Thiazide-Induced Dysglycemia
2008; Lippincott Williams & Wilkins; Volume: 52; Issue: 1 Linguagem: Inglês
10.1161/hypertensionaha.108.114389
ISSN1524-4563
AutoresBarry L. Carter, Paula T. Einhorn, Michael W. Brands, Jiang He, Jeffrey A. Cutler, Paul K. Whelton, George L. Bakris, Frederick L. Brancati, William C. Cushman, Suzanne Oparil, Jackson T. Wright,
Tópico(s)Diet and metabolism studies
ResumoHomeHypertensionVol. 52, No. 1Thiazide-Induced Dysglycemia Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessReview ArticlePDF/EPUBThiazide-Induced DysglycemiaCall for Research From a Working Group From the National Heart, Lung, and Blood Institute Barry L. Carter, Paula T. Einhorn, Michael Brands, Jiang He, Jeffrey A. Cutler, Paul K. Whelton, George L. Bakris, Frederick L. Brancati, William C. Cushman, Suzanne Oparil and Jackson T. WrightJr Barry L. CarterBarry L. Carter From the Division of Clinical and Administrative Pharmacy (B.L.C.), College of Pharmacy and Department of Family Medicine, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa; Division of Prevention and Population Sciences (P.T.E., J.A.C.), National Heart, Lung, and Blood Institute, Bethesda, Md; Department of Physiology (M.B.), Medical College of Georgia, Augusta; Department of Epidemiology (J.H.), Tulane University School of Public Health and Tropical Medicine, New Orleans, La; Loyola University Medical Center (P.K.W.), Chicago, Ill; Hypertensive Diseases Unit (G.L.B.), University of Chicago, Ill; Departments of Medicine and Epidemiology (F.L.B.), Johns Hopkins University, Baltimore, Md; Memphis Veterans' Affairs Medical Center and Department of Preventive Medicine and Medicine (W.C.C.), University of Tennessee College of Medicine, Memphis; Division of Cardiovascular Diseases (S.O.), Department of Medicine, Physiology, and Biophysics, University of Alabama at Birmingham; and the Department of Medicine (J.T.W.), Case Western Reserve University, Cleveland, Ohio. , Paula T. EinhornPaula T. Einhorn From the Division of Clinical and Administrative Pharmacy (B.L.C.), College of Pharmacy and Department of Family Medicine, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa; Division of Prevention and Population Sciences (P.T.E., J.A.C.), National Heart, Lung, and Blood Institute, Bethesda, Md; Department of Physiology (M.B.), Medical College of Georgia, Augusta; Department of Epidemiology (J.H.), Tulane University School of Public Health and Tropical Medicine, New Orleans, La; Loyola University Medical Center (P.K.W.), Chicago, Ill; Hypertensive Diseases Unit (G.L.B.), University of Chicago, Ill; Departments of Medicine and Epidemiology (F.L.B.), Johns Hopkins University, Baltimore, Md; Memphis Veterans' Affairs Medical Center and Department of Preventive Medicine and Medicine (W.C.C.), University of Tennessee College of Medicine, Memphis; Division of Cardiovascular Diseases (S.O.), Department of Medicine, Physiology, and Biophysics, University of Alabama at Birmingham; and the Department of Medicine (J.T.W.), Case Western Reserve University, Cleveland, Ohio. , Michael BrandsMichael Brands From the Division of Clinical and Administrative Pharmacy (B.L.C.), College of Pharmacy and Department of Family Medicine, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa; Division of Prevention and Population Sciences (P.T.E., J.A.C.), National Heart, Lung, and Blood Institute, Bethesda, Md; Department of Physiology (M.B.), Medical College of Georgia, Augusta; Department of Epidemiology (J.H.), Tulane University School of Public Health and Tropical Medicine, New Orleans, La; Loyola University Medical Center (P.K.W.), Chicago, Ill; Hypertensive Diseases Unit (G.L.B.), University of Chicago, Ill; Departments of Medicine and Epidemiology (F.L.B.), Johns Hopkins University, Baltimore, Md; Memphis Veterans' Affairs Medical Center and Department of Preventive Medicine and Medicine (W.C.C.), University of Tennessee College of Medicine, Memphis; Division of Cardiovascular Diseases (S.O.), Department of Medicine, Physiology, and Biophysics, University of Alabama at Birmingham; and the Department of Medicine (J.T.W.), Case Western Reserve University, Cleveland, Ohio. , Jiang HeJiang He From the Division