CME INDIA Presentation by Dr. Bijay Patni, HoD, Diabetes Wellness Care, Kolkata. (Based on the presentation at 16th Asian-pacific Congress of Hypertension on 28th November 2021, New Delhi)
21 Noteworthy Points
1. Understanding Uric Acid in 2021
- Uric acid (UA) is the end product of purine metabolism in higher animals, such as humans and great apes.
- Under physiological conditions, UA synthesis and excretion are balanced in the body. Once this balance is disturbed, it leads to hyperuricemia.
- Normally, male UA levels greater than 7 mg/dL or female UA levels greater than 6 mg/dL are considered to be hyperuricemia (Hao et al., 2019).
- 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 (Virdis et al., 2020).
2. Generation of uric acid, a purine end product. Uric acid can be generated from precursors, primarily
3. Causes of hyperuricemia
4. How Common is it?
5. Signs and Symptoms
- Acute arthritis
- The metatarsophalangeal joint of the first toe often involved
- Nocturnal excruciating pain, swelling, redness and tenderness
- Nonsymmetric synovitis
- Chronic gouty arthritis
- Periarticular tophaceous deposits
6. Comparison between Criteria
7. Hyperuricemia & Hypertension
(N Eng J Med. 2008 Oct 23; 359(17): 1811–1821)
- More common in primary hypertension than in secondary hypertension, at least in adolescents.
- One study an elevated uric acid level (>5.5 mg per deciliter was observed in nearly 90% of adolescents with essential hypertension.
- Whereas uric acid levels were significantly lower in controls and teens with either white-coat or secondary hypertension.
- In some studies hyperuricemia is present in 40 to 60% of subjects with untreated hypertension.
8. Wisdom words from past on Uric acid and Hypertension
9. The way Hyperuricemia induces hypertension
10. Simplified Mechanistic diagram
11. High UA regulates numerous molecular signals
12. Uric Acid: A new look at an old risk marker for CVD, metabolic syndrome & type 2 DM: The urate redox shuttle.
(Hayden, MR & Tyagi SC. Nutrition & Metab. 2004; 1:10, 1 – 15)
- Role of UA, oxidative – redox stress, reactive O2 species, dec endothelial nitric oxide & endothelial dysfunction cannot be over emphasized.
- In the pro – oxidative environment, the antioxidant properties of UA paradoxically become pro – oxidant.
- This contributes to the oxidation of lipoproteins within atherosclerotic plaques
- Elev of uric acid > 4 mg/ml should be a “red flag” to the inc risk of CVD & espec in those at risk for CVD.
13. What a systematic review and meta-analysis 0n Hyperuricemia and incident hypertension tells?
(Arthritis Care & Research; Vol. 63, No. 1, January 2011, pp 102–110)
- A total of 18 prospective cohort studies
- 55,607 participants
- Hyperuricemia was associated with an increased risk for incident hypertension (adjusted risk ratio [RR] 1.41, 95% confidence interval [95% CI] 1.23-1.58)
- Conclusion: Hyperuricemia is associated with an increased risk for incident hypertension, independent of traditional hypertension risk factors. This risk appears more pronounced in younger individuals and women
14. Relationship between carotid-femoral pulse wave velocity and uric acid in subjects with hypertension and hyperuricemia
- A retrospective cross-sectional study.
- Sample Size: 651 patients enrolled
- Group 1: subjects without hypertension and hyperuricemia
- Group 2: hypertension subjects without hyperuricemia
- Group 3: hyperuricemia subjects without hypertension
- Group 4: subjects with hypertension and hyperuricemia
- Conclusion: Carotid-femoral pulse wave velocity (CF-PWV) was significantly higher in hypertension subjects with hyperuricemia compared to hypertension without hyperuricemia subjects, and serum uric acid was an independent associating factor of CF-PWV.
15. Relationship between Uric acid and Blood Pressure in different age groups
(Lee et al. Clinical Hypertension (2015) 21:14)
- Objective: To observe the relationship between serum UA and BP in different age groups
- Sample Size: 45,098 Koreans
- Results: The association between serum UA and BP was stronger in women < 0.001 for systolic BP; β = 0.65, p < 0.001 for diastolic BP) and in between 40 and 59 (β = 0.51, p < 0.001 for diastolic BP).
- Conclusion: Hyperuricemia increased the relative risk of hypertension by approximately 30% in men under 60 and by 2.6-fold in women under 40.
16. Uric acid is a strong risk marker for developing hypertension from prehypertension
(Hypertension, January 2018;71(1):78-86)
- A large-scale, retrospective, single-center cohort study.
- Enrolled 3584 Prehypertensive Japanese Adults.
- The cumulative incidence of hypertension from prehypertension over 5 years was 25.3%.
- Results: The cumulative incidence of hypertension in subjects with hyperuricemia (n=726) was significantly higher than those without hyperuricemia (n=2858; 30.7% versus 24.0%; P<0.001)
- Conclusion: Increased serum uric acid is a strong risk marker for developing hypertension from prehypertension.
