Hypertension, Hypokalemia, and Thiazide-Induced Diabetes
2008; Lippincott Williams & Wilkins; Volume: 52; Issue: 6 Linguagem: Inglês
10.1161/hypertensionaha.108.121970
ISSN1524-4563
Autores Tópico(s)Sodium Intake and Health
ResumoHomeHypertensionVol. 52, No. 6Hypertension, Hypokalemia, and Thiazide-Induced Diabetes Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHypertension, Hypokalemia, and Thiazide-Induced DiabetesA 3-Way Connection Rajiv Agarwal Rajiv AgarwalRajiv Agarwal From the Division of Nephrology, Department of Medicine, Indiana University School of Medicine; and the Richard L. Roudebush Veterans' Affairs Medical Center, Indianapolis, Ind. Originally published3 Nov 2008https://doi.org/10.1161/HYPERTENSIONAHA.108.121970Hypertension. 2008;52:1012–1013Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 3, 2008: Previous Version 1 Reduction in the dose of diuretics to treat essential hypertension occurred with the recognition that higher doses of thiazides cause hypokalemia, glucose intolerance, and hyperuricemia but little additional reduction in blood pressure.1 Subsequently, large randomized, controlled trials have demonstrated a higher incidence of diabetes mellitus with thiazide diuretics compared with other antihypertensive drugs.2 A meta-analysis done with 143153 participants without diabetes mellitus in 22 clinical trials showed that thiazide diuretics and β-blockers had similarly high risks of developing new-onset diabetes mellitus, followed by placebo and calcium channel blockers; the most protective were angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors.3 This detrimental effect on glucose tolerance together with the growing epidemic of diabetes and obesity has reined in the wider use of thiazides despite being effective and inexpensive antihypertensive drugs with strong cardiovascular benefits.Whether thiazide-induced diabetes mellitus has the same adverse prognostic significance as spontaneously occurring diabetes mellitus is not known with certainty.2 If thiazide diuretics unmask the presence of underlying diabetes mellitus, then the earlier detection of diabetes with more aggressive hypertension, lipid, and metabolic control may in fact, instead of being harmful, be protective. There is also some evidence that, although new-onset diabetes mellitus is associated with cardiovascular mortality, treatment of such patients with diuretics has survival benefits. In a long-term analysis of the Systolic Hypertension in Elderly Program with a mean follow-up of 14.3 years, the long-term fatality rate was higher in those with had diabetes mellitus at baseline, followed by patients who developed diabetes during follow-up.4 However, diabetes mellitus that developed among subjects during diuretic therapy (n=258) did not have significant associations with cardiovascular mortality rate (adjusted hazard ratio: 1.043; 95% CI: 0.745 to 1.459) or all-cause mortality rate (adjusted hazard ratio: 1.151; 95% CI: 0.925 to 1.433). Furthermore, diuretic treatment in subjects who had diabetes mellitus was strongly associated with lower long-term cardiovascular and all-cause mortality rates. Given the protective effects of low-dose diuretics through blood pressure lowering, even among patients with diabetes mellitus, but their propensity to cause or unmask diabetes mellitus, interest has been rekindled to explore the provenance of thiazide-induced diabetes.A previous analysis of the Systolic Hypertension in Elderly Program reported that the incidence of diabetes mellitus in the active treatment group of 8.6% was no different from the placebo group (7.5%,; P=0.25).5 The study of Shafi et al6 fills an important gap in our understanding of diuretic-induced diabetes mellitus by providing evidence that incident diabetes in Systolic Hypertension in Elderly Program participants is related to the severity of hypokalemia, even after adjusting for baseline glucose and the dose of diuretic. This risk appears to be log-linear. Thus, the absolute