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.
(inputs from CME INDIA group discussion)
First, see this case scenario
- Diabetic 60 year-old-man, history of diabetes for 5 years, BMI-22, Non-alcoholic
- On metformin 500mg BD, Hb1ac-7.1%
- History of hypertension – 6 year, on Cilnidipine20mg od
- Renal and Cardiac assessment –Normal/ Maintains good LSM
- Family history of Isolated hypertriglyceridemia
- History of One episode of gout 10 years back – that time uric acid was 8.4mg
- T3/T4/TSH – Normal
- Uric acid 8.8mg
- Cholesterol – 201 mg
- TG – 504 mg
- LDL – 70mg
- HDL – 44mg
- Asymptomatic now
- Patient gives history of polyarthralgia as he crosses uric acid 7.5mg
- So, he takes febuxostat intermittently
- Never took statin and fibrate
- But as uric acid gets below 6 mg, TG automatically comes down to 210 to 240
- How do you plan to manage this case?
Uric Acid 2021
- Uric acid is the end product of purine metabolism in higher animals.
- 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 hyperuricemia (Hao et al., 2019).
- The gender difference may be due to lower levels of serum uric acid seen in females due to the hypouricemic effect of oestrogen.
- 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).
- Because uric acid 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.
Ideal way to collect samples for serum uric acid?
Adapted from Ref.3 and ref 4.
- Non-fasting lipid panels are acceptable for initial screening.
- If triglyceride levels are elevated or if genetic dyslipidaemia is suspected, repeat a fasting lipid panel.
- If lipoprotein(a) levels are measured, fasting or nonfasting samples can be obtained.
- There are many factors known to influence sUA level.
- Whether these factors influence a particular sUA report is unclear.
- Vigorous exercise is known to increase uric acid levels while moderate to light exercise reduces sUA levels
- Ethanol intake especially beer is known to elevate serum uric acid
- Smoking is known to be associated with a lower serum uric acid which is attributed to the inactivation of xanthine oxidase
- Apart from these, diet, drugs (e.g. some antihypertensives), state of hydration of the patient, and method of testing are also known to influence the sUA
Rule out always
|Drugs known to cause hyperuricemia.|
|Diuretics – Loop and thiazide diuretics|
|Antitubercular drugs – Pyrazinamide and ethambutol|
|Low dose Aspirin|
|Immunosuppressants – Cyclosporine, Tacrolimus|
|Cancer Chemotherapeutic Agents – Tumour Lysis Syndrome|
- Clinical studies show that hypercholesterolemia and hypertriglyceridemia are associated with a significantly increased risk of gout.
- Approximately 5-8 Gouty patients have high levels of hyper‐cholesterolemia and hypertriglyceridemia,
- Gout control may benefit from cholesterol and triglyceride therapy.
- Febuxostat can significantly decrease cholesterol and triglyceride levels in patients who did not receive lipid-lowering therapy. (5)
- Uric acid-lowering therapy benefits hyperlipidemia in gouty patients.
- Febuxostat effectively improves serum cholesterol and triglyceride levels compared to allopurinol and benzbromarone in patients with gout.
Always rule out Hypothyroidism
- In patients with hyperlipidemia, always rule out hypothyroidism as the cause of the hyperlipidemia before treatment with lipid-lowering medications. (4)
- Hypothyroidism can elevate both cholesterol and triglyceride levels, which improve with treatment. Changes in low-density lipoprotein cholesterol have been observed as early as 3 months after the patient is euthyroid.
Consider SGLT2-Inhibitors, when appropriate
- The use of sodium-glucose cotransporter-2 (SGLT2) inhibitors vs glucagon-like peptide-1 receptor agonists (GLP1-RA) is associated with a 50% reduced risk for gout. (6)
- Empagliflozin reduced UA levels and the composite of gout episodes or prescription of anti-gout medication. These clinically important findings expand the utility of empagliflozin as a potential anti-gout treatment in patients with T2D, beyond well-established cardio-renal benefits. (7)
Cardiometabolic drugs known to have urate lowering properties. (Ref-3)
|Angiotensin receptor blockers-Losartan|
|Calcium channel blockers|
|Lipid lowering agents:|
|High dose aspirin|
CME INDIA Discussion
(Inputs also from RSSDI-Case study group)
Dr. Madanmohan, Hyderabad:
- I think Rosuvastatin in combination with Febuxostat may be required as his cholesterol is also in higher side.
Dr. Sanjeev Rao, former HOD, Dept. of Medicine, Manipal, Bengaluru:
- Losartan is the only drug which can lower both uric acid and B.P, so this should be started at maximum dose of 50 mg bd, then add others except diuretics.
