CME INDIA Presentation by Dr. N. K. Singh, MD, FICP, Diabetologist Physician, Director – Diabetes and Heart Research Centre (DHRC), Dhanbad, Chairman – RSSDI Jharkhand, Editor – CME INDIA.

The “Fourth Highest”

• With increasingly unhealthy lifestyles, the incidence of hyperuricemia is increasing.
• It has become the “fourth highest” after hypertension, hyperglycemia, and hyperlipidemia.

Case Scenario is worth considering

• 56-year-old man.
• Diabetic for 12 years, on Glimepiride 2mg/Sitagliptin 100 mg and Metformin 1.5 gm /day.
• CAD, TMT-positive, so on Nitrates, aspirin and statin.
• Recently got acute flare of Gout, now settled.
• Uric Acid 9.1 mg.
• Cardiologist started Febuxostat 40mg/day.
• Do you want to modify it?

What level of Uric acid is considered HYPERURICEMIA?

• Uric acid (UA) is the end product of purine metabolism in higher animals.
• UA synthesis and excretion are balanced in the body. Once this balance is disturbed, it leads to hyperuricemia.
• UA has limited solubility in bodily fluids, monosodium urate crystal formation occurs above the solubility threshold.
• Urate crystals are deposited preferentially in and around peripheral joints in the feet, knees, hands and elbows, especially those affected by osteoarthritis.
• Normally, male UA levels greater than 7 mg/dL or female UA levels greater than 6 mg/dL are considered hyperuricemia (1).
• However, Virdis et al. confirmed that the threshold of UA level increased total mortality (4.7 mg/dL) and cardiovascular mortality (5.6 mg/dL) risk, which was significantly lower than clinical diagnostic criteria (2). This paper concluded that  UA levels increasing the risk of total mortality and Cardiovascular mortality  are significantly lower than those used for the definition of hyperuricemia in clinical practice.

What the Recent epidemiological studies show?

• Hyperuricemia may be involved
  1. Hypertension.
  2. Diabetes.
  3. Atherosclerosis.
  4. Chronic kidney disease.
  5. Atrial fibrillation (AF).
  6. Occurrence of cardiovascular events.
• The possible mechanisms of UA induced CHD
  • Vascular endothelial damage of large and micro vessels.
  • Urate is easy to deposit in the vascular wall and stimulate the proliferation of vascular smooth muscle cells.
  • High UA can activate the renin-angiotensin system, inhibit nitric oxide production, and induce endothelial cell dysfunction.
  • UA can cause platelet activation, adhesion, and aggregation.
  • Hyperuricemia participates in the production of many inflammatory mediators (such as interleukin, C-reactive protein, etc.)
  • Hyperuricemia can increase the production of oxygen free radicals, which can cause low-density lipoprotein peroxidation, damage endothelial cells, promote vascular smooth muscle and intimal hyperplasia.
  • High UA can directly cause low-density lipoprotein oxidation

All controversial?

• Compared to allopurinol, whether febuxostat improves cardiovascular outcomes remains controversial.
• Whether UA lowering treatment is beneficial to patients with asymptomatic hyperuricemia is uncertain because these patients are often associated with a variety of risk factors (such as old age, chronic kidney disease, cardiovascular disease, obesity, metabolic syndrome, alcohol, or smoking habits, etc.) but without identified diseases.
• The urate oxidant-antioxidant paradox: UA is an effective antioxidant in cardiovascular and neurodegenerative diseases(3), making the relationship between UA and cardiovascular disease more complicated.

How Febuxostat came in controversy?

CARES Trial

• “In the CARES trial, treatment with febuxostat resulted in overall rates of major cardiovascular events that were similar to those associated with allopurinol treatment among patients with gout who had coexisting cardiovascular disease. However, cardiovascular death and deaths from any cause were more frequent in the febuxostat group than in the allopurinol group.”(4)
• Findings were similar in the modified intention-to-treat analysis and in the prespecified analysis that included events that occurred during treatment and within 30 days after treatment discontinuation.
• The mechanism underlying this risk of death is unclear.
• Preclinical cardiovascular studies of febuxostat have shown no toxic effects related to cardiac rhythm, function, or metabolism.
• The rates of adjudicated nonfatal events, including myocardial infarction, coronary revascularization, arrhythmias, and hospitalization for heart failure, were similar in the febuxostat group and the allopurinol group.
• The only heterogeneity in the analyses of cardiovascular mortality occurred in two subgroups — patients with concomitant administration of aspirin or NSAIDs. These drugs may be associated with more frequent gout flares, which, in turn, could lead to increases in cardiovascular events. (4)

What FDA did?

2021 New Insights to use Febuxostat(5)

Allopurinol, not so safe? 20% mortality if DRESS Syndrome

• A syndrome characterized by exfoliative dermatitis, hepatitis, interstitial nephritis, and eosinophilia, termed allopurinol hypersensitivity syndrome, is a dreaded adverse effect.
• Its aetiology is related to the accumulation of one of allopurinol’s metabolites, oxypurinol, of which clearance is decreased in the setting of renal insufficiency and the use of thiazide diuretics.
• The term DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) Syndrome has been recently used to describe an entity.
• Approximately 2% of patients taking the drug develop a mild cutaneous rash.
• A life-threatening toxicity syndrome has been described after its use, which includes some or all of the following: vasculitis, rash, eosinophilia, hepatitis, and progressive renal failure. This condition has been called allopurinol hypersensitivity syndrome (AHS).
• Criteria for the diagnosis of AHS were suggested by Singer and Wallace and include a documented intake of allopurinol, a lack of exposure to a different drug causing a similar clinical picture, and the presence of at least two major criteria or one major and one minor criterion.
  • Major criteria
    • Worsening renal function
    • Acute hepatocellular injury
    • Rash, manifested by toxic epidermal necrolysis, erythema multiforme, diffuse maculopapular rash, or exfoliative dermatitis.
  • Minor criteria
    • Fever
    • Leucocytosis
    • Eosinophilia

How about SGLT2 Inhibitors in hyperuricemia?

