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Impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities of glucose and uric acid metabolisms

Journal of Human Hypertension volume 32, pages 301–310 (2018)Cite this article

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Abstract

Treatment of hypertension with thiazide diuretics may trigger hypokalemia, hyperglycemia, and hyperuricemia. Some studies suggest simultaneous potassium supplementation in hypertensive patients using thiazide diuretics. However, few clinical studies have reported the impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities in blood glucose and uric acid (UA) metabolisms. One hundred hypertensive patients meeting the inclusion criteria were equally randomized to two groups: IND group receiving indapamide (1.25–2.5 mg daily) alone, and IND/KCI group receiving IND (1.25–2.5 mg daily) plus potassium chloride (40 mmol daily), both for 24 weeks. At the end of 24-week follow-up, serum K+ level in IND group decreased from 4.27 ± 0.28 to 3.98 ± 0.46 mmol/L (P < 0.001), and fasting plasma glucose (FPG) and UA increased from 5.11 ± 0.52 to 5.31 ± 0.57 mmol/L (P < 0.05), and from 0.404 ± 0.078 to 0.433 ± 0.072 mmol/L (P < 0.05), respectively. Serum K+ level in IND/KCl group decreased from 4.27 ± 0.36 to 3.89 ± 0.28 mmol/L (P < 0.001), and FPB and UA increased from 5.10 ± 0.41 to 5.35 ± 0.55 mmol/L (P < 0.01), and from 0.391 ± 0.073 to 0.457 ± 0.128 mmol/L (P < 0.001), respectively. The difference value between the serum K+ level and FPG before and after treatment was not statistically significant between the two groups. However, the difference value in UA in IND/KCl group was significantly higher than that in IND group (0.066 (95% confidence interval (CI): 0.041–0.090)  mmol/L vs. 0.029 (95% CI: 0.006–0.058) mmol/L, P < 0.05). The results showed that long-term routine potassium supplementation could not prevent or attenuate thiazide diuretic-induced abnormalities of glucose metabolism in hypertensive patients; rather, it may aggravate the UA metabolic abnormality.

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References

  1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217–23.

    Article  Google Scholar 

  2. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507–20.

    Article  CAS  Google Scholar 

  3. Agarwal R. Hypertension, hypokalemia, and thiazide-induced diabetes: a 3-way connection. Hypertension. 2008;52:1012–3.

    Article  CAS  Google Scholar 

  4. Kostis JB, Wilson AC, Freudenberger RS, Cosgrove NM, Pressel SL, Davis BR, et al. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am J Cardiol. 2005;95:29–35.

    Article  CAS  Google Scholar 

  5. McAdams DeMarco MA, Maynard JW, Baer AN, Gelber AC, Young JH, Alonso A, et al. Diuretic use, increased serum urate levels, and risk of incident gout in a population-based study of adults with hypertension: the Atherosclerosis Risk in Communities Cohort Study. Arthritis Rheum. 2012;64:121–9.

    Article  CAS  Google Scholar 

  6. Jian-Liang Z, Yong-Wen Q, Xing Z, Jian-Li Q, Jiang C, Rong-Liang X. Possible induction of diabetes by treatment of hypertension with indapamide (with four case reports). Diabetes Res Clin Pract. 2004;65:243–146.

    Article  Google Scholar 

  7. Zhang JL, Qin YW, Zheng X, Qiu JL, Zhao XX, Zou DJ. Combination therapy with angiotensin-converting enzyme inhibitors and indapamide impairs glucose tolerance in Chinese hypertensive patients. Blood Press. 2010;19:110–8.

    Article  CAS  Google Scholar 

  8. Rapoport MI, Hurd HF. Thiazide-induced glucose intolerance treated with potassium. Arch Intern Med. 1964;113:405–8.

    Article  CAS  Google Scholar 

  9. Helderman JH, Elahi D, Andersen DK, Raizes GS, Tobin JD, Shocken D, et al. Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium. Diabetes. 1983;32:106–11.

    Article  CAS  Google Scholar 

  10. Shafi T, Appel LJ, Miller ER 3rd, Klag MJ, Parekh RS. Changes in serum potassium mediate thiazide-induced diabetes. Hypertension. 2008;52:1022–9.

    Article  CAS  Google Scholar 

  11. Fathallah N, Slim R, Larif S, Hmouda H, Ben Salem C. Drug-induced hyperglycaemia and diabetes. Drug Saf. 2015;38:1153–68.

    Article  CAS  Google Scholar 

  12. Zillich AJ, Garg J, Basu S, Bakris GL, Carter BL. Thiazide diuretics, potassium, and the development of diabetes: a quantitative review. Hypertension. 2006;48:219–24.

    Article  CAS  Google Scholar 

  13. Roush GC, Ernst ME, Kostis JB, Tandon S, Sica DA. Head-to-head comparisons of hydrochlorothiazide with indapamide and chlorthalidone: antihypertensive and metabolic effects. Hypertension. 2015;65:1041–6.

