Atozet (Ezetimibe/Atorvastatin)
Combination cholesterol-lowering medication — film-coated tablets
Atozet is a prescription combination medication containing ezetimibe and atorvastatin. It is used to lower high cholesterol (hypercholesterolaemia) and to reduce the risk of cardiovascular events such as heart attack and stroke. By combining two complementary mechanisms of action, Atozet provides more effective LDL-cholesterol reduction than either component alone, typically lowering LDL-C by 50–60%.
Quick Facts
Key Takeaways
- Atozet combines ezetimibe and atorvastatin for dual-mechanism cholesterol lowering, reducing LDL-C by up to 60%.
- Taken once daily as a tablet, with or without food — consistency in timing is recommended.
- Strictly contraindicated in pregnancy, breastfeeding, and active liver disease.
- The most common side effects are muscle pain, headache, and gastrointestinal symptoms — report unexplained muscle pain immediately.
- Regular blood tests are needed to monitor liver function and cholesterol levels during treatment.
What Is Atozet and What Is It Used For?
Quick Answer: Atozet is a fixed-dose combination tablet containing ezetimibe (10 mg) and atorvastatin (10, 20, 40, or 80 mg). It is prescribed to lower high cholesterol when diet and lifestyle changes alone are insufficient, and when treatment with both components is appropriate.
Atozet belongs to a class of medicines known as lipid-modifying agents. It contains two active substances that work through different but complementary mechanisms to reduce cholesterol levels in the blood. Ezetimibe is a cholesterol absorption inhibitor that works at the brush border of the small intestine by selectively blocking the Niemann-Pick C1-Like 1 (NPC1L1) transporter protein, thereby reducing the absorption of dietary and biliary cholesterol. Atorvastatin is a statin (HMG-CoA reductase inhibitor) that reduces cholesterol production in the liver by blocking the enzyme responsible for cholesterol synthesis.
The combination of these two mechanisms makes Atozet particularly effective for patients who need significant LDL-cholesterol reduction. Clinical studies have demonstrated that the combination of ezetimibe with atorvastatin can lower LDL-cholesterol by approximately 50–60%, compared to 30–50% with atorvastatin alone. This additional reduction can be crucial for patients at high cardiovascular risk who need to achieve stringent LDL-cholesterol targets.
Atozet is indicated for the following conditions:
- Primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet, in patients who are already treated with a statin and ezetimibe at equivalent doses.
- Homozygous familial hypercholesterolaemia (HoFH), as an adjunct to other lipid-lowering treatments or if such treatments are not available.
- Prevention of cardiovascular events in patients with coronary heart disease and a history of acute coronary syndrome, with or without previous lipid-lowering treatment.
The European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) guidelines on dyslipidaemia management recommend the use of combination therapy with ezetimibe and a statin when statin monotherapy at the maximum tolerated dose fails to achieve LDL-cholesterol goals. The 2019 ESC/EAS guidelines specifically endorse ezetimibe as the first add-on therapy to statins, supported by evidence from the IMPROVE-IT trial, which demonstrated a reduction in cardiovascular events with the addition of ezetimibe to statin therapy.
Atozet should be used as an adjunct to appropriate dietary and lifestyle measures. These include a diet low in saturated fat and cholesterol, regular physical exercise, weight management, and smoking cessation. Your doctor will determine whether Atozet is the right treatment for you based on your individual cardiovascular risk profile and cholesterol levels.
What Should You Know Before Taking Atozet?
Quick Answer: Atozet must not be taken during pregnancy or breastfeeding, in active liver disease, or if you are allergic to either ezetimibe or atorvastatin. Inform your doctor about all medications you take, as several drugs can interact with Atozet and increase the risk of side effects.
Contraindications
You must not take Atozet if any of the following apply to you:
- Allergy to ezetimibe, atorvastatin, or any of the other ingredients in Atozet.
- Active liver disease or unexplained persistent elevations of serum transaminases (liver enzymes) exceeding 3 times the upper limit of normal.
