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Valsartan

Topic: Chemistry

 From HandWiki - Reading time: 15 min

Short description: Angiotensin II receptor antagonist
Valsartan
Clinical data
Trade namesDiovan, others
AHFS/Drugs.comMonograph
MedlinePlusa697015
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classAngiotensin II receptor antagonist
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability25%
Protein binding95%
Elimination half-life6 hours
ExcretionKidney 30%, bile duct 70%
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC24H29N5O3
Molar mass435.528 g·mol−1
3D model (JSmol)
  (verify)

Valsartan, sold under the brand name Diovan among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease.[7] It belongs to a class of medications referred to as angiotensin II receptor blockers (ARBs). It is a reasonable initial treatment for high blood pressure.[7] It is taken by mouth.[7] Versions are available as the combination valsartan/hydrochlorothiazide, valsartan/amlodipine, valsartan/amlodipine/hydrochlorothiazide, or valsartan/sacubitril.[7][8]

Common side effects include feeling tired, dizziness, high blood potassium, diarrhea, and joint pain.[7] Other serious side effects may include kidney problems, low blood pressure, and angioedema.[7] Use in pregnancy may harm the baby and use when breastfeeding is not recommended.[9] It is an angiotensin II receptor antagonist and works by blocking the effects of angiotensin II.[7]

Valsartan was patented in 1990, and came into medical use in 1996.[10] It is available as a generic medication.[11] In 2020, it was the 123rd most commonly prescribed medication in the United States, with more than 5 million prescriptions.[12][13]

Medical uses

Valsartan is used to treat high blood pressure, heart failure, and to reduce death for people with left ventricular dysfunction after having a heart attack.[14][6]

High blood pressure

Valsartan (and other ARBs) are an appropriate initial treatment option for most people with high blood pressure and no other coexisting conditions, as are ACE inhibitors, thiazide diuretics and calcium channel blockers.[15] If patients have coexisting diabetes or kidney disease, ARBs or ACE inhibitors may be considered over other classes of blood pressure medicines.[16][17]

Heart failure

Valsartan has reduced rates of mortality and heart failure hospitalisations when used alone or in combination with beta-blockers in the treatment of heart failure.[18] Importantly, the combination of valsartan and ACE inhibitors has not shown morbidity or mortality benefits but rather increases mortality risk when added to combination beta-blocker and ACE-inhibitor therapy, and increases the risk of adverse events like hyperkalaemia, hypotension and renal failure.[18][19] As shown in the PARADIGM-HF study, valsartan combined with sacubitril for the treatment of heart failure, significantly reduced all cause and cardiovascular mortality and hospitalisations due to heart failure.[20]

Diabetic kidney disease

In people with type 2 diabetes, antihypertensive therapy with valsartan decreases the rate of progression of albuminuria (albumin in urine), promotes regression to normoalbuminuria and may reduce the rate of progression to end-stage kidney disease.[21][22][23]

Contraindications

The packaging for valsartan includes a warning stating the drug should not be used with the renin inhibitor aliskiren in people with diabetes. It also states the safety of the drug in severe renal impairment has not been established.[6]

Valsartan includes a black box warning for fetal toxicity.[6][9] Discontinuation of these agents is recommended immediately after detection of pregnancy and an alternative medication should be started.[6] Breastfeeding is not recommended.[6][24][25]

Side effects

Rates of side effects depends on the reason the medication is used.

Heart failure

Rates of adverse effects are based on a comparison versus placebo in people with heart failure.[6] Most common side effects include dizziness (17% vs 9% ), low blood pressure (7% vs 2%), and diarrhea (5% vs 4%).[6] Less common side effects include joint pain, fatigue, and back pain (all 3% vs 2%).[6]

Hypertension

Clinical trials for valsartan treatment for hypertension versus placebo demonstrate side effects like viral infection (3% vs 2%), fatigue (2% vs 1%) and abdominal pain (2% vs 1%). Minor side effects that occurred at >1% but were similar to rates from the placebo group include:[6]

Kidney failure

People treated with ARBs including valsartan or diuretics are susceptible to conditions of developing low renal blood flow such as abnormal narrowing of blood vessel in kidney, hypertension, renal artery stenosis, heart failure, chronic kidney disease, severe congestive heart failure, or volume depletion whose renal function is in part dependent on the activity of the renin-angiotensin system like efferent arteriolar vasoconstriction done by angiotensin II are at high risk of deterioration of renal function comprising acute kidney failure, oliguria, worsening azotemia or heightened serum creatinine.[6] When blood flow to the kidneys is reduced, the kidney activates a series of response that triggers angiotensin release to constrict blood vessels and facilitate blood flow in the kidney.[26] So long as the nephron function degradation is being progressive or reaches clinically significant level, withhold or discontinue valsartan is warranted.[6][27][28][29]