    Article  CAS  Google Scholar 

  14. Decaux G, Soupart A. Treatment of symptomatic hyponatremia. Am J Med Sci. 2003;326:25–30.

    Article  Google Scholar 

  15. Kaplan NM, Carnegie A, Raskin P, Heller JA, Simmons M. Potassium supplementation in hypertensive patients with diuretic-induced hypokalemia. N Engl J Med. 1985;312:746–9.

    Article  CAS  Google Scholar 

  16. Ruml LA, Pak CY. Effect of potassium magnesium citrate on thiazide-induced hypokalemia and magnesium loss. Am J Kidney Dis. 1999;34:107–13.

    Article  CAS  Google Scholar 

  17. Maronde RF, Chan LS, Vlachakis N. Hypokalemia in thiazide-treated systemic hypertension. Am J Cardiol. 1986;58:18A–21A.

    Article  CAS  Google Scholar 

  18. Holeggens A, Alderman MH, Kjeldsen S, Julius S, Devereua RB, De Faire U, et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int. 2004;65:1041–9.

    Article  Google Scholar 

  19. Siegel D, Hulley SB, Black DM, Cheitlin MD, Sebastian A, Seeley DG, et al. Diuretics, serum and intracellular electrolyte levels,and ventricular arrhythmias in hypertensive men. JAMA. 1992;267:1083–9.

    Article  CAS  Google Scholar 

  20. Khuri RN, Strieder WN, Giebisch G. Effects of flow rate and potassium intake on distal tubular potassium transfer. Am J Physiol. 1975;228:1249–61.

    Article  CAS  Google Scholar 

  21. Velazquez H, Wright FS. Control by drugs of renal potassium handling. Annu Rev Pharmacol Toxicol. 1986;26:293–309.

    Article  CAS  Google Scholar 

  22. Graham UM, McCance DR, Young IS, Mullan KR. A randomised controlled trial evaluating the effect of potassium supplementation on vascular function and the renin–angiotensin–aldosterone system. J Hum Hypertens. 2014;28:333–9.

    Article  CAS  Google Scholar 

  23. Huang CL, Kuo E. Mechanism of hypokalemia in magnesium deficiency. J Am Soc Nephrol. 2007;18:2649–52.

    Article  Google Scholar 

  24. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981–97.

    Article  Google Scholar 

  25. Hirst JA, Farmer AJ, Feakins BG, Aronson JK, Stevens RJ. Quantifying the effects of diuretics and beta-blockers on glycaemic control in diabetes mellitus—a systematic review and meta-analysis. Br J Clin Pharmacol. 2015;79:733–43.

    Article  CAS  Google Scholar 

  26. Gibson TJ. Hypertension, its treatment, hyperuricaemia and gout. Curr Opin Rheumatol. 2013;25:217–22.

    Article  CAS  Google Scholar 

  27. Morledge JH. Clinical efficacy and safety of indapamide in essential hypertension. Am Heart J. 1983;106(Part 2):229–32.

    Article  CAS  Google Scholar 

  28. Saruta T, Ogihara T, Saito I, Rakugi H, Shimamoto K, Matsuoka H, et al. Comparison of olmesartan combined with a calcium channel blocker or a diuretic in elderly hypertensive patients (COLM Study): safety and tolerability. Hypertens Res. 2015;38:132–6.

    Article  CAS  Google Scholar 

  29. Ito S, Naritomi H, Ogihara T, Shimada K, Shimamoto K, Tanaka H, et al. Impact of serum uric acid on renal function and cardiovascular events in hypertensive patients treated with losartan. Hypertens Res. 2012;35:867–73.

    Article  CAS  Google Scholar 

  30. Bakris G, Molitch M, Hewkin A, Kipnes M, Sarafidis P, Fakouhi K, et al. Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome. Diabetes Care. 2006;29:2592–7.

    Article  CAS  Google Scholar 

  31. Brown MJ, Williams B, Morant SV, Webb DJ, Caulfield MJ, Cruickshank JK, et al. Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase 4 trial. Lancet Diabetes Endocrinol. 2016;4:136–47.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Lou-man Zhang and Tian-tian Zhu for statistical analysis support.

Funding

This study was supported by Changhai Hospital Development Fund (2014012).

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  1. These authors contributed equally: Jian-liang Zhang, Hui Yu, Ying-wei Hou and Ke Wang.

Authors and Affiliations

  1. Department of Cardiology, Changhai Hospital, Second Military Medical University, Shanghai, China

    Jian-liang Zhang, Hui Yu, Ying-wei Hou, Ke Wang, Wen-shan Bi, Liang Zhang, Qian Wang, Pan Li, Man-li Yu & Xian-xian Zhao

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41371_2018_36_MOESM1_ESM.doc

The difference value between the outcome at 12 and 24 weeks after treatment and the baseline [means (95% confidence interval)]

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Zhang, Jl., Yu, H., Hou, Yw. et al. Impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities of glucose and uric acid metabolisms. J Hum Hypertens 32, 301–310 (2018). https://doi.org/10.1038/s41371-018-0036-3

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