ARBs Beyond Losartan: Valsartan, Candesartan, Olmesartan Evidence

Table of contents

• Evidence summary
• What these ARBs are
• How they work
• What they are prescribed for
• What works and what does not
• Benefits by claim
• Risks and all side effects
• All interactions
• Who should avoid these medicines
• Dosage and how to take them
• Follow the money: who makes them and who funded the evidence
• Related research
• Frequently asked questions
• Sources and funding notes

Evidence summary

Independent evidence and credibility scorecard

Independence tiers: 1 = regulator or government body; 2 = academic or Cochrane team with no declared commercial funding for the work; 3 = independent authors analysing mostly manufacturer-run trials, or minor declared industry ties; 4 = manufacturer-funded or manufacturer-authored. Credibility runs from A (highest) to D. The safety sources are mostly American and European regulators, so the safety picture reflects a US and EU lens; the efficacy trials are international but sponsor-led.

What these ARBs are

Angiotensin II receptor blockers, also called ARBs or "sartans", block the AT1 receptor of the renin-angiotensin system (EMA assessment report). The FDA counts olmesartan as one of eight marketed ARBs (FDA 2013). Losartan has its own page (Losartan); this article covers the others.

• Candesartan (Atacand): the DailyMed label lists ANI Pharmaceuticals as labeller (Atacand label). The CHARM trials were registered with AstraZeneca as sponsor.
• Valsartan (Diovan): the label lists Novartis Pharmaceuticals Corporation (Diovan label). Much of the valsartan taken is generic, and the 2018 litigation concerns generic makers (court opinion).
• Olmesartan: sold as Benicar, Benicar HCT, Azor and Tribenzor, and as generics (FDA 2013). The brand maker was Daiichi Sankyo (company release).
• Irbesartan: in the EMA review scope, with a licensed use in kidney disease with type 2 diabetes (EMA), and in the 2018 NDEA recalls (FDA timeline).

Legal status: all are prescription-only in the documents we read. We opened US and EU regulatory documents only; other countries' status was not checked.

How they work

They block the effect of angiotensin II at its AT1 receptor, so blood vessels relax and less salt and water are retained (EMA). That blood-pressure effect is proven in humans. The same pathway explains the main harms: in pregnancy the drugs reduce fetal kidney function, and in some patients they raise potassium and change creatinine (Atacand label). The Atacand label notes that blood-pressure response is dose-related from 2 to 32 mg, with no greater effect from larger doses, and that the maximal effect usually appears within 4 to 6 weeks. Why olmesartan alone harms the gut is not settled. A Mayo laboratory study of 11 patients found immune-cell changes resembling coeliac disease (Marietta 2015), but that is mechanism research, not proof, and the biopsy-plus-cell work has not shown why other ARBs spare the gut.

What they are prescribed for

• Valsartan (US label): hypertension in adults and children from 1 year; heart failure (NYHA II to IV) to reduce hospital admissions; and, after a heart attack, to reduce cardiovascular death in stable patients with left-ventricular failure or dysfunction (Diovan label).
• Candesartan (US label): hypertension in adults and in children aged 1 to under 17; heart failure with ejection fraction of 40% or less, to reduce cardiovascular death and heart-failure admissions (Atacand label).
• Irbesartan and olmesartan (EU): irbesartan for hypertension and kidney disease in type 2 diabetes; olmesartan for hypertension (EMA).

What works and what does not

Benefits by claim

Heart failure: valsartan (Val-HeFT)

Val-HeFT randomised 5,010 patients to valsartan 160 mg twice daily or placebo on top of usual care (ACC summary). Deaths were similar. The combined endpoint of cardiac arrest, heart-failure admission or intravenous drugs fell 13.2%, mostly because admissions dropped from 455 (18.2%) to 346 (13.8%). A post hoc subgroup already on both an ACE inhibitor and a beta-blocker did worse on valsartan, which the authors said raised a safety concern (Cohn 2001). The University of Minnesota stated that Novartis Pharma AG, the valsartan maker, sponsored the trial (release). The US label limits the claim to fewer admissions (Diovan label).

Heart failure: candesartan (CHARM)

CHARM ran three parallel placebo-controlled trials in patients with reduced, preserved or ACE-inhibitor-intolerant heart failure. Pooled, 7,601 patients were followed for a median of about 38 months. Deaths were 23% on candesartan and 25% on placebo (unadjusted HR 0.91, 95% CI 0.83 to 1.00, p=0.055). Cardiovascular deaths and heart-failure admissions were significantly lower, and more patients stopped candesartan for kidney changes, low blood pressure or high potassium (Pfeffer 2003). The registry lists AstraZeneca as sponsor of each component trial (CHARM-Added record). The FDA label restricts the claim to ejection fraction of 40% or less (Atacand label).