Interactions

The U.S. prescribing information lists the following drug interactions for valsartan:

  • Other inhibitors of the renin-angiotensin system may increase the risks of low blood pressure, kidney problems, and hyperkalemia.
  • Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium may increase the risk of hyperkalemia.
  • NSAIDs may increase the risk of kidney problems and may interfere with blood pressure-lowering effects.
  • Valsartan may increase the concentration of lithium.[6]
  • Valsartan and other angiotensin-related blood pressure medications may interact with the antibiotics co-trimoxazole or ciprofloxacin to increase risk of sudden death due to cardiac arrest.[30]

Food interaction

With the tablet, food decreases the valsartan tablet taker's exposure to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%, evidenced by AUC change.[6]

Pharmacology

Mechanism of action

Valsartan blocks the actions of angiotensin II, which include constricting blood vessels and activating aldosterone, to reduce blood pressure.[31] The drug binds to angiotensin type I receptors (AT1), working as an antagonist.[32] This mechanism of action is different than that of the ACE inhibitor drugs, which block the conversion of angiotensin I to angiotensin II. As valsartan acts at the receptor, it can provide more complete angiotensin II antagonism since angiotensin II is generated by other enzymes as well as ACE. Also, valsartan does not affect the metabolism of bradykinin like ACE inhibitors do.[31]

Pharmacodynamics

Pharmacokinetics

AUC and Cmax values of valsartan are observed to be approximately linearly dose-dependent over therapeutic dosing range. Owing to its relatively short elimination half life attribution, valsartan concentration in plasma does not accumulate in response to repeated dosing.[6]

Society and culture

Economics

In 2010, valsartan (trade name Diovan) achieved annual sales of $2.052 billion in the United States and $6.053 billion worldwide.[33] The patents for valsartan and valsartan/hydrochlorothiazide expired in September 2012.[34][35]

Combinations

Further information: amlodipine/valsartan, valsartan/hydrochlorothiazide, valsartan/hydrochlorothiazide/amlodipine, and sacubitril/valsartan
Co-Diovan (valsartan and hydrochlorothiazide)

Valsartan is combined with amlodipine or hydrochlorothiazide (HCTZ) (or both) into single-pill formulations for treating hypertension with multiple drugs.[7][36][37][38] Valsartan is also available as the combination valsartan/sacubitril.[8][39][40] It is used to treat heart failure with reduced ejection fraction.[40][41]

Recalls

On 6 July 2018, the European Medicines Agency (EMA) recalled certain batches of valsartan and valsartan/hydrochlorothiazide film-coated tablets distributed in 22 countries in Europe, plus Canada.[42] Zhejiang Huahai Pharmaceutical Co. (zh) (ZHP) in Linhai, China manufactured the bulk ingredient contaminated by N-nitrosodimethylamine (NDMA), a carcinogen.[43] The active pharmaceutical ingredient was subsequently imported by a number of generic drugmakers, including Novartis, and marketed in Europe and Asia under their subsidiary Sandoz labeling, and in the UK by Dexcel Pharma Ltd and Accord Healthcare.[42]

In Canada , the recall involves five companies and a class action suit has been initiated by a private law firm.[44][45] Authorities believe the degree of contamination is negligible, and advise those taking the drug to consult a doctor and not to cease taking the medication abruptly. On 12 July 2018, The National Agency of Drug and Food Control (NA-DFC or Badan POM Indonesia) announced voluntary recalls for two products containing valsartan produced by Actavis Indonesia and Dipa Pharmalab Intersains.[46] On 13 July 2018, the U.S. Food and Drug Administration (FDA) announced voluntary recalls of certain supplies of valsartan and valsartan/hydrochlorothiazide in the U.S. distributed by Solco Healthcare LLC, Major Pharmaceuticals, and Teva Pharmaceutical Industries.[47][43] Hong Kong's Department of Health initiated a similar recall.[48] On 2 August 2018, the FDA published two lengthy, updated lists, classifying hundreds of specific U.S. products containing valsartan into those included versus excluded from the recall.[49][50] A week later, the FDA cited two more drugmakers, Zhejiang Tianyu Pharmaceuticals of China and Hetero Labs Limited of India, as additional sources of the contaminated valsartan ingredient.[51][50]

