, on average 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose [2].
Population: 12,954 adults with primary hypertension and a baseline blood pressure of 157/101 mm Hg, treated 3 to 12 weeks [1]; about 40,000 treated and 16,000 placebo participants in 354 trials [2].
Sources: [1], [2]
Caveats: Trials lasted 3 to 12 weeks. The lisinopril label reports a smaller blood pressure effect in Black patients than in white patients [3].

Strong

Heart failure with reduced pumping function

Shown to lower deaths by about 20 to 23% and hospital readmissions for heart failure by about a third in people with heart failure or a weakened left ventricle.

The numbers and sources

Effect: Pooling placebo-controlled trials of at least 8 weeks in symptomatic heart failure, ACE inhibitors lowered total mortality (OR 0.77, 95% CI 0.67 to 0.88) and the combination of death or hospitalization for heart failure (OR 0.65, 95% CI 0.57 to 0.74). Most data came from enalapril, captopril, ramipril, quinapril and lisinopril [4]. In individual data from 5 long-term trials, 23.0% died on an ACE inhibitor and 26.8% on placebo (OR 0.80, 95% CI 0.74 to 0.87). Readmission for heart failure occurred in 13.7% against 18.9% (OR 0.67, 95% CI 0.61 to 0.74) and reinfarction in 8.9% against 11.0% [5].
Population: Randomized placebo-controlled trials in symptomatic heart failure [4]; 12,763 people with heart failure or left ventricular dysfunction in 5 trials, followed an average of 35 months [5].
Sources: [4], [5]
Caveats: Three of the 5 long-term trials enrolled people within a week of a heart attack [5]. Both overviews were published by 2000.

Moderate

After a heart attack

Shown to lower deaths in the first 30 days after a heart attack, 7.1% against 7.6%, and more in long-term trials of people with a weakened left ventricle.

The numbers and sources

Effect: In individual data from 4 trials that started an ACE inhibitor within 36 hours of a heart attack and continued it 4 to 6 weeks, 30-day mortality was 7.1% on an ACE inhibitor and 7.6% in controls, a 7% proportional reduction (95% CI 2 to 11%). Nonfatal heart failure occurred in 14.6% against 15.2% [6]. In GISSI-3, the lisinopril trial among them, 6.4% on lisinopril and 7.2% of those not given it died by 6 weeks [3]. In 3 trials that enrolled people with heart failure or left ventricular dysfunction after a heart attack and treated them long term, 23.4% died on an ACE inhibitor and 29.1% on placebo (OR 0.74, 95% CI 0.66 to 0.83) [5].
Population: 98,496 people in 4 trials of early short-term treatment [6]; 19,394 people in GISSI-3 [3]; 5,966 people in 3 long-term trials after a heart attack [5].
Sources: [6], [3], [5]
Caveats: GISSI-3 was unblinded [3]. Persistent low blood pressure was more frequent on an ACE inhibitor in the early trials, 17.6% against 9.3% [6].

Moderate

Heart attack, stroke and death in high-risk adults without heart failure

Shown to lower heart attack, stroke or cardiovascular death from 12.8% to 10.7% over about 4.5 years in adults with vascular disease and no heart failure.

The numbers and sources

Effect: In the HOPE trial, ramipril 10 mg a day for a mean of 5 years lowered the composite of heart attack, stroke or cardiovascular death from 17.8% on placebo to 14.0% (RR 0.78, 95% CI 0.70 to 0.86). Death from any cause was 10.4% against 12.2% and stroke 3.4% against 4.9% [7]. Combining HOPE with two later trials, ACE inhibitors lowered all-cause mortality (7.8% against 8.9%), nonfatal heart attack (5.3% against 6.4%) and stroke (2.2% against 2.8%). The composite of cardiovascular death, nonfatal heart attack or stroke occurred in 10.7% against 12.8% (OR 0.82, 95% CI 0.76 to 0.88) [8]. Across 20 trials in which at least two thirds of participants had hypertension, ACE inhibitors were associated with a 10% reduction in all-cause mortality (HR 0.90, 95% CI 0.84 to 0.97) [9].
Population: 9,297 adults aged 55 or older with vascular disease, or diabetes plus one other risk factor, and no known heart failure [7]; 29,805 people in 3 trials followed a mean of about 4.5 years [8]; 158,998 people in 20 trials [9].
Sources: [7], [8], [9]
Caveats: The evidence in [7] is for ramipril. In ALLHAT, which compared drugs with each other, lisinopril did not differ from the diuretic chlorthalidone on fatal coronary disease or nonfatal heart attack (RR 0.99), and had higher 6-year rates of stroke (6.3% against 5.6%) and heart failure (8.7% against 7.7%) [10].