increase in the incidence of diabetes mellitus was much less when serum potassium concentration dropped from 5.0 to 4.5 mEq/L but much higher when serum potassium dropped from 4.0 to 3.5 mEq/L; however, the increase in relative risk was similar. To interpret the log-linear relationship between serum potassium and incident diabetes mellitus requires consideration of balance studies that relate cumulative negative potassium balance with a fall in serum potassium in healthy volunteers.7 Such studies indicate that, with dietary depletion of potassium, it takes ≥1 week to manifest hypokalemia, at which time ≈150.0 mEq of potassium is lost, and serum potassium falls to ≈0.5 mEq/L. Persistent dietary potassium restriction produces an additional 100-mEq potassium loss with only slight, if any, change in serum potassium over the ensuing week. Thus, it would appear that people with hypokalemia, as reported by Shafi et al,6 may have remarkable depletion of total body potassium. A meta-analysis demonstrates a strong inverse relationship between glucose and potassium with the use of thiazides, which is also consistent with the notion that total body potassium stores may mediate insulin sensitivity.8Was hypokalemia a marker or a mediator of the development of diabetes mellitus? Although the authors did not find a difference in the incidence of diabetes mellitus in those who used potassium supplements versus those who did not, it remains to be seen in large randomized trials whether prevention or treatment of hypokalemia can avoid the development of diabetes mellitus. In fact, mechanistic studies suggest that potassium may have a mediating role as proposed by the epidemiological observations of Shafi et al.6 For example, Helderman et al9 have evaluated the effect of potassium supplementation on glucose tolerance in 7 healthy volunteers receiving high-dose hydrochlorothiazide—100 mg for 10 days. Using a glucose clamp, the investigators demonstrated that, when potassium losses were prevented, thiazides induced no alterations in glucose tolerance, β-cell sensitivity to glucose, or tissue sensitivity to insulin. Two controlled studies in which hypokalemia was allowed to ensue after hydrochlorothiazide ingestion revealed a diminution in glucose tolerance, a consequence of diminished pancreatic β-cell response to glucose. Pathophysiologically, potassium depletion can also cause dysglycemia as a result of altered skeletal muscle blood flow. Potassium is released from contracting skeletal muscle fibers, and its rising concentration in interstitial fluid is thought to dilate arterioles, thereby mediating the normal rise of muscle blood flow during exercise. Knochel and Schlein10 have demonstrated that, in normal dogs, muscle blood flow and potassium release rise sharply during exercise. In contrast, muscle blood flow and potassium release were markedly subnormal in potassium-depleted dogs despite brisk muscle contractions. Thus, a possible but so far little researched mechanism of new-onset, hypokalemia-mediated, thiazide-induced diabetes mellitus may simply be attributable to a reduction in the perfused mass of muscle—a large, glucose-metabolizing organ. Finally, a meta-analysis reported that trials that intervened on hypokalemia due to thiazides had nearly half the changes in potassium and glucose compared with trials that did not.8To settle the question of potassium being a marker or mediator of thiazide-induced diabetes mellitus requires conducting adequately powered randomized, controlled trials.11 The data of Shafi et al6 suggest that thiazide is likely to induce diabetes mellitus within a year, so such trials need not last long. However, until such trials are done, the message for those who care for the patient with hypertension is to avoid hypokalemia, especially when using thiazide or thiazide-like diuretics. In fact, participants in the Systolic Hypertension in Elderly Program trial who experienced hypokalemia after 1 year of treatment with a low-dose diuretic did