of Clinical and Administrative Pharmacy (B.L.C.), College of Pharmacy and Department of Family Medicine, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa; Division of Prevention and Population Sciences (P.T.E., J.A.C.), National Heart, Lung, and Blood Institute, Bethesda, Md; Department of Physiology (M.B.), Medical College of Georgia, Augusta; Department of Epidemiology (J.H.), Tulane University School of Public Health and Tropical Medicine, New Orleans, La; Loyola University Medical Center (P.K.W.), Chicago, Ill; Hypertensive Diseases Unit (G.L.B.), University of Chicago, Ill; Departments of Medicine and Epidemiology (F.L.B.), Johns Hopkins University, Baltimore, Md; Memphis Veterans' Affairs Medical Center and Department of Preventive Medicine and Medicine (W.C.C.), University of Tennessee College of Medicine, Memphis; Division of Cardiovascular Diseases (S.O.), Department of Medicine, Physiology, and Biophysics, University of Alabama at Birmingham; and the Department of Medicine (J.T.W.), Case Western Reserve University, Cleveland, Ohio. , Jeffrey A. CutlerJeffrey A. Cutler From the Division of Clinical and Administrative Pharmacy (B.L.C.), College of Pharmacy and Department of Family Medicine, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa; Division of Prevention and Population Sciences (P.T.E., J.A.C.), National Heart, Lung, and Blood Institute, Bethesda, Md; Department of Physiology (M.B.), Medical College of Georgia, Augusta; Department of Epidemiology (J.H.), Tulane University School of Public Health and Tropical Medicine, New Orleans, La; Loyola University Medical Center (P.K.W.), Chicago, Ill; Hypertensive Diseases Unit (G.L.B.), University of Chicago, Ill; Departments of Medicine and Epidemiology (F.L.B.), Johns Hopkins University, Baltimore, Md; Memphis Veterans' Affairs Medical Center and Department of Preventive Medicine and Medicine (W.C.C.), University of Tennessee College of Medicine, Memphis; Division of Cardiovascular Diseases (S.O.), Department of Medicine, Physiology, and Biophysics, University of Alabama at Birmingham; and the Department of Medicine (J.T.W.), Case Western Reserve University, Cleveland, Ohio. , Paul K. WheltonPaul K. Whelton From the Division of Clinical and Administrative Pharmacy (B.L.C.), College of Pharmacy and Department of Family Medicine, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa; Division of Prevention and Population Sciences (P.T.E., J.A.C.), National Heart, Lung, and Blood Institute, Bethesda, Md; Department of Physiology (M.B.), Medical College of Georgia, Augusta; Department of Epidemiology (J.H.), Tulane University School of Public Health and Tropical Medicine, New Orleans, La; Loyola University Medical Center (P.K.W.), Chicago, Ill; Hypertensive Diseases Unit (G.L.B.), University of Chicago, Ill; Departments of Medicine and Epidemiology (F.L.B.), Johns Hopkins University, Baltimore, Md; Memphis Veterans' Affairs Medical Center and Department of Preventive Medicine and Medicine (W.C.C.), University of Tennessee College of Medicine, Memphis; Division of Cardiovascular Diseases (S.O.), Department of Medicine, Physiology, and Biophysics, University of Alabama at Birmingham; and the Department of Medicine (J.T.W.), Case Western Reserve University, Cleveland, Ohio. , George L. BakrisGeorge L. Bakris From the Division of Clinical and Administrative Pharmacy (B.L.C.), College of Pharmacy and Department of Family Medicine, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa; Division of Prevention and Population Sciences (P.T.E., J.A.C.), National Heart, Lung, and Blood Institute, Bethesda, Md; Department of Physiology (M.B.), Medical College of Georgia, Augusta; Department of Epidemiology (J.H.), Tulane University School of Public Health and Tropical Medicine, New Orleans, La; Loyola University Medical Center (P.K.W.), Chicago, Ill; Hypertensive Diseases Unit (G.L.B.), University of Chicago, Ill; Departments of Medicine and Epidemiology (F.L.B.), Johns Hopkins University, Baltimore, Md; Memphis Veterans' Affairs Medical Center and Department of Preventive Medicine and Medicine (W.C.C.), University of Tennessee College of Medicine, Memphis; Division of Cardiovascular Diseases (S.O.), Department of Medicine, Physiology, and Biophysics, University of Alabama at Birmingham; and the Department of Medicine (J.T.W.), Case Western Reserve University, Cleveland, Ohio. , Frederick L. BrancatiFrederick L. Brancati From the Division of Clinical and Administrative Pharmacy (B.L.C.), College of Pharmacy and Department of Family Medicine, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa; Division of Prevention and Population Sciences (P.T.E., J.A.C.), National Heart, Lung, and Blood Institute, Bethesda, Md; Department of Physiology (M.B.), Medical College of Georgia, Augusta; Department of Epidemiology (J.H.), Tulane University School of Public Health and Tropical Medicine, New Orleans, La; Loyola University Medical Center (P.K.W.), Chicago, Ill; Hypertensive Diseases Unit (G.L.B.), University of Chicago, Ill; Departments of Medicine and Epidemiology (F.L.B.), Johns Hopkins University, Baltimore, Md; Memphis Veterans' Affairs Medical Center and Department of Preventive Medicine and Medicine (W.C.C.), University of Tennessee College of Medicine, Memphis; Division of Cardiovascular Diseases (S.O.), Department of Medicine, Physiology, and Biophysics, University of Alabama at Birmingham; and the Department of Medicine (J.T.W.), Case Western Reserve University, Cleveland, Ohio. , William C. CushmanWilliam C. Cushman From the Division of Clinical and Administrative Pharmacy (B.L.C.), College of Pharmacy and Department of Family Medicine, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa; Division of Prevention and Population Sciences (P.T.E., J.A.C.), National Heart, Lung, and Blood Institute, Bethesda, Md; Department of Physiology (M.B.), Medical College of Georgia, Augusta; Department of Epidemiology (J.H.), Tulane University School of Public Health and Tropical Medicine, New Orleans, La; Loyola University Medical Center (P.K.W.), Chicago, Ill; Hypertensive Diseases Unit (G.L.B.), University of Chicago, Ill; Departments of Medicine and Epidemiology (F.L.B.), Johns Hopkins University, Baltimore, Md; Memphis Veterans' Affairs Medical Center and Department of Preventive Medicine and Medicine (W.C.C.), University of Tennessee College of Medicine, Memphis; Division of Cardiovascular Diseases (S.O.), Department of Medicine, Physiology, and Biophysics, University of Alabama at Birmingham; and the Department of Medicine (J.T.W.), Case Western Reserve University, Cleveland, Ohio. , Suzanne OparilSuzanne Oparil From the Division of Clinical and Administrative Pharmacy (B.L.C.), College of Pharmacy and Department of Family Medicine, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa; Division of Prevention and Population Sciences (P.T.E., J.A.C.), National Heart, Lung, and Blood Institute, Bethesda, Md; Department of Physiology (M.B.), Medical College of Georgia, Augusta; Department of Epidemiology (J.H.), Tulane University School of Public Health and Tropical Medicine, New Orleans, La; Loyola University Medical Center (P.K.W.), Chicago, Ill; Hypertensive Diseases Unit (G.L.B.), University of Chicago, Ill; Departments of Medicine and Epidemiology (F.L.B.), Johns Hopkins University, Baltimore, Md; Memphis Veterans' Affairs Medical Center and Department of Preventive Medicine and Medicine (W.C.C.), University of Tennessee College of Medicine, Memphis; Division of Cardiovascular Diseases (S.O.), Department of Medicine, Physiology, and Biophysics, University of Alabama at Birmingham; and the Department of Medicine (J.T.W.), Case Western Reserve University, Cleveland, Ohio. and Jackson T. WrightJrJackson T. WrightJr From the Division of Clinical and Administrative Pharmacy (B.L.C.), College of Pharmacy and Department of Family Medicine, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa; Division of Prevention and Population Sciences (P.T.E., J.A.C.), National Heart, Lung, and Blood Institute, Bethesda, Md; Department of Physiology (M.B.), Medical College of Georgia, Augusta; Department of Epidemiology (J.H.), Tulane University School of Public Health and Tropical Medicine, New Orleans, La; Loyola University Medical Center (P.K.W.), Chicago, Ill; Hypertensive Diseases Unit (G.L.B.), University of Chicago, Ill; Departments of Medicine and Epidemiology (F.L.B.), Johns Hopkins University, Baltimore, Md; Memphis Veterans' Affairs Medical Center and Department of Preventive Medicine and Medicine (W.C.C.), University of Tennessee College of Medicine, Memphis; Division of Cardiovascular Diseases (S.O.), Department of Medicine, Physiology, and Biophysics, University of Alabama at Birmingham; and the Department of Medicine (J.T.W.), Case Western Reserve University, Cleveland, Ohio. Originally published26 May 2008https://doi.org/10.1161/HYPERTENSIONAHA.108.114389Hypertension. 