- Pregnancy and breastfeeding — cholesterol and its biosynthetic products are essential for foetal development. Statins are classified as teratogenic and must not be used during pregnancy.
- Women of childbearing potential not using effective contraception.
- Concomitant use of hepatitis C antivirals containing glecaprevir/pibrentasvir.
Warnings and Precautions
Before starting Atozet, your doctor should be informed about any of the following conditions, as they may affect whether Atozet is suitable for you or require closer monitoring:
Liver function: Liver function tests should be performed before starting treatment and periodically thereafter. If serum transaminase levels rise to more than 3 times the upper limit of normal, your doctor may consider reducing the dose or discontinuing treatment. Patients who consume substantial quantities of alcohol or have a history of liver disease are at increased risk and require more frequent monitoring.
Muscle effects (myopathy and rhabdomyolysis): Like all statins, atorvastatin can cause myopathy (muscle disease) and, in rare cases, rhabdomyolysis — a serious condition involving the breakdown of skeletal muscle that can lead to acute kidney failure. The risk of myopathy is increased by high-dose statin therapy, older age (over 65 years), hypothyroidism, renal impairment, and concomitant use of certain medications including fibrates, cyclosporine, and strong CYP3A4 inhibitors. You should report any unexplained muscle pain, tenderness, or weakness to your doctor immediately, especially if accompanied by fever or malaise.
Diabetes risk: Statins, including atorvastatin, have been associated with an increased risk of new-onset diabetes mellitus. This risk is generally considered to be outweighed by the cardiovascular benefits of statin therapy, but patients with risk factors for diabetes (fasting glucose 5.6–6.9 mmol/L, BMI greater than 30, elevated triglycerides, hypertension) should be monitored appropriately.
Interstitial lung disease: Rare cases of interstitial lung disease have been reported with some statins. If you develop unexplained dyspnoea (shortness of breath), non-productive cough, deterioration in general health, or fever, consider the possibility of this condition and contact your doctor.
Contact your doctor immediately if you experience unexplained muscle pain, tenderness, weakness, or cramping, especially if accompanied by fever or general malaise. In rare cases, muscle problems can be serious and may lead to a life-threatening condition called rhabdomyolysis, which can cause kidney damage. Your doctor may perform a blood test (creatine kinase) to check for muscle damage.
Pregnancy and Breastfeeding
Atozet is strictly contraindicated during pregnancy. Cholesterol and other products of the cholesterol biosynthesis pathway are essential for foetal development, including the synthesis of steroids and cell membranes. Statins decrease cholesterol synthesis and potentially the synthesis of other biologically active substances derived from cholesterol, and may therefore cause foetal harm when administered to a pregnant woman.
Women of childbearing potential must use effective contraception during treatment with Atozet. If a patient becomes pregnant while taking this medication, treatment must be discontinued immediately and the patient should be informed of the potential risk to the foetus. There are no controlled clinical trials of Atozet in pregnant women.
Atozet is also contraindicated during breastfeeding. It is not known whether ezetimibe is excreted in human breast milk, and atorvastatin has been shown to be present in rat milk. Because of the potential for serious adverse reactions in nursing infants, women taking Atozet should not breastfeed.
How Does Atozet Interact with Other Drugs?
Quick Answer: Atozet can interact with several medications, including cyclosporine, certain antibiotics (clarithromycin, erythromycin), antifungals (itraconazole, ketoconazole), HIV protease inhibitors, fibrates, and warfarin. These interactions can increase the risk of side effects, particularly muscle-related problems. Always inform your doctor about all medications you take.
Drug interactions with Atozet primarily involve the atorvastatin component, which is metabolised by the cytochrome P450 3A4 (CYP3A4) enzyme system. Medications that inhibit this enzyme can increase atorvastatin concentrations in the blood, raising the risk of adverse effects including myopathy. Ezetimibe interactions are generally less clinically significant but should still be considered.
