Side effect from lisinopril

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Lisinopril and Hydrochlorothiazide

Before taking lisinopril and hydrochlorothiazide,

  • tell your doctor and pharmacist if you are allergic to lisinopril; hydrochlorothiazide (HCTZ, Microzide, Oretic); angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec, in Vaseretic), fosinopril (Monopril), lisinopril (in Prinzide, in Zestoretic), moexipril (Univasc, in Uniretic), quinapril (Accupril, in Accuretic, in Quinaretic), ramipril (Altace), and trandolapril (Mavik, in Tarka); sulfa drugs; any other medications, or any ingredients in lisinopril and hydrochlorothiazide tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor or pharmacist if you are taking valsartan and sacubitril (Entresto) or if you have stopped taking it within the last 36 hours. Your doctor will probably tell you not to take lisinopril and hydrochlorothiazide, if you are also taking valsartan and sacubitril. Also, tell your doctor if you have diabetes and you are taking aliskiren (Tekturna, in Amturnide, Tekamlo, Tekturna HCT). Your doctor will probably tell you not to take lisinopril and hydrochlorothiazide if you have diabetes and you are also taking aliskiren.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking. Be sure to mention any of the following: aspirin and other nonsteroidal anti-inflammatory medications (NSAIDs) such as ibuprofen (Advil, Motrin), indomethacin (Indocin), and naproxen (Aleve, Naprosyn); barbiturates such as phenobarbital (Luminal, ); cholestyramine (Prevalite); colestipol (Colestid); digoxin (Lanoxin); insulin or oral medications for diabetes; lithium (Lithobid); oral steroids such as dexamethasone, methylprednisolone (Medrol), and prednisone (Rayos); other diuretics; other medications for high blood pressure; pain medications; and potassium supplements. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you are on dialysis or are being treated with desensitization (a process to reduce your reaction to an allergen) and if you have or have ever had allergies; asthma; diabetes; gout; high cholesterol; collagen vascular disease such as lupus or scleroderma (a condition in which extra tissue grows on the skin and some organs); heart failure; any condition that causes you to urinate less than you normally do; a stroke or ‘mini-stroke’; heart, kidney, or liver disease; or angioedema (condition that causes difficulty swallowing or breathing and painful swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs).
  • tell your doctor if you are breast-feeding.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking lisinopril and hydrochlorothiazide.
  • ask your doctor about the safe use of alcoholic beverages while you are taking lisinopril and hydrochlorothiazide. Alcohol can make the side effects from lisinopril and hydrochlorothiazide worse.
  • you should know that diarrhea, vomiting, not drinking enough fluids, and sweating a lot can cause a drop in blood pressure, which may cause lightheadedness and fainting.
  • you should know that lisinopril and hydrochlorothiazide may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. This is more common when you first start taking lisinopril and hydrochlorothiazide. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.

Medically reviewed by Drugs.com. Last updated on Dec 31, 2018.

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In Summary

Commonly reported side effects of lisinopril include: dizziness, hypotension, hyperkalemia, increased blood urea nitrogen, and increased serum creatinine. Other side effects include: headache. See below for a comprehensive list of adverse effects.

For the Consumer

Applies to lisinopril: oral solution, oral tablet

Warning

Oral route (Tablet; Solution)

Discontinue lisinopril as soon as possible when pregnancy is detected, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Along with its needed effects, lisinopril may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking lisinopril:

More common

  • Blurred vision
  • cloudy urine
  • confusion
  • decrease in urine output or decrease in urine-concentrating ability
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • sweating
  • unusual tiredness or weakness

Less common

  • Abdominal or stomach pain
  • body aches or pain
  • chest pain
  • chills
  • common cold
  • cough
  • diarrhea
  • difficulty breathing
  • ear congestion
  • fever
  • headache
  • loss of voice
  • nasal congestion
  • nausea
  • runny nose
  • sneezing
  • sore throat
  • vomiting

Rare

  • Arm, back, or jaw pain
  • chest discomfort, tightness, or heaviness
  • fast or irregular heartbeat
  • general feeling of discomfort or illness
  • joint pain
  • loss of appetite
  • muscle aches and pains
  • shivering
  • trouble sleeping

Some side effects of lisinopril may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

  • Decreased interest in sexual intercourse
  • inability to have or keep an erection
  • lack or loss of strength
  • loss in sexual ability, desire, drive, or performance
  • rash

Rare

  • Acid or sour stomach
  • belching
  • burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
  • feeling of constant movement of self or surroundings
  • heartburn
  • indigestion
  • muscle cramps
  • sensation of spinning
  • stomach discomfort or upset
  • swelling

For Healthcare Professionals

Applies to lisinopril: oral solution, oral tablet

Cardiovascular

Hypotension is most likely in patients who are sodium and intravascular volume depleted. In large studies, patients have reported “heart pounding” and chest pain, although the relationship to lisinopril is questionable.

Very common (10% or more): Hypotension (11%)

Common (1% to 10%): Chest pain, angina pectoris, orthostatic hypotension, palpitations

Renal

Common (1% to 10%): Creatinine increased (10%)

Very rare (less than 0.01%): Renal insufficiency

Nervous system

Very common (10% or more): Dizziness (19%)

Common (1% to 10%): Headache, syncope

Uncommon (0.1% to 1%): Paresthesias

Respiratory

A study has revealed a significantly higher incidence of discontinuation of angiotensin converting enzyme inhibitor therapy due to cough among black patients compared with nonblack patients (9.6% vs. 2.4%).

Common (1% to 10%): Creatinine increased (10%)

Uncommon (0.1% to 1%): Rhinitis

Very rare (less than 0.01%): Bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia

Metabolic

Common (1% to 10%): Hyperkalemia

Frequency not reported: Gout, hypoglycemia in diabetic patients receiving ACE inhibitors when concurrently treated with oral antidiabetic agents or insulin

Gastrointestinal

Common (1% to 10%): Diarrhea, nausea, vomiting

Frequency not reported: Pancreatitis, constipation, flatulence, dry mouth, taste disturbance

Hypersensitivity

Uncommon (0.1% to 1%): Angioedema

Dermatologic

Uncommon (0.1% to 1%): Rash, pruritus, erythema

Very rare (less than 0.01%): Sweating, skin lesions, skin infections, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, cutaneous pseudolymphoma

Frequency not reported: Photosensitivity, flushing, diaphoresis

Hematologic

Very rare (less than 0.01%): Bone marrow depression, hemolytic anemia, leukopenia/neutropenia, thrombocytopenia, decreases in hemoglobin, decreases in hematocrit

Psychiatric

Rare (0.01% to 0.1%): Memory impairment, confusion, somnolence, irritability, nervousness, hallucinations

Very rare (less than 0.01%): Mania

Hepatic

Common (1% to 10%): Creatinine increased

Very rare (less than 0.01%): Cholestatic jaundice that progresses to fulminant hepatic necrosis and sometimes death (discontinue of therapy if jaundice or markedly elevated hepatic serum enzymes develop)

Endocrine

Very rare (less than 0.01%): Diabetes, syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Other

Common (1% to 10%): Cough

Frequency not reported: Fatigue, asthenia, orthostatic effects, tinnitus, olfactory disturbance

Genitourinary

Uncommon (0.1% to 1%): Impotence

Rare (less than 0.1%): Gynecomastia

Frequency not reported: Proteinuria

1. Cerner Multum, Inc. “UK Summary of Product Characteristics.” O 0

2. “Product Information. Prinivil (lisinopril).” Merck & Co, Inc, West Point, PA.