not have a reduction in cardiovascular events compared with those who did not have hypokalemia.12 Recommending a diet rich in potassium, such as the Dietary Approaches to Stop Hypertension diet,13 would not only avoid hypokalemia but would also lower blood pressure by enhancing natriuresis, modulating baroreflex sensitivity, directing vasodilatation, or lowering cardiovascular reactivity to norepinephrine or angiotensin II.14 Likewise, potassium supplementation in patients with thiazide-induced hypokalemia can lower blood pressure and may improve dysglycemia.15 Using potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers or switching to a dihydropyridine calcium channel blocker are other logical strategies for the management of the patient who develops thiazide-induced hypokalemia. Restoring total body potassium stores may reverse thiazide-induced diabetes mellitus, and if the 3-way connection is indeed operative (Figure), treatment of hypokalemia may have other benefits, such as reducing the severity of spontaneous diabetes mellitus and lowering blood pressure. Download figureDownload PowerPointFigure. Hypertension-hypokalemia-diabetes mellitus: a 3-way relationship. Hypertension treated with thiazides, especially in higher doses, can cause hypokalemia. Hypokalemia, in turn, can aggravate hypertension and also lead to diabetes mellitus via mechanisms discussed in the text. Diabetes, in turn, can cause hypertension, and people with hypertension are more likely to get diabetes mellitus. Correcting potassium stores may, therefore, be beneficial for both diabetes mellitus and hypertension.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Source of FundingFunding from NIH-R01-DK062030-05.DisclosuresR.A. has received speaking fees from Merck and Co.FootnotesCorrespondence to Rajiv Agarwal, Veterans' Affairs Medical Center, 111N, 1481 W 10th St, Indianapolis, IN 46202. E-mail [email protected] References 1 Carlsen JE, Kober L, Torp-Pedersen C, Johansen P. Relation between dose of bendroflumethiazide, antihypertensive effect, and adverse biochemical effects. BMJ. 1990; 300: 975–978.CrossrefMedlineGoogle Scholar2 Barzilay JI, Davis BR, Cutler JA, Pressel SL, Whelton PK, Basile J, Margolis KL, Ong ST, Sadler LS, Summerson J. Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2006; 166: 2191–2201.CrossrefMedlineGoogle Scholar3 Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007; 369: 201–207.CrossrefMedlineGoogle Scholar4 Kostis JB, Wilson AC, Freudenberger RS, Cosgrove NM, Pressel SL, Davis BR. 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.CrossrefMedlineGoogle Scholar5 Savage PJ, Pressel SL, Curb JD, Schron EB, Applegate WB, Black HR, Cohen J, Davis BR, Frost P, Smith W, Gonzalez N, Guthrie GP, Oberman A, Rutan G, Probstfield JL, Stamler J. Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: the Systolic Hypertension in the Elderly Program. SHEP Cooperative Research Group. Arch Intern Med. 1998; 158: 741–751.CrossrefMedlineGoogle Scholar6 Shafi T, Appel LJ, Miller ER III, Klag MJ, Parekh RS. Changes in serum potassium mediate thiazide-induced diabetes. Hypertension. 2008; 52: 1022–1029.LinkGoogle Scholar7 Agarwal R, Afzalpurkar R, Fordtran JS. Pathophysiology of potassium absorption and secretion by the human intestine. Gastroenterology. 1994; 107: 548–571.CrossrefMedlineGoogle Scholar8 Zillich AJ, Garg J, Basu S, Bakris GL, Carter BL. Thiazide diuretics, potassium, and the development of diabetes: a quantitative review. Hypertension. 2006; 48: 219–224.LinkGoogle Scholar9 Helderman JH, Elahi D, Andersen DK, Raizes GS, Tobin JD, Shocken D, Andres R. Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium. Diabetes. 1983; 32: 106–111.CrossrefMedlineGoogle Scholar10 Knochel JP, Schlein EM. On the mechanism of rhabdomyolysis in potassium depletion. J Clin Invest. 1972; 51: 1750–1758.CrossrefMedlineGoogle Scholar11 Carter BL, Einhorn PT, Brands M, He J, Cutler JA, Whelton PK, Bakris GL, Brancati FL, Cushman WC, Oparil S, Wright JT Jr. Thiazide-induced dysglycemia: call for research from a working group from the national heart, lung, and blood institute. Hypertension. 