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Some Anti-Hypertensive Drugs Increase the Risk of Gout

Worst Pills, Best Pills Newsletter article May, 2012

A recent British Medical Journal (BMJ) study indicates that patients taking several types of commonly used anti-hypertensive medications (drugs to treat high blood pressure) have an increased risk for developing gout, a common type of arthritis.

The same study also showed that a limited number of other anti-hypertensive drugs appear to have the opposite effect, decreasing the risk of gout.

While gout has long been a recognized risk of some anti-hypertensive drugs, the study,...

A recent British Medical Journal (BMJ) study indicates that patients taking several types of commonly used anti-hypertensive medications (drugs to treat high blood pressure) have an increased risk for developing gout, a common type of arthritis.

The same study also showed that a limited number of other anti-hypertensive drugs appear to have the opposite effect, decreasing the risk of gout.

While gout has long been a recognized risk of some anti-hypertensive drugs, the study, published online Jan. 12, 2012, more precisely quantified the relative risks of developing gout for different classes of these drugs, taking into account the timing and duration of use.

The findings of this study highlight an issue that Worst Pills, Best Pills News has focused on since its first issue and even earlier, in the first edition of the book Worst Pills, Best Pills: how a drug treatment for one disease, such as hypertension, can cause or contribute to the development of another disease or disorder — in this case, gout.

What is gout?

A type of arthritis, gout occurs when crystals of uric acid — a normal byproduct of body metabolism — form in the fluids around the joints, resulting in inflammation that manifests as severe pain, swelling and redness of the affected joints. Acute attacks of gout typically have an impact on one joint, most commonly the big-toe, knee or ankle joint. Chronic gout is repeated episodes of pain and inflammation from gout, frequently involving multiple joints.

Uric acid levels in the blood rise from either increased production of uric acid by the body — including from the breakdown of certain compounds found in food — or decreased removal of uric acid from the blood by the kidneys. Many drugs increase uric acid levels through the latter mechanism.

Hypertension and gout frequently occur together. For example, approximately three-quarters of U.S. patients diagnosed with gout also have hypertension. The link between gout and hypertension is likely due to the effects on the kidneys from both hypertension itself and the drugs for treating hypertension.

BMJ study overview

Dr. Hyon Choi and his co-authors used computerized medical and pharmacy records for adult patients aged 20 to 89 in the U.K. to assess the risk of developing gout following exposure to anti-hypertensive drugs.

The source population for this study included more than 1.7 million adults who saw a general practitioner at least once between April 2003 and March 2009, had at least one anti-hypertensive prescription in the two years prior to entering the study and had no prior history of gout or cancer. The patients were followed for an average of 5.2 years.

From this population, the researchers identified all patients who were diagnosed with gout for the first time (these patients are referred to as “index cases”). The research team identified 24,768 index cases and compared them to a randomly selected age- and sex-matched control group of 50,000 patients without gout.

Because hypertension itself is a risk factor for gout, and many so-called anti-hypertensive drugs are also taken by patients without hypertension for other conditions (such as congestive heart failure and kidney disease), the investigators made separate comparisons for those patients with hypertension and those without hypertension.

Table 1. Relative Risk of Gout With Anti-Hypertensives (By Timing of Use and Presence of Hypertension)
Drug Class (or Drug) and Timing of Use Relative to Onset of Gout Relative Risk in Patients With Hypertension Relative Risk in Patients Without Hypertension
Never 1.0 1.0
Current 2.2 to 2.5  2.7 to 3.3 
Recent 1.4 to 1.8 1.4 to 2.0 
Past 0.9 to 1.1  0.9 to 1.2 
Never  1.0 1.0
Current 1.4 to 1.6  1.0 to 1.3
Recent 1.1 to 1.4 0.9 to 1.4 
Past  1.0 to 1.1  0.9 to 1.1 
Angiotensin-Converting Enzyme Inhibitors:    
Never 1.0 1.0
Current 1.2 to 1.3  1.2 to 1.5 
Recent 1.2 to 1.5  1.1 to 1.8 
Past 1.0 to 1.2 0.9 to 1.4
Non-Losartan Angiotensin II Receptor Blockers:    
Never  1.0 1.0
Current  1.2 to 1.4  1.0 to 1.9
Recent  0.8 to 1.4  0.6 to 2.8 
Past  0.9 to 1.4  0.6 to 2.6 
Calcium Channel Blockers:    
Never  1.0  1.0 
Current  0.8 to 0.9  0.7 to 1.0 
Recent  0.9 to 1.2  0.6 to 1.0 
Past 1.0 to 1.2  0.8 to 1.1 
Losartan (COZAAR):     
Never 1.0 1.0
Current 0.7 to 0.9 0.6 to 1.3 
Recent  0.7 to 1.4  0.2 to 1.3 
Past  0.9 to 1.4  0.9 to 3.4 

Effect of drug class and timing of use on gout risk

The researchers evaluated the risk of gout for the following drug and classes of anti-hypertensive drugs: diuretics, beta-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, the angiotensin II receptor blocker (ARB) losartan (COZAAR) and non-losartan ARBs. (See Table 2 for a list of drugs in these classes.)