4. Cerner Multum, Inc. “Australian Product Information.” O 0

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.

Related questions

  • Can I just stop taking lisinopril?
  • What is the strength of Qbrelis (lisinopril) oral solution?
  • How long after taking 5 mg lisinopril will my blood pressure drop down?

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Other brands: Zestril, Prinivil, Qbrelis

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When you get stuck behind a driver who forgot green means go, when your friend cancels dinner plans after you’re already at the restaurant, when the person in front of you scores the last chocolate chip muffin you totally had your eye on—all legit reasons for your blood pressure to skyrocket.

Hopefully these are just short-term elevations, but if not, you’re not alone. Chronic high blood pressure affects about one in five women under 32, according to the National Institutes of Health.

If you have high blood pressure, first, kudos for actually knowing it. It’s often called “the silent killer” because on its own, high blood pressure doesn’t show any symptoms and yet can lead to serious problems, including death.

From there, treating high blood pressure, especially in young women, is normally a combination of lifestyle changes—namely diet, exercise, sleep, and stress management, says Adam Splaver, M.D., a cardiologist with NanoHealth Associates in South Florida.

But, if your lifestyle choices are already pretty optimal and you’re still struggling with high blood pressure, your doctor may prescribe you lisinopril—an angiotensin-converting enzyme (ACE) inhibitor—an one of the most common medications used to manage high blood pressure.

The drug works by helping decrease tightness in blood vessels, allowing blood to flow more smoothy and the heart to pump blood more efficiently. Though the drug is super helpful in controlling high blood pressure, there are still some strange side effects to watch out for.

1. You’re not sick, but you’ve got a cough that just won’t quit.

A “non-productive” cough (i.e., a cough that doesn’t bring anything up, like mucous or blood) is one of the most common side effects of lisinopril, says Splaver. It’s weird and annoying, but it’s not dangerous, he adds. However, if it’s really bothering you, definitely bring it up with your doctor, as there are other meds you can try.

2. You feel exhausted and, weirdly enough, kind of tingly.

Lisinopril can cause your potassium levels to skyrocket, a potentially dangerous side effect, says Splaver. That’s because you won’t necessarily know your potassium levels are rising at first, but if they get high enough, they can make you feel exhausted, numb, or tingly.

Splaver says your doctor should do a routine blood test to check your levels one to two weeks after starting the drug to make sure your body is handling it well. If your doctor hasn’t recommended blood tests yet, or if you start to feel strange, call and get a test scheduled asap.

3. Your head is literally always pounding.

Headaches can happen for a myriad of reasons, but if you develop an unrelenting headache, it may be due to the lisinopril. Headaches are the most commonly reported side effect of the drug, according to the NIH. If they’re mild or go away on their own, don’t worry about it. But if they persist, it’s time to give your doctor a call, says Splaver.

4. You know (and use) every bathroom in a 2-mile radius.

Lisinopril dilates your arteries—that’s how it works to lower high blood pressure—but this can affect other parts of your body besides your heart, especially your kidneys. If you already have kidney problems or are prone to getting them, this drug can make them worse, says Splaver.

At first, you likely won’t feel any symptoms, but if you notice changes in how frequently you have to pee or what your pee looks like, along with pain when using the bathroom, lower back pain, or other signs of kidney problems, call your doctor right away, he says.

5. You’re having trouble orgasming.

A decrease in sexual ability is one of the top five most commonly reported side effect of lisinopril, according to the NIH. That’s because your sexual response depends a lot on blood flow to your genitals, so anything that messes with your arteries and blood flow can mess up your orgasms, says Splaver. Call your doctor if you feel like the drug is hurting your sex life, as there are other medical options you can try.

6. You feel really dizzy whenever you go from sitting to standing.

You know that feeling when you stand up quickly and the room starts spinning? That’s actually caused by a rapid drop in blood pressure upon standing (a.k.a orthostatic hypotension) and can cause cause you to feel dizzy, nauseous, or even black out.

Lisinopril can bring this on or make it worse if you are already prone to it, says Splaver. If you’re just dizzy, practice standing up really slowly until you regain your equilibrium—and make sure you’re staying hydrated. If you’re actually fainting, however, it’s time to go back in and see your doctor, he adds.

7. Your face swells up unexpectedly.

Swelling around your face and lips (a.k.a. angioedema) is a rare but potentially serious side effect of lisinopril. If the swelling gets bad enough, it can cause your throat or tongue to block you airway, according to the Mayo Clinic.

If you’re going to get angioedema from lisinopril, it’ll most likely happen shortly after taking the first dose. However, it can occur even after weeks of being on the medication, says Splaver. If you experience swelling and difficulty breathing, call 911 immediately.

Charlotte Hilton Andersen Charlotte Hilton Andersen has been a health and fitness writer for 12 years and is the author of The Great Fitness Experiment.

Hydrochlorothiazide and lisinopril

Generic Name: hydrochlorothiazide and lisinopril (HYE droe KLOR oh THYE a zide and lye SIN oh pril)
Brand Name: Zestoretic, Prinzide

Medically reviewed by Drugs.com on Sep 23, 2019 – Written by Cerner Multum

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What is hydrochlorothiazide and lisinopril?

Hydrochlorothiazide is a thiazide diuretic (water pill) that helps prevent your body from absorbing too much salt, which can cause fluid retention.

Lisinopril is in an ACE inhibitor. ACE stands for angiotensin converting enzyme. Lisinopril lowers blood pressure and also relieves symptoms of fluid retention.

Hydrochlorothiazide and lisinopril is a combination medicine used to treat hypertension (high blood pressure).

Hydrochlorothiazide and lisinopril may also be used for purposes not listed in this medication guide.

Important Information

Do not use if you are pregnant. If you become pregnant, stop taking hydrochlorothiazide and lisinopril and tell your doctor right away.

You should not use this medicine if you have ever had angioedema, if you are unable to urinate, or if you are allergic to sulfa drugs or to any ACE inhibitor. Do not take hydrochlorothiazide and lisinopril within 36 hours before or after taking medicine that contains sacubatril (such as Entresto).

If you have diabetes, do not use hydrochlorothiazide and lisinopril together with any medication that contains aliskiren (such as Tekturna or Tekamlo).

Before taking this medicine

You should not use this medicine if you are allergic to hydrochlorothiazide or lisinopril, or if:

  • you have hereditary angioedema;

  • you are unable to urinate;

  • you recently took a heart medicine called sacubatril;

  • you have an allergy to sulfa drugs; or

  • you have ever had a severe allergic reaction to any ACE inhibitor (benazepril, captopril, enalapril, fosinopril, moexipril, perindopril, quinapril, ramipril, trandolapril).