Major Interactions
The following drug interactions are considered clinically significant and may require dose adjustment, close monitoring, or avoidance of the combination:
| Interacting Drug | Effect | Recommendation |
|---|---|---|
| Cyclosporine | Markedly increases atorvastatin and ezetimibe levels; greatly increased myopathy risk | Combination should be avoided; if necessary, do not exceed atorvastatin 10 mg |
| Clarithromycin / Erythromycin | Strong CYP3A4 inhibition increases atorvastatin exposure | Use with caution; consider temporary statin interruption during antibiotic course |
| Itraconazole / Ketoconazole | Potent CYP3A4 inhibition; substantially increases atorvastatin levels | Avoid combination; if unavoidable, use lowest Atozet dose |
| HIV Protease Inhibitors (ritonavir, lopinavir, saquinavir) | Strong CYP3A4 inhibition; greatly increases statin exposure | Avoid or limit atorvastatin dose to 20 mg; close clinical monitoring |
| Gemfibrozil / Fibrates | Increased risk of myopathy and rhabdomyolysis | Combination generally not recommended; if used, monitor for muscle symptoms |
| Glecaprevir/Pibrentasvir | Significantly increases atorvastatin levels | Contraindicated; do not use together |
Other Notable Interactions
In addition to the major interactions listed above, Atozet may interact with other medications in clinically relevant ways:
- Warfarin and other anticoagulants: Atorvastatin may slightly enhance the anticoagulant effect of warfarin. INR should be monitored when starting or changing Atozet dose in patients on warfarin therapy.
- Digoxin: Co-administration of atorvastatin with digoxin may slightly increase digoxin levels. Patients on digoxin should be monitored appropriately.
- Oral contraceptives: Atorvastatin increases plasma levels of norethindrone and ethinyl oestradiol. This should be considered when selecting oral contraceptive doses.
- Grapefruit juice: Grapefruit juice contains CYP3A4 inhibitors that can increase atorvastatin levels. Avoid consuming more than 1.2 litres of grapefruit juice daily.
- Cholestyramine and other bile acid sequestrants: When taken simultaneously, these can reduce the absorption of ezetimibe. Take Atozet at least 2 hours before or 4 hours after bile acid sequestrants.
- Niacin (nicotinic acid): At doses greater than 1 g/day, niacin may increase the risk of myopathy when combined with statins.
- Diltiazem and verapamil: Moderate CYP3A4 inhibitors that can increase atorvastatin exposure. The atorvastatin dose should not exceed 40 mg when combined with these calcium channel blockers.
- Rifampicin: A potent CYP3A4 inducer that can significantly reduce atorvastatin levels and may reduce its efficacy. Simultaneous co-administration is recommended if both drugs are needed.
Tell your doctor or pharmacist about all medicines you are taking, have recently taken, or might take. This includes prescription medications, over-the-counter medicines, herbal preparations (particularly St. John’s Wort, which can reduce atorvastatin effectiveness), and dietary supplements.
What Is the Correct Dosage of Atozet?
Quick Answer: The usual dose is one Atozet tablet once daily. Available strengths are 10/10 mg, 10/20 mg, 10/40 mg, and 10/80 mg (ezetimibe/atorvastatin). Your doctor will choose the appropriate strength based on your current treatment, cholesterol levels, and cardiovascular risk. The tablet can be taken at any time of day, with or without food.
The dose of Atozet should be individualised according to the patient’s current LDL-cholesterol level, treatment goal, and response to therapy. Before initiating Atozet, patients should be placed on a standard cholesterol-lowering diet and should continue this diet during treatment. The following dosage recommendations are based on international prescribing information and clinical guidelines.