2008;52:30–36Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 26, 2008: Previous Version 1 There are >70-million hypertensive individuals in the United States, and >45-million persons take antihypertensive medications.1,2 Despite the results of the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT), other trials, and the recommendations in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, well under 50% of these regimens include a thiazide-type diuretic.2,3 In the Department of Veterans' Affairs, which participated in several of the studies supporting the use of thiazide diuretics, ≈35% of hypertensive patients on pharmacotherapy had a thiazide diuretic included in their hypertension treatment regimens in 2003.4 In private patient encounters, thiazide diuretic use rose from 19% of all of the antihypertensive patient visits in 2002 to 26% in 2004.5The recommendations for preferred use of thiazide-type diuretics are based on >4 decades of clinical trials, including active-controlled trials, where diuretics were tested against other drugs for their efficacy in preventing hard clinical outcomes, such as myocardial infarction, death, stroke, heart failure, and renal failure. ALLHAT, a randomized, double-blind, active-controlled antihypertensive treatment trial in 42 418 patients assigned to a thiazide-type diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel-blocker, (average follow-up: 4.9 years), or the doxazosin/chlorthalidone comparison (terminated early, average follow-up: 3.2 years) showed that the diuretic was at least as beneficial as the comparator drugs in lowering blood pressure (BP) and preventing cardiovascular (CV) and renal outcomes and was superior for preventing heart failure (versus each comparator arm), combined CV events (versus α-blocker and ACE-inhibitor arms), and stroke (versus ACE inhibitor [black subjects only] and α-blocker).6 The ongoing success of thiazide-type diuretics in large, adequately powered hypertension outcome trials and new guidelines have created the basis for increased diuretic use.2,6However, clinical trials have also frequently shown potentially undesirable metabolic biochemical effects during diuretic treatment compared with other drugs, including an increase in serum glucose levels (dysglycemia).6–14 Diuretic-induced increases in serum glucose levels are small and appear to attenuate over time ("diuretic-induced" indicates the part of the diuretic-associated increase in serum glucose levels that is above the increase related to aging, weight gain, sedentary lifestyle, and other risk factors). Nevertheless, opinion leaders in the medical community have raised concerns about the potential for long-term adverse CV and renal effects of the observed dysglycemia.15 They argue that the average length of follow-up in clinical trials, 4 to 5 years, is not long enough to recognize the potential long-term adverse effects of the known biochemical changes. In addition, they express a concern that patients who develop thiazide-associated diabetes will require monitoring and treatment for diabetes that they would not have experienced without the thiazide.In contrast to the above concerns, the evidence on whether the development of dysglycemia with any antihypertensive drug treatment produces adverse CV effects is mixed, and there are no direct outcome data for diuretic-induced dysglycemia.16 Among large-sample follow-up studies, the largest (ALLHAT) and the longest (from the Systolic Hypertension in the Elderly Program [SHEP]) show no significant adverse CV events from new diuretic-associated diabetes.17,18 Importantly, 83% of the new-onset diabetes that occurred in the ALLHAT