High blood pressure and outcomes: VALUE

VALUE compared valsartan-based and amlodipine-based treatment in 15,245 randomised high-risk hypertensive patients (15,313 enrolled) over 4.2 years. The primary cardiac endpoint was 10.6% vs 10.4% (HR 1.04, 95% CI 0.94 to 1.15). Amlodipine lowered pressure more, especially early on, so the trial could not cleanly test "same pressure, different drug". New-onset diabetes was less frequent on valsartan (13.1% vs 16.4%) and heart failure trended lower (4.2% vs 5.3%, not significant) (ACC summary; Julius 2004). We could not confirm the funder from the records we opened.

ARB versus ACE inhibitor

The Cochrane review of 9 trials (11,007 participants, each at least a year) found no difference in total mortality (RR 0.98, 95% CI 0.88 to 1.10), cardiovascular events (RR 1.07, 0.96 to 1.19) or cardiovascular mortality (RR 0.98, 0.85 to 1.13). Withdrawals for adverse effects were lower on ARBs (RR 0.83, 0.74 to 0.93), with a number needed to treat of 55 over 4.1 years. Dry cough made up 43% of adverse effects on ACE inhibitors vs 4% on ARBs (AAFP summary; Cochrane abstract). The reviewers noted possible publication bias.

What the large ARB-versus-ACE trials show

ONTARGET tested telmisartan, a sister drug, against ramipril and against both together in about 25,600 high-risk patients. Telmisartan was non-inferior (16.7% vs 16.5%, RR 1.01, 95% CI 0.94 to 1.09). The combination did not beat ramipril (16.3%, RR 0.99, 0.92 to 1.07) and caused more hypotension (4.8% vs 1.7%), syncope and kidney dysfunction (ACC summary; ONTARGET). In TRANSCEND, 5,926 people who could not take ACE inhibitors received telmisartan or placebo; the primary outcome was 15.7% vs 17.0% (HR 0.92, 0.81 to 1.05), not significant, and low-pressure symptoms were the commonest reason to stop (TRANSCEND). Telmisartan is not one of the four drugs covered here, so treat this as class evidence.

Cancer: the 2010 debate

In 2010 a Lancet Oncology meta-analysis of five trials reported new cancer in 7.2% of ARB patients vs 6.0% of controls (RR 1.08, 95% CI 1.01 to 1.15; 61,590 patients), with lung cancer higher (0.9% vs 0.7%, RR 1.25, 1.05 to 1.49) and no significant difference in cancer deaths. Telmisartan was the study drug for 85.7% of ARB-treated patients, and the authors said drug-specific risks could not be determined. It carried a US National Heart, Lung, and Blood Institute grant (Sipahi 2010). The 2011 ARB Trialists Collaboration then pooled 15 trials (138,769 people) and found an odds ratio of 1.00 (95% CI 0.95 to 1.04) overall, with no excess of lung, prostate or breast cancer (J Hypertens 2011). The FDA ran its own review of 31 randomised trials and concluded in June 2011 that ARBs do not increase cancer risk; we could only read excerpts of that page (FDA 2011). Our reading: a class-wide cancer signal was not confirmed, but the trials were not designed to detect cancer and follow-up is limited.

Risks and all side effects

Common side effects (labels)

In Val-HeFT (valsartan 3,282 vs placebo 2,740): dizziness 17% vs 9%, hypotension 7% vs 2%, diarrhoea 5% vs 4%, joint pain, fatigue and back pain 3% vs 2%, hyperkalaemia 2% vs 1%. Stopping for side effects was 10% vs 7% (Diovan label). In placebo-controlled hypertension trials the label lists viral infection 3% vs 2%, fatigue 2% vs 1% and abdominal pain 2% vs 1%, with stopping for side effects 2.3% vs 2.0%, and dizziness 8% at 320 mg.

We did not open the irbesartan or olmesartan prescribing labels, so their full adverse-event tables are not reproduced here.

All interactions

• Potassium raisers: potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium supplements, potassium-containing salt substitutes and heparin can raise potassium; monitor if used together (Diovan label).
• NSAIDs (ibuprofen, naproxen, COX-2 inhibitors): in older, dehydrated or kidney-impaired people they risk kidney deterioration, possibly acute failure, and can blunt the blood-pressure effect (Atacand label).
• ACE inhibitors or aliskiren (dual blockade): more hypotension, hyperkalaemia and kidney change; generally avoid. Aliskiren is contraindicated in diabetes and should be avoided if GFR is below 60 mL/min. A triple combination with an ACE inhibitor and a mineralocorticoid antagonist is generally not recommended (Atacand label). ONTARGET showed the same harm for telmisartan plus ramipril.
• Lithium: both labels warn of raised lithium levels and toxicity; monitor serum lithium. See our lithium review.
• Supplements: potassium products and salt substitutes matter most; see supplements and heart medicines.