Do not take hydrochlorothiazide and lisinopril within 36 hours before or after taking medicine that contains sacubatril (such as Entresto).

If you have diabetes, do not use hydrochlorothiazide and lisinopril together with any medication that contains aliskiren (such as Tekturna or Tekamlo).

You may also need to avoid taking hydrochlorothiazide and lisinopril with aliskiren if you have kidney disease.

To make sure hydrochlorothiazide and lisinopril is safe for you, tell your doctor if you have:

  • kidney disease (or if you are on dialysis);

  • cirrhosis or other liver disease;

  • glaucoma;

  • heart disease or congestive heart failure;

  • asthma or allergies;

  • gout;

  • lupus; or

  • an allergy to sulfa drugs or penicillin.

Do not use if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away. Lisinopril can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

This medicine can pass into breast milk and may harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

How should I take hydrochlorothiazide and lisinopril?

Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not take hydrochlorothiazide and lisinopril in larger or smaller amounts or for longer than recommended.

Take each dose with a full glass of water.

Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking this medicine. This can lead to very low blood pressure, electrolyte disorders, or kidney failure.

While using hydrochlorothiazide and lisinopril, you may need frequent blood tests at your doctor’s office. Your blood pressure will need to be checked often.

Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

If you need surgery or medical tests, tell the doctor ahead of time that you are taking medicine that contains hydrochlorothiazide.

Store at room temperature away from moisture, heat, and light.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking hydrochlorothiazide and lisinopril?

Drinking alcohol can further lower your blood pressure and may increase certain side effects of hydrochlorothiazide and lisinopril.

Do not use potassium supplements or salt substitutes while you are taking this medicine, unless your doctor has told you to.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Avoid becoming overheated or dehydrated during exercise, in hot weather, or by not drinking enough fluids. Follow your doctor’s instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

Hydrochlorothiazide and lisinopril side effects

Get emergency medical help if you have signs of an allergic reaction: hives; severe stomach pain; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • a light-headed feeling, like you might pass out;

  • eye pain, vision problems;

  • little or no urination;

  • weakness, drowsiness, or feeling restless;

  • fever, chills, sore throat, mouth sores, trouble swallowing;

  • jaundice (yellowing of the skin or eyes);

  • high potassium–nausea, tingly feeling, chest pain, irregular heartbeats, loss of movement;

  • low potassium–leg cramps, constipation, irregular heartbeats, fluttering in your chest, extreme thirst, increased urination, numbness or tingling, muscle weakness or limp feeling; or

  • low levels of sodium in the body–headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady.

Common side effects may include:

  • cough;

  • headache;

  • dizziness; or

  • tired feeling.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Hydrochlorothiazide and lisinopril dosing information

Usual Adult Dose for Hypertension:

Initial dose: Hydrochlorothiazide 12.5 mg-Lisinopril 10 to 20 mg orally once a day, depending on the current monotherapy dose
Maximum dose: Hydrochlorothiazide 50 mg-Lisinopril 80 mg per day

-May increase dose every 2 to 3 weeks.
-If blood pressure is controlled with monotherapy hydrochlorothiazide 25 mg per day, but significant potassium loss occurs, then similar or greater blood pressure control without electrolyte disturbance may be achieved with hydrochlorothiazide 12.5 mg-lisinopril 10 mg orally once a day.

What other drugs will affect hydrochlorothiazide and lisinopril?

Other drugs may interact with hydrochlorothiazide and lisinopril, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2018 Cerner Multum, Inc. Version: 14.02.

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Lisinopril Dosage

Medically reviewed by Drugs.com. Last updated on Oct 22, 2019.

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Applies to the following strengths: 10 mg; 2.5 mg; 5 mg; 20 mg; 40 mg; 30 mg; 1 mg/mL

Usual Adult Dose for:

  • Hypertension
  • Congestive Heart Failure
  • Myocardial Infarction
  • Diabetic Nephropathy

Usual Geriatric Dose for:

  • Hypertension

Usual Pediatric Dose for:

  • Hypertension

Additional dosage information:

  • Renal Dose Adjustments
  • Liver Dose Adjustments
  • Dose Adjustments
  • Precautions
  • Dialysis
  • Other Comments

Usual Adult Dose for Hypertension

Initial dose: 10 mg orally once a day; 5 mg orally once a day
Maintenance dose: 20 to 40 mg orally once a day
Maximum dose: 80 mg orally once a day

-The initial dose is 5 mg orally once a day in patients receiving a diuretic.
-The 80 mg dose is used but does not appear to give greater effect.
-If blood pressure is not controlled with lisinopril alone, a low dose of a diuretic may be added (e.g., hydrochlorothiazide, 12.5 mg). After the addition of a diuretic, it may be possible to reduce the dose of lisinopril.

Usual Adult Dose for Congestive Heart Failure

Initial dose: 2.5 to 5 mg orally once a day
Maintenance dose: Dosage should be increased as tolerated
Maximum dose: 40 mg orally once a day

-The diuretic dose may need to be adjusted to help minimize hypovolemia, which may contribute to hypotension. The appearance of hypotension after the initial dose of lisinopril does not preclude subsequent careful dose titration with the drug.

Usual Adult Dose for Myocardial Infarction

Initial dose: 5 mg orally (within 24 hours of the onset of acute myocardial infarction)
Subsequent doses: 5 mg orally after 24 hours, then 10 mg orally after 48 hours.
Maintenance dose: 10 mg orally once a day. Dosing should continue for at least 6 weeks.

-Therapy should be initiated at 2.5 mg in patients with a low systolic blood pressure (less than or equal to 120 mm Hg and greater than 100 mmHg) during the first 3 days after the infarct. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than 1 hour) therapy should be withdrawn.
Uses: Reduction of mortality in acute myocardial infarction

Usual Adult Dose for Diabetic Nephropathy

Initial dose: 10 to 20 mg orally once a day
Maintenance dose: 20 to 40 mg orally once a day
Dosage may be titrated upward every 3 days

-Not an approved indication.

Usual Geriatric Dose for Hypertension

Initial dose: 2.5 to 5 mg orally once a day
Maintenance dose: Dosages should be increased at 2.5 mg to 5 mg per day at 1 to 2 week intervals.
Maximum dose: 40 mg orally once a day

Usual Pediatric Dose for Hypertension

Pediatric patients greater than or equal to 6 years of age:
Initial dose: 0.07 mg/kg orally once a day (Maximum initial dose is 5 mg once a day)
Maintenance dose: Dosage should be adjusted according to blood pressure response at 1 to 2 week intervals.
Maximum dose: Doses above 0.61 mg/kg or greater than 40 mg have not been studied in pediatric patients

-This drug is not recommended in pediatric patients less than 6 years old or in pediatric patients with glomerular filtration rate less than 30 mL/min.