In September 2018, the FDA announced that retesting of all valsartan supplies had found a second carcinogenic impurity, N-nitrosodiethylamine (NDEA), in the recalled products made by ZHP in China and marketed in the U.S. under the Torrent Pharmaceuticals (India) brand.[52]

According to a 2018 Reuters analysis of national medicines agencies' records, more than 50 companies around the world have recalled valsartan mono-preparations or combination products manufactured from the tainted valsartan ingredient. The contamination has likely been present since 2012 when the manufacturing process was changed and approved by EDQM and FDA authorities. Based on inspections in late 2018, both agencies have suspended the Chinese and Indian manufacturers' certificates of suitability for the supply of valsartan in the EU and the U.S.[53]

In 2019, many more preparations of valsartan and its combinations were recalled due to the presence of the contaminant NDMA.[54][55]

In August 2020, the European Medicines Agency (EMA) provided guidance to marketing authorization holders on how to avoid the presence of nitrosamine impurities in human medicines and asked them to review all chemical and biological human medicines for the possible presence of nitrosamines and to test the products at risk.[56]

Shortages

Since July 2018, numerous recalls of losartan, valsartan and irbesartan drug products have caused marked shortages of these life saving medications in North America and Europe, particularly for valsartan. In March 2019, the FDA approved an additional generic version of Diovan™ to address the issue.[57] According to the agency, the shortage of valsartan was resolved on 3 April 2020,[58] but the availability of the generic form remained unstable into July 2020. Pharmacies in Europe were notified that the supply of the drug, particularly for higher dosage forms, would remain unstable well into December 2020.[59]

Research

In people with impaired glucose tolerance, valsartan may decrease the incidence of developing diabetes mellitus type 2. However, the absolute risk reduction is small (less than 1 percent per year) and diet, exercise or other drugs, may be more protective. In the same study, no reduction in the rate of cardiovascular events (including death) was shown.[60]

In one study of people without diabetes, valsartan reduced the risk of developing diabetes mellitus over amlodipine, mainly for those with hypertension.[61]

A prospective study demonstrated a reduction in the incidence and progression of Alzheimer's disease and dementia.[62]