Moderate

Slowing kidney disease

Shown to slow kidney function loss in people with diabetic kidney disease and in non-diabetic kidney disease with protein in the urine.

The numbers and sources

Effect: In people with type 1 diabetes and kidney disease, serum creatinine doubled in 25 of 207 on captopril and 43 of 202 on placebo, a 48% reduction in risk. The combined risk of death, dialysis or transplantation fell 50% [11]. In individual data from 11 trials in mostly non-diabetic kidney disease, regimens with an ACE inhibitor lowered end-stage kidney disease (RR 0.69, 95% CI 0.51 to 0.94) and the combination of doubled creatinine or end-stage kidney disease (RR 0.70, 95% CI 0.55 to 0.88), with more benefit at higher urine protein [12]. A Cochrane review of 50 studies in diabetic kidney disease found ACE inhibitors and ARBs had similar benefits on kidney outcomes. Mortality against placebo did not differ significantly (RR 0.91, 95% CI 0.71 to 1.17) [13].
Population: 409 people with type 1 diabetes, urine protein of 500 mg a day or more [11]; 1,860 people without diabetes followed a mean of 2.2 years [12]; 13,215 people with diabetic kidney disease in 50 studies [13].
Sources: [11], [12], [13]
Caveats: The evidence in [11] is for captopril. Results were inconclusive for people with urine protein below 0.5 g a day [12].

LimitedVery common

Migraine prevention

One small crossover trial found lisinopril lowered days with migraine by 21% against placebo in adults with 2 to 6 attacks a month.

The numbers and sources

How common: Very common: more than 1 in 10 people.
Effect: Over 12-week periods, lisinopril lowered hours with headache by 20% (95% CI 5 to 36), days with headache by 17% (95% CI 5 to 30) and days with migraine by 21% (95% CI 9 to 34) against placebo. Days with migraine fell by at least half in 14 of the 47 participants with complete data [17].
Population: 60 adults aged 19 to 59 with 2 to 6 migraine episodes a month, 47 with complete data [17].
Sources: [17]
Caveats: One small trial from one clinic, of lisinopril only. Not an FDA-approved use [3].

Mixed results1

Limited

Physical function in older adults

Small trials found mixed results: perindopril raised 6-minute walking distance by 31 m in one trial and did not change physical performance in another.

The numbers and sources

Effect: Over 20 weeks, 6-minute walking distance improved by 31.4 m more on perindopril than on placebo (95% CI 10.8 to 51.9) in older adults with mobility problems [18]. Over 12 months in older adults with sarcopenia, perindopril 4 mg did not change the short physical performance battery score (difference -0.1 points, 95% CI -1.2 to 1.0) or any secondary outcome [19].
Population: 130 adults aged 65 and older with functional impairment, 95 completing [18]; 145 adults aged 70 and older with sarcopenia [19].
Sources: [18], [19]
Caveats: Both trials tested perindopril. The sarcopenia trial recruited 145 of a planned 440 people, and adherence to perindopril was lower than to placebo [19].

Not shown to help2

Moderate

Compared with ARBs

Not shown to differ from ARBs in deaths or cardiovascular events in people with high blood pressure or vascular disease. Fewer people stopped ARBs over side effects.

The numbers and sources

Effect: In 9 head-to-head trials lasting at least a year, total mortality (RR 0.98, 95% CI 0.88 to 1.10), total cardiovascular events (RR 1.07, 95% CI 0.96 to 1.19) and cardiovascular mortality (RR 0.98, 95% CI 0.85 to 1.13) did not differ between ACE inhibitors and ARBs. Withdrawals over adverse effects were lower on ARBs (RR 0.83, 95% CI 0.74 to 0.93), an absolute difference of 1.8% over 4.1 years, mainly from dry cough on ACE inhibitors [14]. In ONTARGET, the composite of cardiovascular death, heart attack, stroke or heart failure hospitalization occurred in 16.5% on ramipril and 16.7% on telmisartan (RR 1.01, 95% CI 0.94 to 1.09) [15].
Population: 11,007 people with primary hypertension in 9 trials [14]; 17,118 people with vascular disease or high-risk diabetes assigned to ramipril or telmisartan, median 56 months [15].
Sources: [14], [15]
Caveats: The Cochrane authors rated the evidence moderate for mortality and low for cardiovascular events, citing possible publication bias [14].