Renal Dose Adjustments

CrCl greater than 30 mL/min: No adjustment recommended
CrCl 10 mL/min to less than or equal to 30 mL/min: Recommended initial dose is half of the usual recommended dose (i.e., hypertension, 5 mg; systolic heart failure, 2.5 mg, and acute MI, 2.5 mg. Up titrate as tolerated to a maximum of 40 mg daily)
CrCl less than 10 mL/min or on hemodialysis: Recommended initial dose is 2.5 mg orally once a day

Liver Dose Adjustments

Patients who develop jaundice or marked elevations of hepatic enzymes should discontinue therapy and receive appropriate medical treatment.

Dose Adjustments

-The antihypertensive effect may diminish toward the end of the dosing interval regardless of the administered dose, but most commonly with a dose of 10 mg or less daily. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, an increase in dose should be considered. If blood pressure is not adequately controlled with lisinopril alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of lisinopril.
-In all high risk patients, such as patients with ischemic heart or cerebrovascular disease, in whom excessive falls in blood pressure may lead to myocardial infarction or cerebrovascular accident the manufacturer advises treatment initiation at lower dosages.
-Dosage adjustments in the elderly should be made with particular caution.
-In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy. Then, if blood pressure is not controlled with lisinopril alone, diuretic therapy should be resumed. If diuretic therapy cannot be discontinued, an initial dose of 5 mg should be used with careful medical supervision for several hours and until blood pressure has stabilized.

Precautions

US BOXED WARNINGS:
-FETAL TOXICITY: Angiotensin converting enzyme (ACE) inhibitor use during pregnancy can cause morbidity and death to the developing fetus. When used during the second and third trimesters, ACE inhibitors have been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Exposure to ACE inhibitors during the first trimester of pregnancy has been associated with prematurity, intrauterine growth retardation, patent ductus arteriosus, other structural cardiac malformations, and neurological malformations. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. If no alternative to ACE inhibitor therapy is available, patients should be made aware of the risks to their fetuses and the intra-amniotic environment should be evaluated by serial ultrasound examinations. If oligohydramnios develops, this drug should be discontinued unless it is considered lifesaving for the mother. Depending on the week of pregnancy, contraction stress testing, a nonstress test, or biophysical profiling may be appropriate. Oligohydramnios may not show until after the fetus has suffered irreversible injury.
Safety and efficacy have not been established in patients younger than 6 years.
Consult WARNINGS section for additional precautions.

Dialysis

This drug can be removed by hemodialysis.

Other Comments

Administration advice:
-Should be given as a single daily dose.
-May be given with or without food.
-In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with this drug. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of may be necessary.
General:
-This drug is indicated as adjunctive therapy with diuretics and digitalis for treating heart failure.
-Following first time MI, all ACE inhibitors, at comparable appropriate dosages, appear to be equally effective for reducing mortality and recurrent MI rates.
-Prior to therapy, patients at high risk of symptomatic hypotension such as patients with salt depletion with or without hyponatremia, hypovolemia or those receiving vigorous diuretic therapy should have these conditions corrected. Renal function and serum potassium should be monitored.
-If it is not feasible to discontinue diuretic therapy prior to starting lisinopril, the patient should be closely monitored for several hours following the initial dose of this drug, and until the blood pressure has stabilized. The antihypertensive effects of lisinopril and diuretics used in combination are approximately additive.
-Achievement of optimal blood pressure reduction may require 2 to 4 weeks of therapy.
-Acute myocardial infarction: in addition to this drug, patients should receive, if appropriate, standard treatments, such as thrombolytics, aspirin, and a beta-blocker.
-Antihypertensive effects of this drug are maintained during long-term therapy. Abrupt withdrawal has not been associated with a rapid increase in blood pressure, or a significant increase in blood pressure compared to pretreatment levels.
Patient advice:
-This drug may be taken with or without food, but should be taken at the same time each day.
-This drug may impair your ability to drive or operate machinery.

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NEW ORLEANS, Louisiana – New research suggests that administering lisinopril on a twice-daily basis outperformed the standard once-daily dosing.

“Traditionally lisinopril is prescribed as a once-daily medication despite its 12-hour half life with repeated dosing, but there is no current data suggesting efficacy or safety of twice-daily dosing,” said study author Tiffany Tsai, a PharmD candidate at the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of Colorado.

After controlling for race and age, the authors found that the twice-daily dosing was associated with greater BP reduction and no increase in adverse events or discontinuation of use. Patients receiving lisinopril once a day had SBP of 141.8 mm Hg, while patients receiving two doses per day had an average SBP of 131.5 mm Hg.

“Our findings suggest that patients may be able to achieve a greater decrease in systolic blood pressure with twice-daily dosing without significant differences in safety,” Ms. Tsai said. “Thus, patients may have the option of increasing the frequency of lisinopril before adding a new antihypertensive to their regimen. Although some prescribers prescribe twice-daily dosing already, our results provide some evidence that such dosing may have increased efficacy.”

“Our study result may open up opportunities for more research on a larger scale than what we present,” Ms. Tsai said. “Due to the nature of our retrospective study, there were some limitations, such as sample size and assessment of adherence, that could be overcome with a different study design.”

The poster was presented during the student session at the midyear meeting of the American Society of Health-System Pharmacists in New Orleans. The authors are affiliated with: the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, the Colorado School of Public Health, the University of Florida Colleges of Pharmacy and Medicine, and the University of Colorado School of Medicine.

The authors had no financial or personal relationships with commercial entities to disclose.

–Stephanie Vaccaro

Reference:

1. Tsai T, Kroehl M, Smith S, Thompson A, Trinkley K. Efficacy and safety of twice- versus once-daily dosing of lisinopril for the treatment of hypertension. Presented at: 50th Midyear meeting of the American Society of Health-System Pharmacists. December 7, 2015; New Orleans, LA. Poster presentation.

Zestril

CLINICAL PHARMACOLOGY

Mechanism Of Action

Lisinopril inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of lisinopril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with Zestril alone for up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however, approximately 15% of patients had increases greater than 0.5 mEq/L and approximately 6% had a decrease greater than 0.5 mEq/L. In the same study, patients treated with Zestril and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.1 mEq/L; approximately 4% of patients had increases greater than 0.5 mEq/L and approximately 12% had a decrease greater than 0.5 mEq/L . Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Zestril remains to be elucidated.

While the mechanism through which Zestril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Zestril is antihypertensive even in patients with low-renin hypertension. Although Zestril was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than non Black patients.

Concomitant administration of Zestril and hydrochlorothiazide further reduced blood pressure in Black and non-Black patients and any racial differences in blood pressure response were no longer evident.

Pharmacodynamics

Adult Patients: Administration of Zestril to patients with hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is usually not observed although it can occur and should be anticipated in volume and/or salt-depleted patients . When given together with thiazide-type diuretics, the blood pressure lowering effects of the two drugs are approximately additive.

In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of Zestril, with peak reduction of blood pressure achieved by 6 hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses; however, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was 6 hours after dosing.

The antihypertensive effects of Zestril are maintained during long-term therapy. Abrupt withdrawal of Zestril has not been associated with a rapid increase in blood pressure, or a significant increase in blood pressure compared to pretreatment levels.

Non-Steroidal Anti-Inflammatory Agents

In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of Zestril alone were compared to Zestril given concomitantly with indomethacin, the use of indomethacin was associated with a reduced effect, although the difference between the two regimens was not significant.