References

  1. ↑ "Valsartan Use During Pregnancy". 28 March 2019. https://www.drugs.com/pregnancy/valsartan.html. 
  2. ↑ "Diovan valsartan 40mg film-coated tablet blister pack". https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=93165. 
  3. ↑ "Diovan valsartan 80mg film-coated tablet blister pack". https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=80868. 
  4. ↑ "Diovan valsartan 160mg film-coated tablet blister pack". https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=80871. 
  5. ↑ "Valsartan 160 mg capsules - Summary of Product Characteristics (SmPC)". 19 February 2019. https://www.medicines.org.uk/emc/medicine/30901. 
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 "Diovan- valsartan tablet". 12 June 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5ddba454-f3e6-43c2-a7a6-58365d297213. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 "Valsartan Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/valsartan.html. 
  8. ↑ 8.0 8.1 "Sacubitril and Valsartan Monograph for Professionals". 7 November 2019. https://www.drugs.com/monograph/sacubitril-and-valsartan.html. 
  9. ↑ 9.0 9.1 "Valsartan Pregnancy and Breastfeeding Warnings". https://www.drugs.com/pregnancy/valsartan.html. 
  10. ↑ Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 470. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA470. 
  11. ↑ British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 179. ISBN 9780857113382. 
  12. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  13. ↑ "Valsartan - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Valsartan. 
  14. ↑ "Chapter 26. Renin and Angiotensin". Goodman & Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill. 2011. ISBN 978-0-07-162442-8. 
  15. ↑ "Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis". Lancet 387 (10022): 957–967. March 2016. doi:10.1016/s0140-6736(15)01225-8. PMID 26724178. 
  16. ↑ "Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy". The New England Journal of Medicine 345 (12): 861–869. September 2001. doi:10.1056/nejmoa011161. PMID 11565518. 
  17. ↑ "2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)". European Heart Journal 34 (28): 2159–2219. July 2013. doi:10.1093/eurheartj/eht151. PMID 23771844. 
  18. ↑ 18.0 18.1 "A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure". The New England Journal of Medicine 345 (23): 1667–1675. December 2001. doi:10.1056/NEJMoa010713. PMID 11759645. 
  19. ↑ "Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials". BMJ 346 (jan28 1): f360. January 2013. doi:10.1136/bmj.f360. PMID 23358488. 
  20. ↑ "Angiotensin-neprilysin inhibition versus enalapril in heart failure". The New England Journal of Medicine 371 (11): 993–1004. September 2014. doi:10.1056/NEJMoa1409077. PMID 25176015. 
  21. ↑ "Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect". Circulation 106 (6): 672–678. August 2002. doi:10.1161/01.CIR.0000024416.33113.0A. PMID 12163426. 
  22. ↑ "Antiproteinuric effects of angiotensin receptor blockers: telmisartan versus valsartan in hypertensive patients with type 2 diabetes mellitus and overt nephropathy". Nephrology, Dialysis, Transplantation 23 (10): 3174–3183. October 2008. doi:10.1093/ndt/gfn230. PMID 18450829. 
  23. ↑ "Albuminuria response to very high-dose valsartan in type 2 diabetes mellitus" (in en-US). Journal of Hypertension 25 (9): 1921–1926. September 2007. doi:10.1097/HJH.0b013e328277596e. PMID 17762658. 
  24. ↑ "Diovan Product Monograph". Novartis Pharmaceuticals Canada Inc.. http://webprod5.hc-sc.gc.ca/dpd-bdpp/index-eng.jsp. 
  25. ↑ "Product Monograph - PrDIOVAN® (valsartan)". May 12, 2015. https://pdf.hres.ca/dpd_pm/00030565.PDF. 
  26. ↑ "11". Pathologic Basis of Disease (8th ed.). Saunders Elsevier. 2010. p. 493. ISBN 978-1-4160-3121-5. 
  27. ↑ "AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation". Circulation (Ovid Technologies (Wolters Kluwer Health)) 124 (22): 2458–2473. November 2011. doi:10.1161/cir.0b013e318235eb4d. PMID 22052934. 
  28. ↑ "KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease". KDIGO. January 2013. https://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf. 
  29. ↑ "Recognition, treatment, and prevention of propylene glycol toxicity". Seminars in Dialysis (Wiley) 20 (3): 217–219. 7 June 2007. doi:10.1111/j.1525-139x.2007.00280.x. PMID 17555487. 
  30. ↑ "Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study". BMJ 349: g6196. October 2014. doi:10.1136/bmj.g6196. PMID 25359996. 
  31. ↑ 31.0 31.1 "Chapter 11". Basic & Clinical Pharmacology (13th ed.). McGraw-Hill Education. 2015. ISBN 978-0071825054. http://accessmedicine.mhmedical.com/book.aspx?bookid=1193. 
  32. ↑ "Significance of angiotensin type 1 receptor blockade: why are angiotensin II receptor blockers different?". The American Journal of Cardiology 84 (10A): 9S–15S. November 1999. doi:10.1016/s0002-9149(99)00728-6. PMID 10588089. 
  33. ↑ "Novartis Annual Report 2010". https://www.novartis.com/sites/www.novartis.com/files/novartis-annual-report-2010-en.pdf. 
  34. ↑ "Blockbuster Drugs That Will Go Generic Soon". U.S. News & World Report. 29 April 2011. http://money.usnews.com/money/blogs/the-best-life/2011/04/29/blockbuster-drugs-that-will-go-generic-soon. 