Who should avoid these medicines

• Pregnancy and planning pregnancy: boxed warning above. See heart disease during pregnancy.
• Breastfeeding: neither label recommends it. Valsartan is present in rat milk with no human milk data, and candesartan excretion in human milk is unknown (Diovan; Atacand).
• Diabetes with aliskiren: contraindicated.
• Allergy: known hypersensitivity to any component.
• Children: valsartan is not recommended under 1 year. Candesartan must not be used for hypertension under 1 year, and the label sets separate limits for children with low kidney function.
• Narrowed kidney arteries, chronic kidney disease, severe heart failure or dehydration: need closer monitoring (kidney disease and the heart).
• Severe diarrhoea with weight loss on olmesartan: report promptly (chronic diarrhoea; coeliac disease).

Dosage and how to take them

These are label and trial doses, not personal advice.

• Valsartan, adult hypertension: label start 80 or 160 mg once daily; range 80 to 320 mg. Heart failure: start 40 mg twice daily; range 40 to 160 mg twice daily. After a heart attack: start 20 mg twice daily; range 20 to 160 mg twice daily. Children 1 to 16 years: 1 mg/kg once daily to start, range 1 to 4 mg/kg (Diovan label).
• Candesartan: hypertension label start 16 mg once daily, total 8 to 32 mg, with an 8 mg start in moderate liver impairment. Heart failure: start 4 mg once daily with a target of 32 mg, doubling about every 2 weeks as tolerated (Atacand label).
• Irbesartan and olmesartan: label doses not reviewed here.
• Quality and contamination: the FDA published interim acceptable limits for nitrosamine impurities in ARBs in December 2018, and describes 0.096 micrograms of NDMA per day as a reasonably safe reference intake (FDA; timeline). Patients cannot check this themselves; recall lists sit on regulator websites.

Follow the money: who makes them and who funded the evidence

Who made them, and who sells them now

• Brand makers named in our sources: Novartis (Diovan; Val-HeFT sponsor), AstraZeneca (CHARM sponsor), ANI Pharmaceuticals (Atacand labeller on DailyMed) and Daiichi Sankyo (olmesartan brands). We did not verify head-office countries or ownership chains for these companies from the pages we opened.
• Generic valsartan: the federal court describes many generic makers who sourced active ingredient from others and contracted with makers such as Teva (court opinion). The 2018 FDA recalls named Major Pharmaceuticals, Solco Healthcare, Teva, Camber (Hetero active ingredient), Torrent, Mylan and Aurobindo, among others (FDA; timeline).

Who funded the trials

• CHARM: AstraZeneca is the registered sponsor of all three component trials (Alternative; Added; Preserved).
• Val-HeFT: Novartis Pharma AG (University of Minnesota release).
• VALUE: sponsor not confirmed from sources we could open.
• ONTARGET and TRANSCEND: Boehringer Ingelheim is lead sponsor (registry record), with Canadian public funders (ACC; TRANSCEND).
• Safety work: the olmesartan case series was funded by an NIDDK (NIH) grant; the 2010 cancer meta-analysis by an NHLBI (NIH) grant.

Documented integrity events

• Valsartan NDMA (2018): on 5 July 2018 the EU reported that Zhejiang Huahai, a company in Linhai, China, had detected NDMA in its valsartan active substance, thought linked to changes in the manufacturing process (EMA). The FDA announced voluntary recalls on 13 July 2018, expanded them in August, placed the company on import alert on 28 September 2018 and issued Warning Letter 320-19-04 on 29 November 2018 (FDA timeline; warning letter).
• What the FDA found: the company approved a valsartan process change in November 2011 that added a solvent to improve yield and lower costs, but did not adequately assess mutagenic-impurity formation. FDA called its investigation of an unknown peak inadequate and found NDMA in batches made by a different process too (warning letter). The EMA noted that its estimate uses NDMA levels since the 2012 change and that NDEA was found in valsartan made before it (EMA update).
• Spread to other ARBs: NDMA also appeared in valsartan from Zhejiang Tianyu and other makers, and the EMA widened its review to every sartan with a tetrazole ring (candesartan, irbesartan, losartan, olmesartan and valsartan) (EMA report). The first non-valsartan product recalled for NDEA was ScieGen irbesartan on 30 October 2018 (FDA timeline).
• Risk estimates differ by method: FDA, one additional cancer over the lifetimes of 8,000 people who took 320 mg daily for four years; EMA, about 1 in 5,000 lifetime for NDMA alone, and a theoretical worst case of 29.5 per 100,000 (1 in 3,390) combining NDEA and NDMA, against a lifetime cancer risk near 50% in Europe. The EMA said the real extent of patient exposure is unknown.
• Litigation: valsartan, losartan and irbesartan claims are consolidated as MDL 2875 in federal court in New Jersey (opinion). We did not verify a final outcome.
• Olmesartan: Daiichi Sankyo announced a settlement programme in August 2017 for US claims that Benicar-family drugs caused sprue-like enteropathy. The fund is capped at $358 million, over 97% of eligible claimants opted in, and the company says the claims are without merit and does not admit liability (company release).