Pharmacokinetics

Adult Patients: Following oral administration of Zestril, peak serum concentrations of lisinopril occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. Food does not alter the bioavailability of Zestril. Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Upon multiple dosing, lisinopril exhibits an effective half-life of 12 hours.

Lisinopril does not appear to be bound to other serum proteins. Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25%, with large intersubject variability (6-60%) at all doses tested (5-80 mg). The absolute bioavailability of lisinopril is reduced to 16% in patients with stable NYHA Class II-IV congestive heart failure, and the volume of distribution appears to be slightly smaller than that in normal subjects. The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that in healthy volunteers.

Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged . Lisinopril can be removed by hemodialysis.

Pediatric Patients: The pharmacokinetics of lisinopril were studied in 29 pediatric hypertensive patients between 6 years and 16 years with glomerular filtration rate > 30 mL/min/1.73 m . After doses of 0.1 to 0.2 mg per kg, steady state peak plasma concentrations of lisinopril occurred within 6 hours and the extent of absorption based on urinary recovery was about 28%. These values are similar to those obtained previously in adults. The typical value of lisinopril oral clearance (systemic clearance/absolute bioavailability) in a child weighing 30 kg is 10 L/h, which increases in proportion to renal function. In a multicenter, open-label pharmacokinetic study of daily oral lisinopril in 22 pediatric hypertensive patients with stable kidney transplant (ages 7-17 years; estimated glomerular filtration rate > 30 mL/min/1.73 m²), dose normalized exposures were in the range reported previously in children without a kidney transplant.

Clinical Studies

Hypertension

Two dose-response studies utilizing a once-daily regimen were conducted in 438 mild to moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after dosing. An antihypertensive effect of Zestril was seen with 5 mg of Zestril in some patients. However, in both studies blood pressure reduction occurred sooner and was greater in patients treated with 10, 20 or 80 mg of Zestril than patients treated with 5 mg of Zestril.

In controlled clinical studies of patients with mild to moderate hypertension, patients were treated with Zestril 20-80 mg daily, hydrochlorothiazide 12.5-50 mg daily or atenolol 50-200 mg daily; and in other studies of patients with moderate to severe hypertension, patients were treated with Zestril 20-80 mg daily or metoprolol 100-200 mg daily. Zestril demonstrated superior reductions of systolic and diastolic compared to hydrochlorothiazide in a population that was 75% Caucasian. Zestril was approximately equivalent to atenolol and metoprolol in reducing diastolic blood pressure, and had somewhat greater effects on systolic blood pressure.

Zestril had similar blood pressure reductions and adverse effects in younger and older ( > 65 years) patients. It was less effective in reducing blood pressure in Blacks than in Caucasians.

In hemodynamic studies of Zestril in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of Zestril, there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of lisinopril on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.

In patients with renovascular hypertension Zestril has been shown to be well tolerated and effective in reducing blood pressure .

Pediatric Patients: In a clinical study involving 115 hypertensive pediatric patients 6 to 16 years of age, patients who weighed < 50 kg received either 0.625, 2.5 or 20 mg of Zestril once daily and patients who weighed ≥ 50 kg received either 1.25, 5, or 40 mg of Zestril once daily. At the end of 2 weeks, Zestril lowered trough blood pressure in a dose-dependent manner with antihypertensive efficacy demonstrated at doses > 1.25 mg (0.02 mg per kg). This effect was confirmed in a randomized withdrawal phase, where the diastolic pressure rose by about 9 mmHg more in patients randomized to placebo than compared to patients who remained on the middle and high doses of lisinopril. The dosedependent antihypertensive effect of Zestril was consistent across several demographic subgroups: age, Tanner stage, gender, and race. In this study, lisinopril was generally well-tolerated.

In the above pediatric studies, Zestril was given either as tablets or in a suspension for those children and infants who were unable to swallow tablets or who required a lower dose than is available in tablet form .

Heart Failure

In two placebo controlled, 12-week clinical studies compared the addition of Zestril up to 20 mg daily to digitalis and diuretics alone. The combination of Zestril, digitalis and diuretics reduced the following signs and symptoms of heart failure: edema, rales, paroxysmal nocturnal dyspnea and jugular venous distention. In one of the studies, the combination of Zestril, digitalis and diuretics reduced orthopnea, presence of third heart sound and the number of patients classified as NYHA Class III and IV; and improved exercise tolerance. A large (over 3000 patients) survival study, the ATLAS Trial, comparing 2.5 and 35 mg of lisinopril in patients with systolic heart failure, showed that the higher dose of lisinopril had outcomes at least as favorable as the lower dose.

During baseline-controlled clinical trials, in patients with systolic heart failure receiving digitalis and diuretics, single doses of Zestril resulted in decreases in pulmonary capillary wedge pressure, systemic vascular resistance and blood pressure accompanied by an increase in cardiac output and no change in heart rate.

Acute Myocardial Infarction

The Gruppo Italiano per lo Studio della Sopravvienza nell’Infarto Miocardico (GISSI-3) study was a multicenter, controlled, randomized, unblinded clinical trial conducted in 19,394 patients with acute myocardial infarction (MI) admitted to a coronary care unit. It was designed to examine the effects of short-term (6 week) treatment with lisinopril, nitrates, their combination, or no therapy on short-term (6 week) mortality and on long-term death and markedly impaired cardiac function. Hemodynamicallystable patients presenting within 24 hours of the onset of symptoms were randomized, in a 2 x 2 factorial design, to six weeks of either 1) Zestril alone (n=4841), 2) nitrates alone (n=4869), 3) Zestril plus nitrates (n=4841), or 4) open control (n=4843). All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a beta blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients.

The protocol excluded patients with hypotension (systolic blood pressure ≤ 100 mmHg), severe heart failure, cardiogenic shock, and renal dysfunction (serum creatinine > 2 mg per dL and/or proteinuria > 500 mg per 24 h). Patients randomized to Zestril received 5 mg within 24 hours of the onset of symptoms, 5 mg after 24 hours, and then 10 mg daily thereafter. Patients with systolic blood pressure less than 120 mmHg at baseline received 2.5 mg of Zestril. If hypotension occurred, the Zestril dose was reduced or if severe hypotension occurred Zestril was stopped .

The primary outcomes of the trial were the overall mortality at 6 weeks and a combined end point at 6 months after the myocardial infarction, consisting of the number of patients who died, had late (day 4) clinical congestive heart failure, or had extensive left ventricular damage defined as ejection fraction ≤ 35% or an akinetic-dyskinetic score ≥ 45%. Patients receiving Zestril (n=9646), alone or with nitrates, had an 11% lower risk of death (p = 0.04) compared to patients who did not receive Zestril (n=9672) (6.4% vs. 7.2%, respectively) at six weeks. Although patients randomized to receive Zestril for up to six weeks also fared numerically better on the combined end point at 6 months, the open nature of the assessment of heart failure, substantial loss to follow-up echocardiography, and substantial excess use of Zestril between 6 weeks and 6 months in the group randomized to 6 weeks of lisinopril, preclude any conclusion about this end point.