| Patient Group | Recommended Dose | Maximum Dose | Notes |
|---|---|---|---|
| Adults — Primary hypercholesterolaemia | 10/10 mg to 10/80 mg once daily | 10/80 mg | Start at dose equivalent to current therapy; adjust after 4 weeks |
| Adults — Cardiovascular prevention | 10/20 mg to 10/80 mg once daily | 10/80 mg | Titrate to achieve ESC/EAS LDL-C targets |
| Adults — Homozygous FH | 10/40 mg to 10/80 mg once daily | 10/80 mg | Used as adjunct to other lipid-lowering treatments |
| Elderly (over 65) | Same as adults | 10/80 mg | No dose adjustment required; monitor for muscle symptoms |
| Renal impairment | Same as adults | 10/80 mg | No dose adjustment for mild-moderate; caution in severe impairment |
| Hepatic impairment | Contraindicated in active liver disease | N/A | Use with caution in mild impairment; monitor liver enzymes |
Adults
The recommended starting dose depends on whether the patient is statin-naïve or currently receiving lipid-lowering therapy. For patients not currently on a statin, the usual starting dose is Atozet 10/10 mg or 10/20 mg once daily. For patients already on a statin, the atorvastatin component should correspond to the equivalent dose of their current statin, with the addition of 10 mg ezetimibe. The dose can be titrated upward after a minimum of 4 weeks based on LDL-cholesterol response.
Atozet can be taken at any time of day, with or without food. It is recommended to take the tablet at approximately the same time each day to maintain consistent drug levels. The tablet should be swallowed whole with a glass of water and should not be crushed, chewed, or split.
Children and Adolescents
Atozet is not recommended for children under 18 years of age. The safety and efficacy of this combination product have not been established in the paediatric population. For children with familial hypercholesterolaemia, statin monotherapy at appropriate paediatric doses is the recommended approach, under specialist supervision.
Elderly Patients
No dose adjustment is necessary for elderly patients. However, older patients may be at increased risk of statin-related myopathy, particularly at higher doses. Physicians should exercise appropriate caution when prescribing higher doses of Atozet to patients over 65 years of age. Renal function should be assessed and any co-medications that may increase the risk of myopathy should be reviewed.
Missed Dose
If you forget to take your Atozet tablet, take it as soon as you remember, unless it is almost time for your next dose. In that case, skip the missed dose and take your next dose at the usual time. Do not take a double dose to make up for a forgotten dose. If you are unsure what to do, consult your doctor or pharmacist.
Overdose
There is no specific treatment for Atozet overdose. In the event of an overdose, the patient should be treated symptomatically and supportive measures should be instituted as required. Due to extensive drug binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance. Ezetimibe was not removed by haemodialysis in clinical studies. If overdose is suspected, contact your local poison control centre or seek emergency medical attention immediately.
What Are the Side Effects of Atozet?
Quick Answer: Common side effects of Atozet include muscle pain (myalgia), headache, nasopharyngitis, diarrhoea, joint pain, and fatigue. Most side effects are mild and transient. Serious but rare side effects include rhabdomyolysis (severe muscle breakdown), liver damage, and allergic reactions. Contact your doctor if you experience persistent or severe symptoms.
Like all medicines, Atozet can cause side effects, although not everybody gets them. The side effects listed below are based on the combined safety profiles of ezetimibe and atorvastatin from clinical trials and post-marketing surveillance. Most side effects are mild to moderate in intensity and generally resolve upon dose reduction or discontinuation.
Very Common
Affects more than 1 in 10 people
- Nasopharyngitis (common cold symptoms, runny nose, sore throat)
Common
Affects 1 to 10 in 100 people
- Myalgia (muscle pain, aching, or stiffness)
- Headache
- Arthralgia (joint pain)
- Diarrhoea
- Flatulence (gas)
- Dyspepsia (indigestion)
- Nausea
- Fatigue
- Elevated liver enzymes (ALT and/or AST)
- Elevated creatine kinase (CK) in blood
- Upper respiratory tract infection
- Urinary tract infection
- Pain in extremity
- Back pain
- Insomnia
Uncommon
Affects 1 to 10 in 1,000 people
- Myopathy (muscle disease with persistent weakness)
- Dizziness
- Paraesthesia (tingling or numbness)
- Abdominal pain
- Constipation
- Vomiting
- Pruritus (itching)
- Rash
- Urticaria (hives)
- Alopecia (hair loss)
- Blurred vision
- Tinnitus (ringing in ears)
- Peripheral neuropathy
- New-onset diabetes mellitus
- Elevated blood glucose
Rare
Affects less than 1 in 1,000 people
- Rhabdomyolysis (severe muscle breakdown — seek immediate medical attention)
- Hepatitis (liver inflammation)
- Cholestasis (impaired bile flow)
- Angioedema (severe swelling of face, lips, tongue, throat)
- Stevens-Johnson syndrome (severe skin reaction)
- Pancreatitis (inflammation of the pancreas)
- Thrombocytopenia (low platelet count)
- Immune-mediated necrotising myopathy
- Interstitial lung disease
- Tendon rupture
- Memory impairment
- Sexual dysfunction
- Depression
- Gynecomastia (breast enlargement in males)
Contact your doctor or go to the nearest emergency department immediately if you experience: unexplained muscle pain, tenderness or weakness (especially with fever); signs of severe allergic reaction such as swelling of face, lips, tongue or throat, difficulty breathing; yellowing of skin or eyes (jaundice); dark urine; or severe abdominal pain. These may be signs of serious conditions requiring urgent treatment.