- For HTG commence non-pharmacological methods of management if not controlled then consider statins, some statin is better than no statin.
- If still not controlled, consider fenofibrate.
- For hyperuricemia: diet, weight reduction and allopurinol.
- Also, Allopurinol is better option for CKD patients with Hyperuricemia.
- CARES STUDY favours Allopurinol vs Febuxostat in CVD and ACM increased by 50%. Sudden cardiac death increased by 34%. But there were many issues in CARES study and people say who CARES.
- Febuxostat – be careful in patients with CLD and ASCVD.
- Allopurinol remains 1st line drug and go low and slow in CKD.
- Both are NO for Acute Gouty attacks.
Dr. Narsingh Verma, Lucknow:
- Very correct assessment
Dr. Deepak Rastogi, Kotdwara, Uttarkhand:
- Febuxostat can also cause sudden death.
- Febuxostat works better than allopurinol, I am using it in each case with elevated S. URIC levels with promising results
- Uric acid levels are usually high in CKD, most of the nephrologist do not treat it.
- Our genetic constitution is such that in most of the people’s TG is on the higher side, we have inherited this very property.
- Rosuvastatin along with fenofibrate works better to bring down not only raised TG but also elevated CHOLESTEROL.
- We have to treat elevated TG levels by all means.
- Elevated TG levels are more dangerous in females as compared to males.
Dr. Mahesh Chhabra:
- Fenofibrate alone can be used though exact quantum of its uricosuric effect is not known.
Dr. Surendra Kumar Goyal, Kota:
- Patient can be put on Losartan, which will further reduce uric acid level.
- Allopurinol May be preferred over febuxostat.
- Fenofibrate May be added for HTG.
Dr. Somnath, Hyderabad:
- Control TG, no need of febuxostat or allopurinol if patient is not having symptoms.
Dr. Ronak Shah, Senior physician, Anand, Gujrat:
- Reversible cause of Hyperuricemia may be searched before deciding pharmacotherapy.
- In my practice, diuretics and other drugs, hypothyroidism, obesity alcohol, non-veg diet and cold drinks, HT, psoriasis are commonly found responsible.
- Fenofibrate and Losartan have uricosuric property which can be used in this patient.
Dr. Praveen Shukla, DM, Card., Kolkata:
- Need fenofibrate 160 mg daily with atorvastatin 20 mg as additional medicines to reduce triglycerides level.
Dr. Alok Rai, Sr. Diabetologist, Raipur:
- SGLT2I will help in reducing SUA levels. Also, rule out hypothyroidism.
Dr. B. K. Singh, MD, Samastipur, Bihar:
- It is better to initially treat hyperuricemia with Allopurinol.
- Fenofibrate, rosuvastatin low dose, and some other OHA in low dose may have to be added for better glycaemic control and dyslipidaemia.
Dr. P. R. Parthsarathy, Chest Physician, Chennai:
- One has to rule out poorly controlled Diabetes as the cause of increased triglycerides (secondary causes) before attempting changes in OHA s and labelling as familial.
- Hb1Ac for his age + LSM looks good, still Fasting sugar should be done for assessment.
- Regarding uric acid, the patient is asymptomatic. The increase in uric acid has not been sudden. I think one can wait and recheck uric acid after 3 months and see the variation.
Dr. Premchand Singh, Diabetologist, Imphal:
- Obesity, hypothyroidism and chronic alcoholism are also common causes of hypertriglyceridemia.
Dr. N. K. Singh:
- Why not to add Sglt2 Inhibitors?
- It can help to reduce sugar and uric acid-All.
- This case – Asymptomatic hyperuricemia.
- So first decide to treat or not?
- Is it possible if we only add Febuxostat, then we get both TG and uric acid in desirable range?
Dr. Ripun Borpujari, Sivasagar, Assam:
- Good question. I think it would be a better option adding to Cilnidipine.
- As he had gout in the past, so hyperuricemia treatment is indicated.
- SGLT2-Inhibitors lowers TG too. (8,9)
Dr. Raju Sharma, Sr Physician, Jamshedpur:
- Short term outlook is TG. Adding statin to reduce risk of future cardiac events at this age is an overkill. Add late, rather replace later. Often possible.
Dr. Noni G. Singha, Dibrugarh, Assam:
- He needs to check at his diet and hydration part.
- His glycemia part is okay so no need to alter the metformin at this moment.
- Antihypertensive should be changed to Losartan plus cilnidipine instead of maximum dose of cilnidipine.