Limited

Preventing type 2 diabetes

One trial found ramipril did not lower new diabetes or death over 3 years in adults with raised blood sugar, 18.1% against 19.5% on placebo.

The numbers and sources

Effect: Diabetes or death occurred in 18.1% on ramipril and 19.5% on placebo (HR 0.91, 95% CI 0.81 to 1.03). More people on ramipril returned to normal blood sugar (HR 1.16, 95% CI 1.07 to 1.27). Glucose 2 hours after a glucose load was lower on ramipril (135.1 against 140.5 mg/dL), and fasting glucose did not differ significantly [16].
Population: 5,269 adults without cardiovascular disease with impaired fasting glucose or impaired glucose tolerance, median 3 years [16].
Sources: [16]
Caveats: One trial, of ramipril up to 15 mg a day.
Why limited: This rests on one trial, of 5,269 people. Strength counts independent studies that agree, so one trial is limited at any size.

Doses studied

The lisinopril label gives a starting dose of 10 mg once daily for high blood pressure and a usual range of 20 to 40 mg a day. Doses up to 80 mg were used and did not appear to give a greater effect. For heart failure the label starts at 5 mg once daily, up to 40 mg. After a heart attack, GISSI-3 gave 5 mg within 24 hours, 5 mg after 24 hours and then 10 mg daily for 6 weeks. The ATLAS heart failure trial compared 2.5 mg with 35 mg of lisinopril a day [3].

HOPE and ONTARGET used ramipril 10 mg once daily [7][15], and the diabetes prevention trial used ramipril up to 15 mg a day [16]. ALLHAT used lisinopril 10 to 40 mg a day [10]. The migraine trial used lisinopril 20 mg a day [17], and the sarcopenia trial used perindopril 4 mg a day [19].

Risks

Reported risks13

StrongVery common

Dry cough

Shown to raise cough, reported by 13.5% on an ACE inhibitor against 8.5% on placebo across 22 trials.

The numbers and sources

How common: Very common: more than 1 in 10 people.
Effect: In 22 placebo-controlled trials, cough was reported by 13.5% on an ACE inhibitor and 8.5% on placebo, so about 37% of cough reports on the drug were attributable to it. The attributable share was highest in hypertension trials (85%) and lowest in heart failure trials (29%) [22]. A network meta-analysis of 135 trials found a relative risk of cough of 2.21 against placebo (95% CI 2.05 to 2.39) and 3.2 against ARBs (95% CI 2.91 to 3.51), with similar risk across the 11 ACE inhibitors studied [23]. Across 125 trials, the pooled incidence of cough on enalapril was 11.48% and withdrawal over cough was 2.57% [24].
Population: 65,054 people with cardiovascular disease in 22 trials [22]; 45,420 people on 11 ACE inhibitors in 135 trials [23]; 198,130 people in 125 trials [24].
Sources: [22], [23], [24]
Caveats: Cough was also frequent on placebo, especially in heart failure [22]. Trial rates were several times higher than older label figures [24].

ModerateVery common

With an ARB or aliskiren

Shown to raise high potassium, low blood pressure and kidney failure when an ACE inhibitor is combined with an ARB or aliskiren, with no fewer deaths.

The numbers and sources

How common: Very common: more than 1 in 10 people.
Effect: Across 33 trials, combining two blockers of the renin-angiotensin system did not lower all-cause mortality against one (RR 0.97, 95% CI 0.89 to 1.06) and raised hyperkalemia by 55%, low blood pressure by 66% and kidney failure by 41% [26]. In ONTARGET, ramipril plus telmisartan brought more low blood pressure symptoms (4.8% against 1.7%), fainting (0.3% against 0.2%) and kidney dysfunction (13.5% against 10.2%) than ramipril alone, with no difference in cardiovascular events (16.3% against 16.5%) [15]. In people with diabetic kidney disease, lisinopril added to losartan raised hyperkalemia (6.3 against 2.6 events per 100 person-years) and acute kidney injury (12.2 against 6.7), and the trial was stopped early [27].
Population: 68,405 people in 33 trials, mean 52 weeks [26]; 17,078 people assigned to the combination or ramipril alone [15]; 1,448 people with type 2 diabetes and kidney disease [27].
Sources: [26], [15], [27]
Caveats: Hospital admissions for heart failure fell 18% on dual therapy in the pooled analysis [26]. The lisinopril label describes the same findings [3].