17. Management of Hyperuricemia & Effects on BP Control
- The aims of treatment are to:
- Decrease the symptoms of an acute attack
- Decrease the risk of recurrent attacks
- Lower serum urate levels
- Usually there is no justification for treatment of asymptomatic hyperuricemia. But some physicians treat if serum uric acid is > 12 mg/dl and there is risk of nephrolithiasis.
- In the setting of malignancy, when tumor lysis can cause hyperuricemia, allopurinol is recommended.
18. Therapeutic Basket
19. How Anti-hyperurecemic Drugs work
20. Some Important Trials and their messages
1. FAST Study Group. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020
Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol.
2. Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED) Eur Heart J 2019;40:1778-86.
- Febuxostat significantly decreased SUA levels
- This effect was associated with greater reduction in the incidence of cerebral, cardiovascular, and renal events, which was used as the primary composite endpoint, in patients aged ≥65 years with asymptomatic hyperuricaemia than in their counterparts who underwent conventional therapy with lifestyle modifications.
- However, the FREED did not report any adverse events owing to excessive reduction in the SUA levels.
3. FREED-Posy-hoc analysis 2021 (Rheumatology, 2021)
- The Febuxostat for Cerebral and Cardiorenovascular Events Prevention Study (FREED in this post-hoc analysis, febuxostat treatment for achieving SUA levels of between 5 and 6 mg/dL reduced a composite of all deaths, cerebral, cardiovascular, and renal events with a pronounced effect compared with SUA levels of ≤4, >4 to ≤5, >6 to ≤7, and >7 mg/dL and excessive SUA reduction may be harmful in participants with hyperuricaemia.
4. The recent CARES trial adds new information on comparative CV safety between two XO inhibitors (XOIs), febuxostat and allopurinol, in patients with gout. Curr Rheumatol Rep 21, 48 (2019)
- It remains unclear whether ULT reduces CV risk in patients with gout or hyperuricemia.
- Comparative CV safety studies of XOIs suggest that additional mechanisms beyond urate-lowering effect or XO inhibition are likely involved in CV risk modification in patients with gout risk.
5. The NU-FLASH trial 2015
- In cardiac surgery patients with renal dysfunction, febuxostat reduced uric acid earlier than allopurinol, had a stronger reno-protective effect than allopurinol, and also had superior antioxidant and anti-inflammatory effects.
21. Recent Advances In Treatment
- Proinflammatory cytokines like IL-1 and TNF-a are also being targeted in the new drug development program in gout.
- IL-1 receptor antagonist is anakinra, and TNF-a inhibitors are infliximab and etanercept.
- Rilonacept (also known as IL-1 trap) is also being used with success; rilonacept binds to IL-1a, IL-1b and IL-1Ra, and thus preventing IL-1 from binding to IL-1R1.
- Anakinra is used at a dose of 100 mg/day subcutaneously for 3 days, while the dose of rilonacept is 320 mg subcutaneous loading, followed by 160 mg subcutaneous weekly for 16 weeks. These drugs are basically useful in chronic active
- Nizam’s Institute of Medical Sciences (NIMS) at Hyderabad has used anakinra in few patients with some success.
- Canakinumab, a human monoclonal antibody targeted at IL-1b, is recently being used in acute gout and chronic gout with acute flare.
- Uric Acid Is a Biomarker of Oxidative Stress in the Failing Heart: Lessons Learned from Trials With Allopurinol and SGLT2 Inhibitors:
- Sodium-glucose cotransporter 2 inhibitors induce a state of nutrient deprivation that includes activation of sirtuin-1, suppression of xanthine oxidase, and lowering of serum uric acid.
- The intermediary role of sirtuin-1 in both uric acid-lowering and cardioprotection may explain why, in mediation analyses of large-scale cardiovascular trials, the effect of sodium-glucose cotransporter 2 inhibitors to decrease serum uric acid is a major predictor of the ability of these drugs to decrease serious heart failure events.
- SGLT-2 inhibitors are particularly suitable for reducing the risk of cardiovascular death in patients with T2D with hyperuricemia.
CME INDIA Learning Points
- At least in adolescents, uric acid contributes, mechanistically, to the development of elevated blood pressure.
- Patients with elevated uric acid may be more responsive to uric acid-lowering therapy early in the course of their disease.
- Allopurinol and probenecid have side effect profiles that are inferior to conventional antihypertensive medication so are not optimal alternatives for preventive therapy.
- Reduction in dietary sweetener intake may be a useful approach to uric acid reduction in elect patients.
CME INDIA Tail Piece
- Gout only affects humans and great apes.
- Most animals produce urate oxidase, an enzyme that converts uric acid into the more soluble allantoin so it can’t precipitate in the joints. Unlike the majority of mammals, uric acid is the end product of purine metabolism in humans, due to the loss of uricase activity during the evolution of hominids.
- One hypothesis claims this is because uric acid is a strong antioxidant, protecting us against free radicals.
- Look beyond Gout and Uric Acid as there is increasing evidence of a relationship between hyperuricaemia and hypertension, renal disease, metabolic syndrome, diabetes and cardiovascular disease.
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