The team looked at losartan separately because prior studies had suggested that, unlike other ARBs, losartan lowers uric acid levels in the blood. In this case, it would be expected to decrease the risk of gout.

For each drug class and losartan, the researchers first assessed how the timing of drug use in those using anti-hypertensives affected the risk of gout in comparison to people who never used the drug. For this part of the study, the researchers categorized the patients into three user groups — current users, recent users and past users — based on how recently they took these drugs prior to the development of gout in the index case.

Current users were those patients whose supply of the most recent prescription for an anti-hypertensive overlapped with the date that gout was diagnosed for the first time in the index case or ended less than 30 days before that date. Recent users were those patients whose most recent prescription for a drug ended between 31 and 365 days before the date that gout was first diagnosed in the index case, and past users were those patients whose most recent prescription ended more than 365 days before that date.

Risks were presented relative to patients who never took the class of drugs listed. By definition, the relative risk in patients who never used the drug is 1.0. A relative risk higher than 1.0 indicated an increased risk of gout in comparison to the risk in people who never took the drug. A relative risk lower than 1.0 indicated a decreased risk of gout in comparison to the risk in people who never took the drug.

After adjusting for various known risk factors for gout, the investigators found that current users of diuretics, beta-blockers, ACE inhibitors or non-losartan ARBs had an increased risk of gout in comparison to patients who never used those particular drug types (see Table 1 above). This increased risk was greatest in patients currently taking diuretics, with a 2.2- to 2.5-fold increased risk in hypertensive patients and a 2.7- to 3.3-fold increased risk in nonhypertensive patients, in comparison to patients who never used diuretics.

Generally, in comparison to current users, recent users experienced a less pronounced increased risk of developing gout while taking a drug in these five classes. The increased risk appeared only minimally higher or no longer present in past users. For example, in comparison to hypertensive patients who never used diuretics, hypertensive patients who were recent users of diuretics had only a 1.4- to 1.8-fold higher risk of gout, whereas the relative risk in past users was 0.9 to 1.1. These numbers for past users indicate no change in risk in comparison to patients who never used diuretics.

In contrast, current users of calcium channel blockers and the ARB losartan had a decreased risk of gout. The relative risk of gout in current users of calcium channel blockers was 7 to 18 percent lower in hypertensive patients and 3 to 27 percent lower in nonhypertensive patients, compared to patients who never took these drugs. Likewise, the relative risk in current users of losartan was 6 to 30 percent lower in hypertensive patients. The study found no clear effect on risk of gout in current users of losartan who did not have hypertension.

It is important to note that, although the increase in the relative risk of gout with some of these types of drugs was more than double the risk in people who had never taken the drugs, the absolute increase in risk was much smaller. For example, the authors noted that if 1,000 patients took diuretics for one year, there would be six extra cases of gout diagnosed, in comparison to 1,000 patients who did not take diuretics over that same year. Also, if 1,000 patients took one of the other drug types associated with an increased risk of gout for one year, there would be one or two extra cases of gout diagnosed.

Table 2. Classes of Anti-Hypertensive Drugs
Generic Name Brand Name
Angiotensin II Receptor Blockers (ARBs)
candesartan** ATACAND 
eprosartan** TEVETEN
irbesartan** AVAPRO
losartan** COZAAR
olmesartan** BENICAR
telmisartan** MICARDIS
valsartan** DIOVAN
ARB-Diuretic Combinations
candesartan and hydrochlorothiazide** ATACAND HCT 
irbesartan and hydrochlorothiazide** AVALIDE 
losartan and hydrochlorothiazide** HYZAAR
olmesartan and hydrochlorothiazide** BENICAR HCT
telmisartan and hydrochlorothiazide** MICARDIS HCT 
valsartan and hydrochlorothiazide** DIOVAN HCT 
Angiotensin-Converting Enzyme (ACE) Inhibitors
benazepril** ETHEX, LOTENSIN
captopril** CAPOTEN
enalapril** VASOTEC
fosinopril** MONOPRIL
lisinopril** PRINIVIL, ZESTRIL
moexipril** UNIVASC
perindopril** ACEON
quinapril ACCUPRIL
ramipril** ALTACE
trandolapril** MAVIK
ACE Inhibitor-Calcium Channel Blocker Combinations
benazepril and amlodipine * LOTREL
enalapril and diltiazem * TECZEM
enalapril and felodipine* LEXXEL
trandolapril and verapamil* TARKA
ACE Inhibitor-Diuretic Combinations
benazepril and hydrochlorothiazide** LOTENSIN HCT
captopril and hydrochlorothiazide** CAPOZIDE
enalapril and hydrochlorothiazide** VASERETIC
lisinopril and hydrochlorothiazide** PRINZIDE, ZESTORETIC
acebutolol SECTRAL
atenolol TENORMIN
betaxolol KERLONE