ModerateCommon

Low blood pressure and dizziness

Shown to raise low blood pressure and dizziness, most often in heart failure and soon after a heart attack.

The numbers and sources

How common: Common: between 1 in 100 and 1 in 10 people.
Effect: In hypertension trials of lisinopril, dizziness was 3.5 percentage points more frequent than on placebo. In heart failure trials, low blood pressure was 3.8 points more frequent than on placebo. In GISSI-3, persistent low blood pressure occurred in 9.0% on lisinopril and 3.7% of those not given it. In the ATLAS heart failure trial, the high dose brought more dizziness (19% against 12%), low blood pressure (11% against 7%) and fainting (7% against 5%) than the low dose [3]. Across 4 trials started within 36 hours of a heart attack, persistent low blood pressure occurred in 17.6% on an ACE inhibitor and 9.3% of controls [6].
Population: Lisinopril trials in hypertension and heart failure, 3,164 people in ATLAS and 19,394 in GISSI-3 [3]; 98,496 people in 4 trials [6].
Sources: [3], [6]
Caveats: The label gives the hypertension and heart failure figures as the excess over placebo, not as two rates. The band here is taken from the 9.0% in GISSI-3, and rates were higher in the pooled heart attack trials [6].

ModerateCommon

High blood potassium

Shown to raise blood potassium, above 5.7 mEq/L in 2.2% of people treated for high blood pressure and 4.8% treated for heart failure.

The numbers and sources

How common: Common: between 1 in 100 and 1 in 10 people.
Effect: In clinical trials of lisinopril, serum potassium above 5.7 mEq/L occurred in 2.2% of people with hypertension and 4.8% of people with heart failure. In ATLAS, hyperkalemia was reported in 6% on the high dose and 4% on the low dose. The label lists kidney impairment, diabetes, potassium-sparing diuretics, potassium supplements and potassium salt substitutes as risk factors [3].
Population: People in lisinopril clinical trials, including 3,164 in ATLAS [3].
Sources: [3]
Caveats: The label gives no placebo rate for these figures.

ModerateCommon

Kidney function changes

Shown to raise creatinine in some people, with kidney dysfunction in 2.4% on lisinopril against 1.1% of controls after a heart attack.

The numbers and sources

How common: Common: between 1 in 100 and 1 in 10 people.
Effect: Minor, reversible rises in blood urea nitrogen and creatinine occurred in about 2% of people with hypertension on lisinopril alone and in 11.6% of people with heart failure also taking a diuretic. In GISSI-3, kidney dysfunction, defined as creatinine above 3 mg/dL or doubled, occurred in 2.4% on lisinopril and 1.1% of those not given it. In ATLAS, raised creatinine was reported in 10% on the high dose and 7% on the low dose. The label warns that acute kidney failure can occur, particularly with renal artery stenosis, chronic kidney disease, severe heart failure or volume depletion [3].
Population: People in lisinopril clinical trials, including 19,394 in GISSI-3 and 3,164 in ATLAS [3].
Sources: [3]
Caveats: Rises were more frequent with diuretics and often resolved when the diuretic dose was lowered [3]. For the long-term effect on kidney disease, see the kidney outcome block above.

ModerateUncommon

Angioedema

Shown to raise angioedema, swelling of the face, tongue or throat, to 0.30% against 0.07% on placebo. The label reports a higher rate in Black patients.

The numbers and sources

How common: Uncommon: between 1 in 1,000 and 1 in 100 people.
Effect: Across 26 trials, the weighted incidence of angioedema was 0.30% on ACE inhibitors (95% CI 0.28 to 0.32), 0.11% on ARBs and 0.07% on placebo. In 7 head-to-head trials the risk was 2.2 times that on ARBs (95% CI 1.5 to 3.3). Incidence was higher in heart failure trials [25]. In ONTARGET, angioedema occurred in 0.3% on ramipril and 0.1% on telmisartan [15]. The label states that fatal cases have occurred, that it can happen at any time during treatment, that the rate is higher in Black than in non-Black patients, and that people taking an mTOR inhibitor such as sirolimus or everolimus, or a neprilysin inhibitor, may be at increased risk. It also describes angioedema of the intestine [3].
Population: 74,857 people on ACE inhibitors in 26 trials with 232,523 person-years of follow-up [25]; 17,118 people in ONTARGET [15].
Sources: [25], [15], [3]
Caveats: Trials of at least 100 people and 8 weeks. The label gives no rate by race [3].