- Lipid lowering drugs statin is indicated in this patient at moderate dose as the age is 60, hypertensive and diabetic and total non-HDL is above 130. Moderate to high dose intensity statin itself may cause reduction in 50 percent of TG. Later on, Fenofibrate may be used if statin does not control TG.
- One episode of gout 5 yrs. back does not fulfil the criteria of starting Urate lowering drugs at level below 9 mg %.
- No, Febuxostat is not indicated here.
Dr. Santosh Kumar Singh, DM Endo., Patna:
- There’s history of gout hence hypouricemic treatment is required.
Dr. Noni G. Singha:
- Partially agree Sir. Here h/o gout 5 yrs. back. According to ACR it should be within 3 yrs. and more than two episodes of gout attack in a year should be there to start the treatment or there should be any level of bony erosions due to gout or there should be subcutaneous tophi.
- Only one episode of gout may be treated in pts with CKD with level 9.
- Different guideline may have different recommendation.
- Real world experience also counts. But motto is to do no harm to the patients. No guideline is perfect that’s why it keeps changing. Guidelines are for learning the subject and one needs to use wisdom.
- He needs to be ruled out for other inflammatory disorder like RA, Lupus, Psoriasis etc as intermittent flare may increase both SUA and Triglycerides.
- Also, rule out any other intra-abdominal disease like cholecystitis, cholelithiasis, IBD etc.
Dr. Awadhesh K. Singh, DM Endo., Kolkata:
- I failed to understand such a heterogeneous suggestion in this simple case.
- My thoughts:
- Always better to use a combo of RASB plus CCB vs CCB alone – best CV and renal data for former compared to later.
- Losartan plus Cilnidipine perfect in this case with high UA despite Febuxostat.
- History of one episode of gout and current UA of 8.8 on Fabuxo (Intermittent), continue febuxostat without any controversy!
- Febuxostat is always preferred over Allopurinol except in known CVD.
- TG>500 mg: primary target is to prevent pancreatitis not CV protection – go for fibrate straightforward.
- Statin can be added or replaced once TG target is desirable.
- Diabetes, hypertension and dyslipidaemia at 60 years – high risk – replace 2-tab Metformin with SGLT2i plus Metformin.
Dr. Praveen Shukla, DM, Card., Kolkata:
- I think, statin should be added as per lipid guideline as patient aged >40 yrs. and diabetic, so moderate dose statin as a routine.
Dr. Awadhesh K. Singh, DM, Endo., Kolkata:
- True! That everyone knows but here priority is to reduce TG first. By the way, role of statin in primary prophylaxis is less robust but as I said add or replace once TG has come down. Short term Motto is to prevent pancreatitis – use fibrate. Long term goal is to reduce CVD – use statin. Hope that clarifies my approach!
Dr. Noni G. Singha:
- Level to cause/risk pancreatitis is 1000 mg % (which is accepted by most of teachings) so no immediate threat from the level of 500. Still agree no harm in using fibrate. But starting Statin is of also no harm as we don’t know hidden cardiac status of this particular pt., also associated with raised total non-HDL.
Dr. A. K. Virmani, Jamshedpur:
- More than 500 TG is a risk for pancreatitis and should be treated. Latest Lipid Association of India Guidelines 2020:
Dr. Awadhesh K. Singh, DM, Endo., Kolkata:
- Let’s be clear on one point – when TG is of such high value – lab value of all other lipid parameters is considered false analytically due to lipemia and one should the repeat the test once TG comes down.
- Serum becomes lipemic once TG>350.
- There is no exact cut off value above which pancreatitis triggered. Some study says TG >450, some says >500 and others >1000 but majority of recommendation is to intervene once TG>500.
- Risk of pancreatitis is linearly correlated once TG>500. Let’s not waste time in proving the point that it happens only if TG>1000!
Dr. Basab Ghosh, Agartala:
- So, if TG more than 400, only TC, TG and HDL should be mentioned in calculation method. Otherwise in case of TG more than 400, direct method is needed.
CME INDIA Learning Points
- For patients with asymptomatic hyperuricemia (SU >6.8 mg/dl with no prior gout flares or subcutaneous tophi), we conditionally recommend against initiating any pharmacologic ULT (allopurinol, febuxostat, probenecid) over initiation of pharmacologic ULT. Certainty of evidence-High-American College of Rheumatology (ACR-2020).
- There are no clear clinical practice guidelines on management of asymptomatic hyperuricemia from India. Unnecessary investigation of serum uric acid for all patients with rheumatological symptoms should be discouraged
- LAI recommendations Both fasting and non-fasting lipid profiles are important for managing Indian patients with dyslipidaemia. For routine screening, a fasting lipid profile is not mandatory.