Generic Name (continued) Brand Name (continued)
bisoprolol ZEBETA
carvedilol COREG
labetalol NORMODYNE
metoprolol succinate TOPROL XL
nadolol CORGARD
penbutolol LEVATOL
pindolol VISKEN
Beta-Blocker – Diuretic Combinations
atenolol and chlorthalidone** TENORETIC
bisoprolol and hydrochlorothiazide** ZIAC
metoprolol and hydrochlorothiazide** LOPRESSOR HCT
propranolol and hydrochlorothiazide** INDERIDE LA
timolol and hydrochlorothiazide** TIMOLIDE
Calcium Channel Blockers   
amlodipine** NORVASC
felodipine PLENDIL
nicardipine** CARDENE, CARDENE SR
nisoldipine SULAR
amiloride and hydrochlorothiazide* MODURETIC
bumetanide** BUMEX
chlorothiazide DIURIL
chlorthalidone HYGROTON
epleronone** INSPRA
furosemide** LASIX
indapamide* LOZOL
methyclothiazide ENDURON
polythiazide RENESE
spironolactone** ALDACTONE
spironolactone and hydrochlorothiazide* ALDACTAZIDE
triamterene* DYRENIUM
triamterene and hydrochlorothiazide** DYAZIDE, MAXZIDE

* Do Not Use
** Limited Use (offers limited benefit or benefits certain people or conditions)

Effect of duration of use on gout risk

For this part of the BMJ study, the researchers assessed whether the duration of use of each class of anti-hypertensive drug or losartan affected the risk for gout. They divided subjects into three groups — those taking anti-hypertensives for less than one year, one to less than two years, and two or more years.

The team found increasing duration of diuretic use to be strongly associated with an increasing risk of gout in patients with hypertension and without hypertension. They observed a similar association in hypertensive patients treated with ACE inhibitors. On the other hand, increasing duration of calcium channel blocker or losartan use was strongly associated with a decreasing risk of gout in hypertensive patients.

What You Can Do

If you have a history of gout, make sure your health care provider is aware of this condition before starting any new anti-hypertensive drug, especially diuretics, beta-blockers, ACE inhibitors and non-losartan ARBs.

Patients with a previous history of frequent acute episodes of gout or chronic gout should consider using drugs associated with a lower gout risk (a calcium channel blocker or losartan) and should avoid using drugs associated with a higher gout risk (diuretics, beta-blockers, ACE inhibitors and non-losartan ARBs) whenever medically feasible.

However, even in patients with gout, the benefits of diuretics, beta-blockers, ACE inhibitors and non-losartan ARBs in many cases will still outweigh the risk of gout, especially if these medications can better control your hypertension or other medical conditions treated with these drugs. (Also, as mentioned earlier, the absolute increased gout risk is small.) Discuss the risks and benefits with your health care provider.

All patients, regardless of prior history of gout, should be informed of the risk of gout with diuretics, beta-blockers, ACE inhibitors and non-losartan ARBs when started on these medications or whenever the dose of such medications is increased.

If you develop symptoms of arthritis while taking any of these drugs, see your doctor to find out whether there is evidence that this new arthritis is actually gout. To do this, your doctor can check your blood level of uric acid, take a sample of joint fluid to test for gout crystals or look for other signs of gout.

If you are found to have gout, discuss with your doctor whether your dose of any of the drugs in the above-mentioned categories could be reduced or whether you should be changed to a different medication that has a lower gout risk. However, maintaining proper control of your hypertension is of utmost importance.

Consumers may report serious adverse events or product quality problems to the Food and Drug Administration’s (FDA’s) MedWatch Adverse Event Reporting program online or by regular mail, fax or phone.