The reported incidence of muscle-related side effects varies in clinical practice. The IMPROVE-IT trial, which studied ezetimibe added to simvastatin (a related statin), found no significant increase in muscle-related adverse events compared to statin monotherapy. However, individual susceptibility varies, and patients should be counselled to report any unexplained muscle symptoms promptly.
If you experience any side effects that concern you, or if you notice side effects not listed above, please tell your doctor or pharmacist. You can also report side effects directly via your national adverse drug reaction reporting system (e.g., the Yellow Card Scheme in the UK, MedWatch in the USA, or the corresponding system in your country).
How Should You Store Atozet?
Quick Answer: Store Atozet at room temperature below 30°C (86°F) in the original packaging to protect from moisture and light. Keep out of reach of children. Do not use after the expiry date printed on the packaging.
Proper storage of medications is essential to maintain their effectiveness and safety. Atozet film-coated tablets should be stored according to the following guidelines:
- Temperature: Store below 30°C (86°F). Do not refrigerate or freeze.
- Protection: Keep the tablets in the original blister packaging to protect from moisture and light.
- Safety: Keep out of the sight and reach of children. Store in a secure location.
- Expiry: Do not use this medicine after the expiry date stated on the carton and blister. The expiry date refers to the last day of that month.
- Disposal: Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
If the tablets appear discoloured, damaged, or if the blister pack is compromised, do not take them and consult your pharmacist for a replacement. Medications stored improperly may lose potency or become harmful.
What Does Atozet Contain?
Quick Answer: Each Atozet tablet contains two active substances: ezetimibe (10 mg) and atorvastatin (as atorvastatin calcium trihydrate) in strengths of 10 mg, 20 mg, 40 mg, or 80 mg. The tablets also contain inactive ingredients necessary for manufacturing.
Active substances:
- Ezetimibe — 10 mg per tablet (all strengths)
- Atorvastatin (as atorvastatin calcium trihydrate) — 10 mg, 20 mg, 40 mg, or 80 mg per tablet depending on the strength
Other ingredients (excipients):
The inactive ingredients help to form the tablet, ensure stability, and provide the film coating. Typical excipients include:
- Tablet core: Calcium carbonate, croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, sodium lauryl sulfate
- Film coating: Hypromellose, macrogol 8000, titanium dioxide (E171), talc. Some strengths may contain iron oxide yellow (E172) or iron oxide red (E172) for colour differentiation.
Atozet tablets contain lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. The amount of lactose in each tablet is generally small, but patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
The appearance of Atozet tablets varies by strength: the 10/10 mg tablets are typically white, capsule-shaped film-coated tablets; other strengths may differ slightly in colour and markings to aid identification. The tablets are marked with “257” (10/10 mg), “333” (10/20 mg), “337” (10/40 mg), or “341” (10/80 mg) on one side.
Frequently Asked Questions About Atozet
Atozet is a fixed-dose combination tablet that contains both ezetimibe and atorvastatin in a single pill. The clinical effect is the same as taking the two medicines separately at the same doses. The main advantage of Atozet is convenience — taking one tablet instead of two can improve medication adherence, which is particularly important for long-term treatments like cholesterol management. Studies have shown that patients taking combination pills are more likely to continue their treatment compared to those taking multiple separate tablets.