• SGLT-2 inhibitors are particularly suitable for reducing the risk of cardiovascular death in patients with T2D with hyperuricemia
• Sodium glucose cotransporter 2 inhibitors (SGLT-2; dapagliflozin, empagliflozin, canagliflozin, etc.) can effectively reduce UA level by accelerating the excretion of UA.
• The UA-lowering effect of SGLT-2 inhibitors can be attributed to glucose transporter-9 (GLUT-9) isoform 2. SGLT-2 inhibitors increased glucose concentration in renal tubules, activated GLUT-9 in proximal tubules, promoted glucose transport to cells, and excreted UA, and high glucose in collecting tubules inhibited the reabsorption of UA, both of which increased the excretion of UA.
• Many clinical studies and meta-analyses confirmed that SGLT-2 inhibitors can reduce main cardiovascular adverse events, HF admission rate, and all-cause mortality in patients with hyperuricemia.

CME INDIA Learning Points

• High UA regulates numerous molecular signals such as inflammation, oxidative stress, insulin resistance, and endothelial dysfunction. It can thus affect the progression and prognosis of cardiovascular diseases.
• While there are clear guidelines concerning management of symptomatic hyperuricemia in acute conditions such as gout, urolithiasis or acute urate nephropathy, less is known about their secondary prevention.
• Despite the ongoing debate on the role of UA in the pathogenesis of chronic kidney disease, hypertension, cardiovascular disease and heart failure, the management of asymptomatic hyperuricemia in patients with these chronic conditions is still mainly up to physicians’ judgement.
• Individual considerations should always be taken into account when prescribing urate-lowering therapy.
• Most clinical studies show that febuxostat improves cardiovascular outcomes in patients with gout, but whether it is as effective as allopurinol remains controversial.
• Allopurinol may increase the risk of serious adverse reactions, so it has not been widely used in clinical practice.
• Fortunately, SGLT-2 inhibitors (dapagliflozin, etc.) have a good prospect in ULT, meanwhile reducing main cardiovascular adverse events, HF admission rate, and all-cause mortality in patients with T2D and hyperuricemia.
• In terms of drug selection, previous studies have suggested that febuxostat is more effective and safer than allopurinol.
• Recent studies have shown cardiovascular death appeared to be higher in the febuxostat group compared to the allopurinol group. Therefore, febuxostat is neither recommended as the first-line ULT in the latest gout management guidelines nor for the treatment of asymptomatic hyperuricemia.
• 2021 new inputs do not tell the same story. It appears CARES Trial is not the final word. Recent network meta-analysis has clearly shown that Febuxostat can be used in patients with cardiovascular diseases. But no clear recommendations exist. Till, Allopurinol should be used in such situations.

References:

1. Yu W, Cheng JD. Uric Acid and Cardiovascular Disease: An Update from Molecular Mechanism to Clinical Perspective. Front Pharmacol. 2020;11:582680. Published 2020 Nov 16. doi:10.3389/fphar.2020.582680
2. Virdis A, Masi S, Casiglia E, Tikhonoff V, et al. From the Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension. Identification of the Uric Acid Thresholds Predicting an Increased Total and Cardiovascular Mortality Over 20 Years. Hypertension. 2020 Feb;75(2):302-308. doi: 10.1161/HYPERTENSIONAHA.119.13643. Epub 2019 Dec 9. PMID: 31813345.
3. Huang, Z., Hong, Q., Zhang, X. et al. Aldose reductase mediates endothelial cell dysfunction induced by high uric acid concentrations. Cell Commun Signal 15,3 (2017). https://doi.org/10.1186/s12964-016-0158-6
4. White, William B. Saag, Kenneth G.Becker, Michael A.et al.Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. New England Journal of Medicine March 29, 2018 378(13):1200 https://www.nejm.org/doi/full/10.1056/NEJMoa1710895
5. Zhang Shengzhao, Xu Ting, Shi Qingyang, Li Sheyu, Wang Ling, An Zhenmei, Su Na.Cardiovascular Safety of Febuxostat and Allopurinol in Hyperuricemic Patients With or Without Gout: A Network Meta-Analysis  Frontiers in Medicine. 2021,8:891  https://www.frontiersin.org/article/10.3389/fmed.2021.698437     DOI=10.3389/fmed.2021.698437    
6. Kang, E.H., Kim, S.C. Cardiovascular Safety of Urate Lowering Therapies. Curr Rheumatol Rep 21, 48 (2019). https://doi.org/10.1007/s11926-019-0843-8
7. Yu W and Cheng J-D (2020) Uric Acid and Cardiovascular Disease: An Update From Molecular Mechanism to Clinical Perspective. Front. Pharmacol. 11:582680. doi: 10.3389/fphar.2020.582680
8. Shalom R, Rimbroth S, Rozenman D, Markel A. Allopurinol-induced recurrent DRESS syndrome: pathophysiology and treatment. Ren Fail. 2008;30(3):327-9. doi: 10.1080/08860220701861045. PMID: 18350453.
9. Zinger JZ, Wallace SL. The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality. Arthritis Rheum. 1986; 29: 82–87
10. Sapan Kumar Behera, Saibal Das, Alphienes Stanley Xavier & Sandhiya Selvarajan (2018) DRESS syndrome: a detailed insight, Hospital Practice, 46:3, 152-162, DOI: 10.1080/21548331.2018.1451205

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