diuretic arm was apparently not because of the diuretic. Although many of these patients had only 3- to 4-mg/dL increases in blood sugar over baseline that tipped them over the threshold, the vast majority who developed new-onset diabetes (NOD) had a ≥10-mg/dL increase in glucose.18,19 Thus, most NOD occurs regardless of medication used. Diuretic-based therapy still afforded similar or superior major CV benefits compared with lisinopril or amlodipine, even in patients with diabetes and in those with the metabolic syndrome.20–23 Conversely, a small study with only 63 events suggested that NOD carried the same CV risk as diabetes when present before therapy.15 These findings are in contrast to those of the much larger SHEP study (see below).17This ongoing debate hampers adoption of the hypertension treatment guidelines, and prescribing momentum for diuretic therapy has been slowed by this controversy.6,13,24 Avoidance of diuretics leaves millions of patients on diuretic-free regimens that may impart a higher risk of new-onset heart failure and, especially in black patients, also a higher risk of stroke, while providing no clear advantages. It is possible that the clinical advantages of the thiazide-type diuretics could be enhanced by eliminating or diminishing their biochemical effects. Evidence suggests that hypokalemia may be a contributing cause of NOD.8,19 The purpose of this article was to review the possible mechanisms for diuretic-induced dysglycemia, especially hypokalemia, and to outline recommendations for a proposed research agenda developed by a working group appointed by the National Heart, Lung, and Blood Institute (NHLBI). The details of the NHLBI Working Group process, additional references, and information about critical basic science and observational and clinical studies are included in the data supplement available online at http://hyper.ahajournals. org. Further details of the meeting and deliberations of the working group can be found at http://www.nhlbi.nih.gov.Observational StudiesWe conducted a literature search using Medline (1950 to December 2007) to identify observational studies that examined the relationship of thiazide diuretics to the incidence of diabetes. A total of 12 observational studies (11 cohort and 1 case-control) were evaluated. None of the observational studies specifically addressed the relationship between hypokalemia and NOD. A table that summarizes the design and results of these studies is included in the data supplement.In general, observational studies showed an increased risk of NOD among hypertensive patients taking diuretics when compared with those with normal BP.25–27 Bengtsson et al25 followed a cohort of 1462 women without diabetes at baseline for 12 years and reported that, compared with normotensive subjects, the relative risk of NOD was 3.4 (95% CI: 1.5 to 7.9) for hypertensive patients taking diuretics and 11.4 (95% CI: 5.0 to 26.0) for hypertensive patients taking diuretics and β-blockers. However, previous epidemiological studies clearly and consistently documented that hypertensive patients are at an elevated risk for diabetes compared with normotensive persons.Among hypertensive patients who take diuretics compared with those who do not, the association was inconsistent: a reduced risk,28 no association,29,30 or an increased risk31 of NOD. Gress et al29 evaluated patients with hypertension in the Atherosclerosis Risk in Community Study and reported that those taking thiazide diuretics were not at greater risk for the subsequent development of diabetes compared with those who received no antihypertensive therapy (relative hazard: 0.91; 95% CI: 0.73 to 1.13). On the other hand, Taylor et al31 reported that the relative risk of incident diabetes in hypertensive participants taking a thiazide diuretic compared with those not taking a thiazide was 1.20 (95% CI: 1.08 to 1.33) in the Nurses' Health Study I, 1.45 (95% CI: 1.17 to 1.79) in the Nurses' Health Study II, and 1.36 (95% CI: 1.17 to 1.58) in the Health Professionals Follow-Up Study.Overall, there was no consistent evidence from observational studies that thiazide diuretics increased the risk of diabetes among hypertensive