Patients with acute myocardial infarction, treated with Zestril, had a higher (9.0% versus 3.7%) incidence of persistent hypotension (systolic blood pressure < 90 mmHg for more than 1 hour) and renal dysfunction (2.4% versus 1.1%) in-hospital and at six weeks (increasing creatinine concentration to over 3 mg per dL or a doubling or more of the baseline serum creatinine concentration) .

Lisinopril Versus Hydrochlorothiazide in Obese Hypertensive Patients

Longitudinal studies have shown an increased prevalence of hypertension as patient weight and age increase.1 In fact, up to 30% of hypertension cases can be attributed to obesity,2 and numerous studies have demonstrated a dramatic drop in BP with weight loss.345678 Unfortunately, long-term control of BP by weight reduction has been limited because compliance with weight-reduction programs is poor, with dropout rates ranging from 50% to 70% at 1 to 2 years.910 Consequently, pharmacological treatment of hypertension in obese patients is indicated when nonpharmacological approaches fail or when patients are diagnosed initially with moderate or severe hypertension.11 The class of antihypertensive medication best suited for first-line treatment of hypertension in obesity has not been determined because of the lack of large, placebo-controlled studies comparing different classes of antihypertensive agents in this population.

We report findings from the first multicenter, placebo-controlled study comparing monotherapeutic treatment effects of the ACE inhibitor lisinopril with the diuretic HCTZ in obese patients with hypertension (TROPHY). The TROPHY study is also the first trial to use ABP monitoring to evaluate 24-hour BP control in obese patients.

Methods

Patient Population

Obese men and women (n=334) recruited for this study were between 21 and 75 years of age and had stage I or II hypertension, as defined by the DBP criteria of the fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-V).11 Patients were enrolled in the study if their BMI was within 28 to 40 kg/m2 for men and 27 to 40 kg/m2 for women. Patients were eligible for randomized treatment with lisinopril, HCTZ, or placebo if the average of three seated office DBP measurements was ≥90 mm Hg and ≤109 mm Hg at two consecutive visits during the placebo lead-in period and at the final visit before randomization. A total of 126 patients completed successful baseline ABP monitoring before randomization.

Written informed consent was obtained from all patients before they entered into the study. The protocol was approved by the Institutional Review Board at each center.

Patients were excluded from the study for the following reasons: secondary hypertension; target-organ damage (renal failure, congestive heart failure, myocardial infarction, or cerebrovascular accident 6 months preceding the study); presence of second- or third-degree heart block, valvular heart disease, hepatic disease, hypothyroidism, or diabetes mellitus treated with insulin or oral hypoglycemics; arm circumference greater than 40 cm; weight loss of more than 10 kg or participation in more than two weight-loss programs within 6 months of the present study; and hypersensitivity or contraindication to ACE inhibitors, HCTZ, or other sulfonamide-derived drugs.

Patients were required to maintain their normal eating habits for the duration of the study and not to smoke or consume alcohol in the morning before office BP measurements.

Study Design

After randomization to treatment, patients returned for office visits at 4-week intervals. All patients started at the lowest dose of study medication, and response to treatment was determined from office BP measurements and defined as a DBP <90 mm Hg with a minimal decrease of ≥10 mm Hg from baseline (prerandomization measurement). Patients who did not meet response criteria during an office visit were titrated to the next dose. When the patient met response criteria, he or she remained at that dose for the duration of the study.

Office BP

Office BP measurements were taken 24 hours (±1 hour) after the previous morning dose of study medication with the use of a standard mercury sphygmomanometer and cuff size adapted to the patient’s arm circumference. The mean of three seated, resting measurements was recorded. One standing BP measurement was also recorded to monitor patients for orthostatic hypertension. Pulse rates were measured coincident with BP.

Ambulatory BP

Twenty-four-hour ABPs and heart rates were monitored twice during the study with a SpaceLabs monitor (model 90207). ABP was monitored 24 hours before randomization to double-blind treatment and 24 hours before the last day of treatment. BPs and heart rates were recorded every 20 minutes from 5 am to 11 pm and every 30 minutes thereafter until 5 am. Successful monitoring meant that at least 80% of readings were valid; ie, there were no more than 3 daytime hours with only one valid reading and no more than 1 nighttime hour with zero valid readings.

Clinical and Laboratory Assessments

Baseline assessments included a physical examination, height and weight measurements, chest radiograph, and electrocardiogram. Patients were weighed at each visit after randomization to treatment. Baseline laboratory assessments included serum chemistry, hemogram, urinalysis, plasma glucose, insulin, thyroid-stimulating hormone, triglycerides, total cholesterol, and high-density and low-density lipoprotein cholesterols. All laboratory assessments, except thyroid-stimulating hormone, were repeated on the last day of double-blind treatment.

Statistical Analyses

The principal statistical analysis was a between-treatment comparison to detect statistically significant differences in changes from baseline to week 12 among the three treatment groups. Comparisons of interest were active treatments versus placebo and lisinopril versus HCTZ.

Sample size (n=80 per treatment group) calculations were based on an 80% power to detect a difference of 5 mm Hg between treatments (standard deviation=11.0) in office DBP change from baseline after 12 weeks of therapy (significance level of .05 for a two-sided T test).

Efficacy analyses included all patients who had baseline data and completed all scheduled visits. Initially, treatments were compared with respect to demographic and office DBP measurements and heart rate. ANCOVA, with the baseline as the covariate, was used to compare office SBP and DBP changes from baseline between treatment groups and to test for center and treatment-by-center interactions. The proportion of responders (based on office DBP criteria) was analyzed with Fisher’s exact test.

For 24-hour ABP, ANCOVA was used to determine treatment differences in average change from baseline (hour 0) in systolic and diastolic ABP measurements across 24 hours as well as during daytime (hours 1 to 12), nighttime (hours 13 to 24), and trough (hours 22 to 24), including tests for treatment, center, and treatment-by-center interaction. Area under the curve was computed for each patient using a trapezoid rule after reducing the number of data points per patient into hourly averages. Mean reduction in the area under the curve from baseline was then compared between treatments.

Mean values for standard laboratory test data were compared for lisinopril, HCTZ, and placebo using descriptive statistics.

Results

Demographics

Of 334 patients who entered the study, 232 were randomized to treatment with lisinopril (n=77), HCTZ (n=76), and placebo (n=79). As seen in Table 1, patients were similarly divided among treatment groups with respect to sex, race, age, height, weight, and BMI. Mean patient weights were similar for all treatment groups.

Patient Withdrawals

A total of 21 patients were withdrawn from the study for the following reasons: adverse events (n=10), refused to continue (n=10), and informed consent withdrawn (n=1). More patients were withdrawn in the placebo group (n=11) than in the lisinopril (n=7) or HCTZ (n=3) groups. In the lisinopril group, 1 patient was withdrawn because of chest pain and increased BP over the limits allowed by the protocol. Patients were withdrawn from HCTZ treatment because of headache (n=3) and dry cough (n=1). Patients in the placebo group were withdrawn because of headache (n=6), dry cough (n=1), a hypertensive crisis (n=1), and non–insulin-dependent diabetes mellitus (n=1) that required pharmacological treatment.