Moderate alcohol consumption is generally acceptable while taking Atozet, but excessive alcohol intake should be avoided. Both alcohol and atorvastatin are metabolised by the liver, and heavy drinking can increase the risk of liver damage. Your doctor may recommend more frequent liver function tests if you regularly consume alcohol. As a general guideline, keep alcohol intake within nationally recommended limits (e.g., no more than 14 units per week in the UK, spread over several days).
Yes, muscle pain (myalgia) is one of the most commonly reported side effects of statin-containing medications, including Atozet. It affects approximately 1–10% of users. In most cases, the muscle pain is mild and may resolve on its own or with a dose adjustment. However, if you experience persistent, unexplained muscle pain, tenderness, weakness, or cramping — particularly if accompanied by fever, dark urine, or general malaise — contact your doctor immediately. These could be signs of a rare but serious condition called rhabdomyolysis. Your doctor may check your creatine kinase (CK) level with a blood test.
Atozet is typically a long-term or lifelong treatment. High cholesterol is a chronic condition, and once you stop taking cholesterol-lowering medication, your cholesterol levels will usually return to their previous elevated levels within weeks. The cardiovascular benefits of statin therapy increase over time, and discontinuation has been associated with increased cardiovascular risk. Never stop taking Atozet without discussing it with your doctor first, even if you feel well or your cholesterol levels have improved.
Yes, statins including atorvastatin can slightly increase blood sugar (glucose) levels and may increase the risk of developing type 2 diabetes in susceptible individuals. This risk is generally considered small compared to the cardiovascular benefits. If you already have diabetes, your doctor may monitor your blood glucose more closely when you start Atozet. The ESC guidelines note that the cardiovascular risk reduction from statin therapy far outweighs the modest increase in diabetes risk in most patient populations.
Small amounts of grapefruit or grapefruit juice (one glass or less per day) are unlikely to cause problems. However, large quantities of grapefruit juice (more than approximately 1.2 litres per day) can inhibit the CYP3A4 enzyme that metabolises atorvastatin, potentially increasing drug levels in your blood and the risk of side effects. It is best to moderate your grapefruit intake and discuss this with your doctor if you regularly consume grapefruit products.
References
This article is based on peer-reviewed medical literature, international clinical guidelines, and official prescribing information. All medical claims are supported by Level 1A evidence where available.
- Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes (IMPROVE-IT). N Engl J Med. 2015;372(25):2387-2397. doi:10.1056/NEJMoa1410489
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2020;41(1):111-188. doi:10.1093/eurheartj/ehz455
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. J Am Coll Cardiol. 2019;73(24):e285-e350. doi:10.1016/j.jacc.2018.11.003
- National Institute for Health and Care Excellence (NICE). Cardiovascular disease: risk assessment and reduction, including lipid modification. Clinical guideline CG181. Updated September 2023.
- European Medicines Agency (EMA). Atozet — Summary of Product Characteristics (SmPC). Last updated 2024.
- Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis. Lancet. 2010;376(9753):1670-1681. doi:10.1016/S0140-6736(10)61350-5
- Ballantyne CM, Weiss R, Moccetti T, et al. Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (EXPLORER study). J Am Coll Cardiol. 2007;49(17):1696-1704.
- World Health Organization. WHO Model List of Essential Medicines. 23rd List, 2023.
Medical Editorial Team
This article has been written and reviewed by the iMedic Medical Editorial Team, which consists of licensed specialist physicians with expertise in cardiology, clinical pharmacology, and internal medicine.
iMedic Medical Editorial Team — specialists in cardiology and clinical pharmacology with peer-reviewed research experience.
iMedic Medical Review Board — independent review according to ESC, ACC/AHA, NICE, and WHO guidelines. GRADE evidence framework applied.
All content follows the iMedic editorial standards, with evidence level 1A based on systematic reviews and meta-analyses of randomised controlled trials. This article contains no commercial funding and is independent of pharmaceutical industry influence.