LimitedUncommon

With trimethoprim-sulfamethoxazole

Linked to hospital admission for high potassium and to sudden death in adults over 65 on an ACE inhibitor or ARB given this antibiotic.

The numbers and sources

How common: Uncommon: between 1 in 1,000 and 1 in 100 people.
Effect: Among older adults on an ACE inhibitor or ARB, hospital admission with hyperkalemia within 14 days was about 7 times as likely after trimethoprim-sulfamethoxazole as after amoxicillin (adjusted OR 6.7, 95% CI 4.5 to 10.0). Other antibiotics studied showed no such rise [29]. Sudden death within 7 days was also more likely than after amoxicillin (adjusted OR 1.38, 95% CI 1.09 to 1.76), about 3 sudden deaths within 14 days per 1,000 prescriptions [30].
Population: Ontario residents aged 66 or older on an ACE inhibitor or ARB, with 4,148 hyperkalemia admissions over 14 years [29] and 39,879 sudden deaths from 1994 to 2012 [30].
Sources: [29], [30]
Caveats: Observational studies in older adults from one province. Ciprofloxacin was also associated with sudden death in the second study [30].

LimitedStudied in pregnancyHow often is not known

Boxed warning: harm to the fetus

FDA states that drugs acting on the renin-angiotensin system can cause injury and death to the developing fetus.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: The boxed warning on the lisinopril label states that drugs acting directly on the renin-angiotensin system can cause injury and death to the developing fetus. The label says use in the second and third trimesters reduces fetal kidney function and raises fetal and newborn illness and death, with low amniotic fluid, underdeveloped lungs, skull underdevelopment and kidney failure among the effects described [3]. In a review of published case reports, 52% of 118 newborns exposed to ACE inhibitors before birth had no complications. The others had kidney failure, low amniotic fluid, low blood pressure, growth restriction or death [20]. In a cohort of 29,507 infants, exposure in the first trimester alone was associated with more major congenital malformations than no exposure to blood pressure drugs (RR 2.71, 95% CI 1.72 to 4.27) [21].
Population: 118 published cases of exposure before birth [20]; 209 infants exposed in the first trimester alone among 29,507 infants without maternal diabetes [21].
Sources: [3], [20], [21]
Caveats: Case reports favor poor outcomes and give no rate [20]. The cohort finding is observational, from one US state [21].

LimitedHow often is not known

Liver failure

The label warns of a syndrome that starts with jaundice or hepatitis and can progress to liver failure and death. It gives no rate.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: The lisinopril label states that ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and sometimes death. The mechanism is not understood [3].
Population: People taking ACE inhibitors, as described in the label [3].
Sources: [3]
Caveats: No rate and no comparison group are given.

LimitedHow often is not known

With NSAIDs

Linked to more acute kidney injury when an NSAID is taken with both a diuretic and an ACE inhibitor or ARB, about 31% higher in one cohort.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: Among users of blood pressure drugs, current use of an NSAID with both a diuretic and an ACE inhibitor or ARB was associated with a higher rate of acute kidney injury (rate ratio 1.31, 95% CI 1.12 to 1.53), highest in the first 30 days (1.82, 95% CI 1.35 to 2.46). An NSAID with only one of those drugs was not associated with a higher rate. Acute kidney injury occurred at 7 per 10,000 person-years in the cohort [28]. The lisinopril label states that NSAIDs taken with ACE inhibitors may worsen kidney function in people who are elderly, volume-depleted or have impaired kidneys, and may weaken the blood pressure effect [3].
Population: 487,372 users of blood pressure drugs in UK general practice, mean follow-up 5.9 years [28].
Sources: [28], [3]
Caveats: Observational. The rate is for the whole cohort, not only people on the three-drug combination [28].