Office BP: Efficacy Analysis

Distribution of Patients and Doses

A total of 211 patients completed the final study visit and were included in efficacy analyses. Baseline office SBP and DBP were similar among treatment groups (lisinopril, 147±15/98±6 mm Hg; HCTZ, 148±14/98±5; placebo, 146±13/96±4). At week 12, both lisinopril and HCTZ significantly reduced DBP from baseline compared with placebo (−8.3 and −7.7 versus −3.3 mm Hg, respectively; P<.005); a significant reduction was also observed in SBP after treatment with lisinopril and HCTZ compared with placebo (−9.2 and −10.0 versus −4.6 mm Hg, respectively; P<.05). No significant difference was observed between the antihypertensive efficacy of lisinopril and HCTZ at week 12; however, lisinopril significantly (P≤.05) decreased DBP at weeks 4 and 8 compared with HCTZ.

Heart rate was not significantly affected by active treatments or placebo. Baseline and final heart rates for the three treatment groups were as follows: lisinopril, 71±7 and 71±9 beats per minute; HCTZ, 74±9 and 73±9; and placebo, 72±9 and 75±8, respectively.

Response According to Race

Response to treatment varied with race. Black patients responded better to HCTZ (52%) than to lisinopril (33%). The mean reduction in office DBP was −10.8 mm Hg from baseline to week 12 for black patients in the HCTZ group; this decrease was significant across treatments (P<.01) and compared with placebo (−1.3 mm Hg, P<.05) but was not statistically different from lisinopril (−7.0 mm Hg). SBP reduction in black patients after 12 weeks of HCTZ therapy was significant across treatments (P<.02) and compared with lisinopril and placebo (−13.7 versus −4.7 and −4.7 mm Hg, respectively; P<.05).

Conversely, white patients responded better to lisinopril (43%) than to HCTZ (20%). The mean reduction in office DBP was −9.4 mm Hg from baseline to week 12 for white patients in the lisinopril group; this reduction was significant across treatments (P<.001) and compared with HCTZ and placebo (−5.2 and −1.9 mm Hg, respectively; P<.05). SBP reduction in white patients after 12 weeks of lisinopril therapy (−11.4 mm Hg) was significant across treatments (P<.001) and compared with placebo (−1.4 mm Hg; P<.05) but was not statistically different from HCTZ (−6.4 mm Hg).

Response According to Age, Sex, and Weight

Response to lisinopril was better in young patients (ages 20 to 39 years) of both races than to HCTZ (46% versus 15%, respectively). Patients 40 years of age or older responded similarly to treatment with lisinopril and HCTZ. Women and men responded similarly to lisinopril treatment (38% and 42%, respectively), although women responded better to HCTZ than did men (41% versus 26%, respectively). Patient response to therapy did not appear to be related to baseline BMI. No statistically significant change in weight was observed for any treatment group (Table 3). Furthermore, no correlation existed between changes in weight or BMI and changes in DBP with treatment.

Ambulatory BP: Efficacy Analysis

Table 2 summarizes the results of 24-hour ABP monitoring. Mean baseline 24-hour SBP and DBP were similar among the three treatment groups. At week 12, both lisinopril and HCTZ effectively lowered BP throughout the 24-hour monitoring period compared with placebo (P<.001); however, no significant difference was observed between active treatments (Figs 1 and 2). Lisinopril and HCTZ showed similar efficacy regardless of whether ABP was elevated during daytime hours (hours 1 to 12) or at night (hours 13 to 24). Although lisinopril effectively lowered BP through hours 22 to 24 compared with placebo, HCTZ was slightly more effective during these hours.

Clinical Laboratory Assessments

Table 3 details results of several laboratory assessments. Significant (P<.001) treatment differences were found between plasma glucose levels of patients in the lisinopril and HCTZ groups. At week 12, plasma glucose levels decreased by 0.21 mmol/L from baseline in the lisinopril group, while increasing by 0.31 mmol/L in the HCTZ group. The overall change from baseline in insulin levels and the glucose-insulin ratio was not statistically significant among treatments. An analysis of several lipid subfractions revealed no statistically significant changes between treatments. At week 12, a significant decrease from baseline was observed in potassium levels of patients receiving HCTZ (4.3 to 3.9 mmol/L; P<.0001).

Significant associations (P<.05) were found, at both baseline and week 12, between increased patient weights and higher glucose and insulin levels and glucose-insulin ratio. However, no significant association was observed during the study between changes in weight or BMI and changes in glucose, insulin, or the glucose-insulin ratio.

Safety

Headache and hypokalemia (potassium <3.5 mmol/L) were the only treatment-related adverse experiences that occurred in 3% or more of patients in any treatment group. Headache was reported in 5.1% of patients in the placebo group; hypokalemia was reported in 3.9% of patients in the HCTZ group and 1.3% of patients in the placebo group. The incidence of cough was low and reported with similar frequency among treatment groups (lisinopril, 2.6%; HCTZ, 1.3%; placebo, 2.5%).

Discussion

Findings from this multicenter, placebo-controlled study in obese patients with hypertension showed similar reductions in office SBP and DBP after 12 weeks of monotherapy with lisinopril or HCTZ. Most patients who responded to lisinopril therapy (57%) were controlled with the initial 10-mg dose, whereas a large percentage of patients (46%) who responded to HCTZ required the highest dose (50 mg) of study medication to maintain BP control. Additionally, this study showed that obese white and young patients responded better to ACE inhibitor therapy, whereas obese black patients responded better to diuretic therapy.

We did not find a correlation between changes in weight or BMI and changes in DBP. Thus, we concluded that the antihypertensive effects were correlated solely with the therapy received.

Another unique feature of this study was that it examined ABP monitoring in obese hypertensive patients. ABP tracings showed that at week 12, both antihypertensive agents effectively lowered systolic and diastolic ABPs throughout a 24-hour period.

Analysis of clinical laboratory data revealed treatment differences between lisinopril and HCTZ. Twelve weeks of lisinopril therapy reduced plasma glucose levels, whereas HCTZ therapy increased plasma glucose. HCTZ also significantly reduced serum potassium levels after 12 weeks of therapy.

Earlier studies described some pathophysiological abnormalities associated with hypertension in obese patients, such as renin dependency5 and salt sensitivity.1213 Sodium retention, a characteristic of salt sensitivity, increases extracellular fluid volume, elevates cardiopulmonary volume, and increases cardiac output in obesity hypertension.14 Salt sensitivity is associated with an increase in glomerular filtration fraction and proteinuria in patients with obesity hypertension.1213 These renal hemodynamic changes may not only fuel the hypertensive process but may also lead to progressive renal injury. Insulin resistance may also be associated with similar renal hemodynamic changes.15

We used an ACE inhibitor (lisinopril) in this study because its primary mechanism of action is selective control of BP through blockade of the renin-angiotensin-aldosterone system.1617 This action can occur at both systemic and tissue autocrine-paracrine levels18 and may, through dilating the efferent glomerular arterioles, restore the ability of the kidney to excrete salt and water as well as control glomerular hyperfiltration.19

Lisinopril effectively controlled BP, with 40% of patients meeting strict response criteria (ie, DBP <90 mm Hg and a decrease in DBP of ≥10 mm Hg from baseline). Moreover, the rate of response to lisinopril was more rapid than to HCTZ. These findings support the importance of targeting the renin-angiotensin system and salt sensitivity when treating obese patients for hypertension.