  35. ↑ "Novartis's Jimenez Has Blockbuster Plans For Diovan After Patent Expires". Bloomberg. 5 August 2011. https://www.bloomberg.com/news/2011-08-05/novartis-has-blockbuster-diovan-plans-after-patent-expires-1-.html. 
  36. ↑ "Exforge- amlodipine besylate and valsartan tablet, film coated". 12 June 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d0caec89-96ec-411d-a933-63eda74a6da7. 
  37. ↑ "Diovan HCT- valsartan and hydrochlorothiazide tablet, film coated". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d76a0419-05ee-437e-884c-65807aea9569. 
  38. ↑ "Exforge HCT- amlodipine valsartan and hydrochlorothiazide tablet, film coated". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=18d7820d-471f-4ee2-9ec6-25d8d27c77de. 
  39. ↑ "Entresto- sacubitril and valsartan tablet, film coated". 1 September 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=000dc81d-ab91-450c-8eae-8eb74e72296f. 
  40. ↑ 40.0 40.1 "Entresto (Sacubitril/Valsartan): First-in-Class Angiotensin Receptor Neprilysin Inhibitor FDA Approved for Patients with Heart Failure". American Health & Drug Benefits 8 (6): 330–334. September 2015. PMID 26557227. 
  41. ↑ "Entresto, a New Panacea for Heart Failure?". Cardiovascular & Hematological Agents in Medicinal Chemistry 16 (1): 5–11. 2018. doi:10.2174/1871525716666180313121954. PMID 29532764. 
  42. ↑ 42.0 42.1 "Common heart drug recalled in 22 countries for possible cancer link". https://www.cnn.com/2018/07/06/health/valsartan-heart-drug-recall-intl/index.html. 
  43. ↑ 43.0 43.1 "Carcinogens Have Infiltrated the Generic Drug Supply in the U.S.". Bloomberg News. 12 September 2019. https://www.bloomberg.com/news/features/2019-09-12/how-carcinogen-tainted-generic-drug-valsartan-got-past-the-fda. 
  44. ↑ "Several drugs containing valsartan being recalled due to contamination with a potential carcinogen". 9 July 2018. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2018/67202a-eng.php. 
  45. ↑ "Valsartan Class Action". http://valsartanclassaction.com/. 
  46. ↑ "Penjelasan BPOM RI Tentang Penarikan Obat Antihipertensi Yang Mengandung Zat Aktif Valsartan" (in id). https://www.pom.go.id/new/view/more/klarifikasi/88/PENJELASAN-BPOM-RI--TENTANG--PENARIKAN-OBAT-ANTIHIPERTENSI-YANG-MENGANDUNG-ZAT-AKTIF-VALSARTAN.html. 
  47. ↑ "FDA joins 22 countries' recall of common heart drug". CNN. https://www.cnn.com/2018/07/13/health/valsartan-recall-fda-bn/index.html. 
  48. ↑ "Hong Kong health department issues recall for five heart drugs containing valsartan that was made in China". 20 July 2018. https://www.scmp.com/news/hong-kong/health-environment/article/2154171/hong-kong-health-department-issues-recall-five. 
  49. ↑ "FDA updates on valsartan recalls". 2 August 2018. https://www.fda.gov/Drugs/DrugSafety/ucm613916.htm. 
  50. ↑ 50.0 50.1 "FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan)". 20 August 2018. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan. 
  51. ↑ "More Drug Makers Tagged as Valsartan Recall Grows". 13 August 2018. https://www.webmd.com/heart-disease/news/20180813/more-drug-makers-tagged-as-valsartan-recall-grows. 
  52. ↑ "FDA provides update on its ongoing investigation into valsartan products; and reports on the finding of an additional impurity identified in one firm's already recalled products". Food and Drug Administration (FDA) (Press release). 13 September 2018. Retrieved 14 September 2018.
  53. ↑ "Toxin at heart of drug recall shows holes in medical safety net". 22 August 2018. https://www.reuters.com/article/us-health-pharmaceuticals-china-insight-idUSKCN1L71D8. 
  54. ↑ "Chemical Impurities: An Epistemological Riddle with Serious Side Effects". International Journal of Environmental Research and Public Health 17 (3): 1030. February 2020. doi:10.3390/ijerph17031030. PMID 32041209. 
  55. ↑ "ARB Recalls: Valsartan, Losartan and Irbesartan". 3 February 2020. http://www.fda.gov/drugs/drug-safety-and-availability/recalls-angiotensin-ii-receptor-blockers-arbs-including-valsartan-losartan-and-irbesartan. 
  56. ↑ "Nitrosamine impurities". 23 October 2019. https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/nitrosamine-impurities.  Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  57. ↑ Clanton, N. (13 March 2019). FDA approves generic blood pressure drug to alleviate shortages caused by numerous recalls The Atlanta Journal-Constitution. Retrieved 13 July 2020.
  58. ↑ Current and Resolved Drug Shortages and Discontinuations Reported to FDA accessdata.fda.gov. Retrieved 13 July 2020.
  59. ↑ Lieferengpass Valsartan-CT 160mg . Gelbe Liste (in German). Pharmindex. Retrieved 13 July 2020.
  60. ↑ "Effect of valsartan on the incidence of diabetes and cardiovascular events". The New England Journal of Medicine 362 (16): 1477–1490. April 2010. doi:10.1056/NEJMoa1001121. PMID 20228403. 
  61. ↑ "Progressive effects of valsartan compared with amlodipine in prevention of diabetes according to categories of diabetogenic risk in hypertensive patients: the VALUE trial". Blood Pressure 17 (3): 170–177. 2008. doi:10.1080/08037050802169644. PMID 18608200. 
  62. ↑ "Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis". BMJ 340: b5465. January 2010. doi:10.1136/bmj.b5465. PMID 20068258. 



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