LimitedHow often is not known

With potassium supplements and potassium-sparing diuretics

The label warns that potassium-sparing diuretics, potassium supplements and potassium salt substitutes raise the risk of high blood potassium on an ACE inhibitor.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: The lisinopril label states that potassium-sparing diuretics, naming spironolactone, amiloride and triamterene, can increase the risk of hyperkalemia, and lists potassium supplements and potassium-containing salt substitutes among the risk factors. It also notes that lisinopril reduces the potassium loss caused by thiazide diuretics [3].
Population: People taking lisinopril, as described in the label [3].
Sources: [3]
Caveats: The label gives no rate for the combination.

LimitedHow often is not known

With lithium

Linked to lithium toxicity, with hospital admission about 7.6 times as likely in the month after an older adult on lithium started an ACE inhibitor.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: Among older adults taking lithium, admission for lithium toxicity was more likely within a month of starting an ACE inhibitor (RR 7.6, 95% CI 2.6 to 22.0) [31]. The lisinopril label states that lithium toxicity has been reported with ACE inhibitors and was usually reversible when both drugs were stopped [3].
Population: 10,615 Ontario residents aged 66 and older on lithium, of whom 413 (3.9%) were admitted for lithium toxicity over 10 years [31].
Sources: [31], [3]
Caveats: Observational, with a wide interval. The 3.9% is for all lithium users over 10 years, not for the combination.

LimitedHow often is not known

With diabetes medication

The label warns that an ACE inhibitor taken with insulin or oral diabetes drugs may lower blood sugar further. It gives no rate.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: The lisinopril label states that taking it with insulin or oral diabetes medicines may cause an increased blood-glucose-lowering effect with a risk of hypoglycemia [3].
Population: People taking lisinopril with diabetes medication, as described in the label [3].
Sources: [3]
Caveats: The label cites no study and gives no rate.

Mixed results1

LimitedHow often is not known

Lung cancer

Linked to slightly more lung cancer than ARBs in observational studies, 1.6 against 1.2 cases per 1,000 person-years. Pooled trials found no rise in cancer overall.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: In a UK cohort, ACE inhibitor use was associated with more lung cancer than ARB use (1.6 against 1.2 per 1,000 person-years, HR 1.14, 95% CI 1.01 to 1.29), rising to HR 1.31 after more than 10 years of use [32]. A meta-analysis of 7 cohort and 4 case-control studies found a pooled OR of 1.19 (95% CI 1.05 to 1.36) with very high heterogeneity (I² 98%) [33]. In a network meta-analysis of 70 randomized trials, cancer of any type occurred in 2.03% on ACE inhibitors and 2.02% on placebo (OR 1.00, 95% CI 0.92 to 1.09) [34].
Population: 992,061 people newly treated with blood pressure drugs, mean follow-up 6.4 years [32]; 11 observational studies [33]; 324,168 participants in 70 randomized trials [34].
Sources: [32], [33], [34]
Caveats: The lung cancer findings are observational. The randomized trials counted all cancers together and ran at least 1 year, shorter than the 5 years after which the cohort association appeared [32][34].

Claims tested and not found

That ACE inhibitors and ARBs worsen COVID-19. In 659 people hospitalized with mild to moderate COVID-19, days alive and out of hospital did not differ between stopping and continuing these drugs (21.9 against 22.9 days) [35]. Across 14 randomized trials with 1,838 participants, all-cause mortality did not differ (7.2% against 7.5%, RR 0.95, 95% CI 0.69 to 1.30), though acute kidney injury was more frequent in trials that started the drugs (7.0% against 3.6%) [36].
That stopping an ACE inhibitor or ARB in advanced kidney disease preserves kidney function. In 411 people with an eGFR below 30, eGFR at 3 years was 12.6 after stopping and 13.3 after continuing (difference -0.7, 95% CI -2.5 to 1.0). End-stage kidney disease or kidney replacement occurred in 62% and 56% [37].
That adding an ARB to an ACE inhibitor lowers heart attacks and strokes further. In ONTARGET the combination did not differ from ramipril alone (16.3% against 16.5%, RR 0.99, 95% CI 0.92 to 1.07) [15], and pooled trials found no drop in deaths (RR 0.97) [26].
That ACE inhibitors raise the risk of cancer overall. In 70 randomized trials, cancer occurred in 2.03% on ACE inhibitors and 2.02% on placebo (OR 1.00, 95% CI 0.92 to 1.09) [34].

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