The significant reduction in plasma glucose levels after 12 weeks of lisinopril therapy may relate to the described effects of ACE inhibition on insulin sensitivity17 ; however, no relationship was observed in our study between reductions in DBP and glucose or insulin levels or the glucose-insulin ratio. Hence, the effect of lisinopril on glucose levels in this patient population may or may not be attributed to improved insulin sensitivity.

We used HCTZ in this study because it controls hypertension by causing diuresis and natriuresis,20 which first reduces extracellular fluid volume, thereby decreasing cardiac output.21 Extracellular fluid volume is reduced 3 to 4 days after an initial dose of HCTZ, and subsequently a new equilibrium is established at a lower volume and BP is reduced.20 HCTZ may also decrease peripheral resistance.21 Consequently, diuretics, like ACE inhibitors, may be a good pharmacological approach when treating obese patients for hypertension, and may improve the hemodynamic pattern—increased intravascular volume and cardiac output—that is a hallmark of obese hypertensive patients.19

Despite the high dosages of HCTZ (50 mg/d) used in our study, the lipid profile of our patients was not affected as in previous studies.22 We did, however, show a significant increase in plasma glucose and a decrease in serum potassium levels in the HCTZ group when compared with the lisinopril or placebo groups.

We conclude that a rational monotherapy approach for initial treatment of obese patients with hypertension may include an ACE inhibitor or diuretic. The choice of agent may be determined by the patient’s race and age. Lisinopril was more effective than HCTZ in white and young patients, whereas HCTZ was more effective in black patients. However, further research is needed with larger numbers of patients to confirm our findings. Patients generally responded to low doses of lisinopril and high doses of HCTZ. As previously demonstrated,23 ACE inhibitors may also offer a treatment advantage when comparing certain metabolic profiles.

Selected Abbreviations and Acronyms

ABP = ambulatory blood pressure
ACE = angiotensin-converting enzyme
BMI = body mass index
BP = blood pressure
DBP = diastolic blood pressure
HCTZ = hydrochlorothiazide
SBP = systolic blood pressure

BP values and changes are shown in mm Hg. At baseline, n=67 for lisinopril, n=64 for HCTZ, and n=65 for placebo.

1P<.05 active treatments vs placebo;

2P<.05 HCTZ vs lisinopril.

HDL indicates high-density lipoprotein; LDL, low-density lipoprotein; and VLDL, very-low-density lipoprotein. Values in parentheses are SD.

1P<.001,

2P<.0001 lisinopril vs HCTZ.

Figure 1. Mean change from baseline to week 12 in diastolic ABP over 24 hours for patients in lisinopril, HCTZ, and placebo groups.

Figure 2. Mean change from baseline to week 12 in systolic ABP over 24 hours for patients in lisinopril, HCTZ, and placebo groups.

This study was supported by a grant from Zeneca Pharmaceuticals. The authors thank the following people for participating in the TROPHY Study Group: Dr Kenneth V. Adams, Dr M. Eileen Cook, Dr Gary Enzmann, Dr Barry Gould, Dr Ronald J. Graf, Dr Edward Meyer, Dr David T. Nash, Dr Dennis A. Ruff, Dr Ziad Zawaideh, Dr Dale Murphy, Dr H. Morgan Ashurst, Dr Robert Finklehor, Dr F. Gilbert McMahon, and Stacy Wilson. The authors also thank Mary Jo Psomas for editing the manuscript.

Footnotes

Correspondence to Efrain Reisin, MD, LSUMC Medical Center, Section of Nephrology, 1542 Tulane Ave, New Orleans, LA 70112-2822.

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Blood pressure drug could help weight loss

Subsequent experiments confirmed that the mice had a higher rate of metabolism when resting and gained less fat as they aged, indicating their higher metabolism was sustained throughout life.

The deficient mice also cleared glucose faster than normal mice, suggesting a lower susceptibility to diabetes.

The enzyme is called angiotensin converting enzyme and helps fat cells help regulate blood pressure and blood volume through what scientists call the renin-angiotensin system.

What is remarkable is that “ACE inhibitor” and “Angiotensin Receptor Blocker” drugs are already widely available to treat hypertension.

Dr Michael Mathai of the Florey says: “This is a significant discovery”.

“Our results show that mice with a deficiency in angiotensin have an increase in metabolic rate compared to normal mice, which we attribute to increased burning of fat by the liver.

“Since the intake of food was not altered, this meant that there were less excess calories to be stored as fat, thereby reducing fat mass and body weight. We also showed that glucose tolerance was improved in these mice, which is important in the prevention of diabetes.”

Drugs that block the same hormone (angiotensin) that we targeted in this study are prescribed currently for the treatment of hypertension.

“ACE inhibitor and Angiotensin Receptor Blocker (ARB) drugs are already widely available to treat hypertension and have been found to have this same effect on fat and glucose metabolism, but many people using these drugs may not have noticed any significant weight loss because their lean body mass could have increased,” he says, a reference to how treated animals show an increase of muscle mass which could offset the reduction in fat mass.

“It is possible that the ACE inhibitor and ARB drugs could be adapted to become specific weight loss drugs – it may be a question of the correct dosage,” he says.

“However, such a weight loss drug would need to be accompanied by a healthy diet and lifestyle to achieve and maintain weight loss, and to reduce the likelihood of developing diabetes,” he stresses

“Two things need to be done to determine if these antihypertensive drugs will also be useful for selective reduction of fat mass and weight loss in humans.

“Firstly, we need to establish if the effect on metabolic rate is directly by inhibiting the action of angiotensin on liver and fat, or whether it is an indirect effect mediated by blocking the action of angiotensin in the brain.

“Secondly, we will use the information from the first study to predict which drugs and what dosage should be tested for efficacy in fat reduction and weight loss in humans. For example, if we find that the effect primarily involves blockade of brain angiotensin, then we can select drugs which cross the blood-brain barrier, which is often a property of drugs in this class of medications.

“There is already a fair amount of interest in investigating the use of these drugs in the prevention of diabetes,” he adds.

“I anticipate that the assessment of these drugs for efficacy in the treatment of obesity and associated disorders such as diabetes will take several years. They would be best used in combination with diet and exercise to ensure that the benefit derived from increased metabolic rate and burning of calories is not cancelled out by an increase in calories ingested in food.”

This study was conducted by researchers from the Howard Florey Institute, Victoria University, La Trobe University, Deakin University, Baker Institute and the University of Melbourne. The mouse colony was established with mice originally provided by Pierre Meneton of the Institut National de la Santé et de la Recherche Médicale, Paris.

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