- Direct LDL-C measurement is preferred if TG is ≥200 mg/dl or LDL-C is < 150 mg/dl, preferably.
- In patients with elevated TG levels, rule out secondary causes for hypertriglyceridemia.
- Lifestyle changes are recommended for all patients with hypertriglyceridemia: Regular exercise, maintenance of appropriate body weight, avoidance of alcohol and smoking, eating a diet with reduced saturated fat and refined carbohydrates. Lifestyle modification can reduce TG by as much as 50%.
- Adequate glycaemic control in DM will result in substantial fall in triglyceride levels.
- Among Non-Statin drugs, omega-3 fatty acids especially icosapent ethyl in dose of 4 grams per day is preferred as it has been shown to reduce adverse CV events in patients with ASCVD or diabetes and multiple risk factors. In subjects with very high TG levels, fibrates are to be initiated first with simultaneous identification and control of secondary causes.
- Most guidelines conditionally recommend testing HLA–B*5801 prior to starting allopurinol for patients of Southeast Asian descent (e.g., Han Chinese, Korean, Thai) and African American patients, who have a higher prevalence of HLA–B*5801.This is to prevent – Allopurinol induced dermatological reactions such as Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS) and allopurinol induced hypersensitivity are severe and life threatening.
- For patients with gout taking febuxostat with a history of CVD or a new CV event, we conditionally recommend switching to an alternative ULT agent if available and consistent with other recommendations in this guideline.
- Febuxostat is considered safe in CKD as it is metabolised by the hepatic route and it has renal benefits which are as good or perhaps better than allopurinol and hence, we recommend that it should be used as a first line agent in CKD patients. Starting dose for Febuxostat is 40 mg/day once daily, which can be titrated gradually in order to achieve target.
- Case Highlight:
- Wide variation in approach evident as per CME INDIA Case discussion.
- Losartan and Cilnidipine – Looks better choice.
- SGLT2-Inhibitor and Metformin – Appear better choice.
- Febuxostat looks preferred choice to continue.
- As per history, just by taking febuxostat reduction is evident. Some studies also favour it. There is need for large scale study to explore its role in reducing TG without using anti-lipid agents.
CME INDIA Tail Piece
- 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.
- Nicholls A, Snaith M L, Scott J T. Effect of Oestrogen Therapy on Plasma and Urinary Levels of Uric Acid Br Med J 1973; 1 :449 doi:10.1136/bmj.1.5851.449
- Valsaraj, Rahul & Singh, Awadhesh & Gangopadhyay, Kalyan & Ghoshdastidar, Biswajit & Goyal, Ghanshyam & Batin, Masood & Mukherjee, Dibyendu & Sengupta, Upal & Chatterjee, Sanjay & Sengupta, Nilanjan. (2020). Management of Asymptomatic Hyperuricemia: Integrated Diabetes & Endocrine Academy (IDEA) consensus statement. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 14. 10.1016/j.dsx.2020.01.00
- Connie B Newman, Michael J Blaha, Jeffrey B Boord, Bertrand Cariou, Alan Chait, Henry G Fein, Henry N Ginsberg, Ira J Goldberg, M Hassan Murad, Savitha Subramanian, Lisa R Tannock, Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 105, Issue 12, December 2020, Pages 3613–3682, https://doi.org/10.1210/clinem/dgaa674
- Wu J, Zhang YP, Qu Y, Jie LG, Deng JX, Yu QH. Efficacy of uric acid-lowering therapy on hypercholesterolemia and hypertriglyceridemia in gouty patients. Int J Rheum Dis. 2019 Aug;22(8):1445-1451. doi: 10.1111/1756-185X.13652. Epub 2019 Jul 17. PMID: 31317680.
- Lund LC, Højlund M, Henriksen DP, Hallas J, Kristensen KB. Sodium-glucose cotransporter-2 inhibitors and the risk of gout: a Danish population based cohort study and symmetry analysis. Pharmacoepidemiol Drug Saf. Published online April 21, 2021. doi:10.1002/pds.5252
- Ferreira, Joao & Inzucchi, Silvio & Mattheus, Michaela & Meinicke, Thomas & Steubl, Dominik & Wanner, Christoph & Zinman, Bernard. (2021). Empagliflozin and uric acid metabolism in diabetes: a post‐hoc analysis of the EMPA‐REG OUTCOME trial. Diabetes, Obesity and Metabolism. 10.1111/dom.14559.
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