Convergence: the maker-run trials and the regulators agree that these drugs are acceptable for their licensed uses and that the main hazards are pregnancy, potassium and kidney function. The gut and contamination problems were found by regulators and public researchers, not by the trial sponsors.

Related research

For wider, evidence-graded context, see these Pure City Research guides:

• Losartan: uses, potassium, monitoring and pregnancy safety
• Blood pressure medicines
• Hypertension
• Ramipril (the ACE inhibitor comparator)
• Amlodipine
• Heart failure
• Heart failure with reduced ejection fraction
• Chronic kidney disease and the heart
• Heart disease during pregnancy
• Supplements and heart medicines
• Lithium (interacts with ARBs)
• Coeliac disease

Frequently asked questions

Sources and funding notes

Gaps we could not close: we could not open the NICE hypertension guideline (access blocked), the irbesartan and olmesartan prescribing labels, the Lancet funding statements for CHARM-Overall and VALUE, the full text of the Cochrane review (we used its abstract record and the AAFP summary), or the FDA 2011 cancer page beyond search excerpts. The Lancet issued a correction notice for CHARM-Overall in 2009 that we did not read. The final outcome of the US valsartan litigation, the ownership of the generic makers and the current recall status of any product were not verified. Irbesartan and olmesartan are covered only through regulator notices.

1. Diovan label: FDA-approved label, Novartis; role: dosing, boxed warning, adverse events; US regulator.
2. Atacand label: FDA-approved label, ANI Pharmaceuticals as labeller; role: CHARM safety data and dosing.
3. Pfeffer et al., Lancet 2003 (CHARM-Overall): role: pooled heart-failure result; AstraZeneca-sponsored trials.
4. CHARM-Added; CHARM-Preserved; CHARM-Alternative: registry records showing AstraZeneca as sponsor.
5. Julius et al., Lancet 2004 (VALUE) and ACC VALUE summary: role: valsartan versus amlodipine; funder not confirmed.
6. Cohn et al., NEJM 2001 (Val-HeFT), ACC Val-HeFT summary and University of Minnesota release: role: valsartan in heart failure; Novartis sponsor.
7. ONTARGET, NEJM 2008, ACC ONTARGET summary, TRANSCEND, Lancet 2008 and registry record: role: ARB versus ACE inhibitor; Boehringer Ingelheim plus Canadian public funders.
8. Li et al., Cochrane 2014 and AAFP summary: role: ARB versus ACE inhibitor; funding not retrieved.
9. Sipahi et al., Lancet Oncology 2010: role: cancer meta-analysis; NHLBI grant.
10. ARB Trialists Collaboration, J Hypertens 2011: role: cancer pooled analysis; funding not in the record.
11. FDA Drug Safety Communication, June 2011: role: FDA cancer review (excerpts only); US government.
12. Rubio-Tapia et al., Mayo Clin Proc 2012 and Marietta et al., 2015: role: olmesartan case series and mechanism study; NIDDK (NIH) grants.
13. FDA Drug Safety Communication, July 2013: role: olmesartan regulatory warning; US government.
14. Herman et al., ACG Case Rep J 2015: role: single valsartan enteropathy case report; funding not listed.
15. Daiichi Sankyo US release, June 2018: role: Benicar settlement facts; company statement.
16. FDA ARB recall timeline, FDA valsartan laboratory analysis and FDA warning letter 320-19-04: role: recalls, risk estimate and plant findings; US government.
17. EMA, 5 July 2018, EMA update, 13 September 2018 and EMA/CHMP assessment report: role: EU nitrosamine review and risk estimate; EU regulator.
18. MDL 2875 opinion, D.N.J. 2021: role: US federal court opinion describing the valsartan litigation; US judiciary.

Educational research reviewed 6 October 2026. This article is not medical advice; talk to a qualified clinician or pharmacist before starting, stopping or combining treatments.