2008; 52: 30–36.LinkGoogle Scholar12 Franse LV, Pahor M, Di BM, Somes GW, Cushman WC, Applegate WB. Hypokalemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly Program. Hypertension. 2000; 35: 1025–1030.CrossrefMedlineGoogle Scholar13 Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, Bray GA, Vogt TM, Cutler JA, Windhauser MM, Lin PH, Karanja N. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997; 336: 1117–1124.CrossrefMedlineGoogle Scholar14 Barri YM, Wingo CS. The effects of potassium depletion and supplementation on blood pressure: a clinical review. Am J Med Sci. 1997; 314: 37–40.MedlineGoogle Scholar15 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: 746–749.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Gál G, May N, Trif L, Mihály J and Bombicz P (2021) Solvatomorph and polymorph screening of clopamide drug and its copper( ii ) complex crystals , CrystEngComm, 10.1039/D1CE00995H, 23:42, (7425-7441) Zhang J, Yu H, Hou Y, Wang K, Bi W, Zhang L, Wang Q, Li P, Yu M and Zhao X (2018) Impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities of glucose and uric acid metabolisms, Journal of Human Hypertension, 10.1038/s41371-018-0036-3, 32:4, (301-310), Online publication date: 1-Apr-2018. Ali S, Sharma P, Garg V, Singh A and Mondal S (2011) The target-specific transporter and current status of diuretics as antihypertensive, Fundamental & Clinical Pharmacology, 10.1111/j.1472-8206.2011.01012.x, 26:2, (175-179), Online publication date: 1-Apr-2012. Carter B (2012) Guidelines for Use of Diuretics: A View From a Member of JNC 7, The Journal of Clinical Hypertension, 10.1111/j.1751-7176.2012.00621.x, 14:5, (273-276), Online publication date: 1-May-2012. García-Donaire J, Segura J, Cerezo C and Ruilope L (2011) A review of renal, cardiovascular and mortality endpoints in antihypertensive trials in diabetic patients, Blood Pressure, 10.3109/08037051.2011.602878, 20:6, (322-334), Online publication date: 1-Dec-2011. Cooper-DeHoff R, Wen S, Beitelshees A, Zineh I, Gums J, Turner S, Gong Y, Hall K, Parekh V, Chapman A, Boerwinkle E and Johnson J (2009) Impact of Abdominal Obesity on Incidence of Adverse Metabolic Effects Associated With Antihypertensive Medications, Hypertension, 55:1, (61-68), Online publication date: 1-Jan-2010. Duarte J and Cooper-DeHoff R (2014) Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics, Expert Review of Cardiovascular Therapy, 10.1586/erc.10.27, 8:6, (793-802), Online publication date: 1-Jun-2010. Campbell N, Leiter L, Larochelle P, Tobe S, Chockalingam A, Ward R, Morris D and Tsuyuki R (2009) Hypertension in diabetes: A call to action, Canadian Journal of Cardiology, 10.1016/S0828-282X(09)70493-3, 25:5, (299-302), Online publication date: 1-May-2009. (2009) Current awareness: Pharmacoepidemiology and drug safety, Pharmacoepidemiology and Drug Safety, 10.1002/pds.1648, 18:5, (i-x), Online publication date: 1-May-2009. Smith S, Anderson S, Wen S, Gong Y, Turner S, Cooper-DeHoff R, Schwartz G, Bailey K, Chapman A, Hall K, Feng H, Boerwinkle E, Johnson J and Gums J (2009) Lack of Correlation Between Thiazide-Induced Hyperglycemia and Hypokalemia: Subgroup Analysis of Results from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study, Pharmacotherapy, 10.1592/phco.29.10.1157, 29:10, (1157-1165), Online publication date: 1-Oct-2009. Abensur Vuillaume L, Ferreira J, Asseray N, Trombert-Paviot B, Montassier E, Legrand M, Girerd N, Boivin J, Chouihed T, Rossignol P and Chen X (2020) Hypokalemia is frequent and has prognostic implications in stable patients attending the emergency department, PLOS ONE, 10.1371/journal.pone.0236934, 15:8, (e0236934) December 2008Vol 52, Issue 6 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.108.121970PMID: 18981319 Originally publishedNovember 3, 2008 PDF download Advertisement SubjectsClinical StudiesEtiology
Referência(s)