patients. However, observational studies are subject to selection and diagnostic bias, underscoring the need for evidence from prospective, randomized, controlled trials.Clinical TrialsSeveral large intervention studies did not find an increased risk of diabetes with thiazides, usually after posthoc analyses.11,32,33 The European Working Party Study found a nonsignificant elevation in blood sugar with triamterene plus hydrochlorothiazide compared with placebo.33 In the SHEP Trial, NOD occurred in 8.6% of those treated with chlorthalidone and in 7.5% of those treated with placebo (hazard ratio [HR]: 1.2; 95% CI: 0.9 to 1.5; P=0.25).11 In addition, CV mortality was not increased in those who received chlorthalidone and developed diabetes (HR: 1.04; 95% CI: 0.75 to 1.46). Treatment with a diuretic in subjects who had diabetes was associated with lower CV mortality (HR: 0.69; 95% CI: 0.53 to 0.85) and total mortality (HR: 0.81; 95% CI: 0.68 to 0.95).Multiple Risk Factor Intervention Trial investigators found that NOD was nonsignificantly higher in the special intervention group (11.5%) compared with the usual care group (10.8%) after 6 years of follow-up (HR: 1.08; 95% CI: 0.96 to 1.20); there was heterogeneity in this outcome depending on smoking status at baseline, with a lower rate in special intervention nonsmokers but a higher rate among special intervention smokers, presumably because of weight gain among those who quit smoking.34 In ALLHAT, the odds ratio for developing NOD at 2 years with lisinopril (0.55; 95% CI: 0.43 to 0.70) or amlodipine (0.73; 95% CI: 0.58 to 0.91) versus chlorthalidone was significantly <1.0 (P<0.01).18 However, by 4 and 6 years, the odds ratios were no longer significant. The odds ratio at 6 years for lisinopril:chlorthalidone was 0.86 (95% CI: 0.40 to 1.86) and for amlodipine:chlorthalidone was 0.96 (95% CI: 0.58 to 1.90).The Intervention as a Goal in Hypertension Trial found fewer cases of NOD with nifedipine (4.3%) versus the potassium-sparing/thiazide combination coamilozide (5.6%; P=0.023).35 The Study of Tamoxifen and Raloxifene Trial evaluated glucose tolerance in people with the metabolic syndrome and hypertension. This study found an incidence of NOD of 11% with trandolapril/verapamil compared with 26.6% with losartan/hydrochlorothiazide after 52 weeks of treatment (P=0.002).24Elliott and Meyer36 recently conducted a meta-analysis of 22 clinical trials involving 143 153 participants and found that placebo groups had a significantly lower odds ratio of developing diabetes (0.77; 95% CI: 0.63 to 0.94) when compared with thiazide-assigned groups as the referent. The odds ratio for β-blockers (0.90; 95% CI: 0.75 to 1.09) compared with diuretics was not significantly different than 1.0, but the corresponding odds ratios for calcium channel blockers (0.75; 95% CI: 0.62 to 0.90), ACE inhibitors (0.67; 95% CI: 0.56 to 0.80), and angiotensin II receptor blocker (0.57; 95% CI: 0.46 to 0.72) were significantly reduced.Possible Relationship to HypokalemiaCompounding the difficulty in establishing a clinical link between diuretic treatment and NOD is the absence of a defined mechanistic link between diuretics and hyperglycemia. Potassium is perhaps the most attractive variable to begin with in developing a hypothesized mechanism. Diuretic-related reductions in serum K+ are typically dose related and usually range from 0.2 to 0.6 mmol/L.11–14,37–41 This well-described relationship is depicted by arrow "A" in Figure 1. A recent meta-analysis of 59 studies involving 83 thiazide diuretic treatment arms found a significant correlation between the degree of diuretic-induced hypokalemia and the increase in plasma glucose, and there was evidence that prevention of hypokalemia with K+ supplementation or potassium-sparing agents lessened the degree to which plasma glucose increased consequent to diuretic therapy.8 Thus, the change in plasma K+ appears to be related inversely to blood glucose, but how? The well-described effects of hyperkalemia to stimulate insulin secretion13,42,43 (arrow "B" in Figure 1) and insulin to induce cellular uptake of potassium44,45 suggest that low plasma potassium could impair insulin secretion and thereby increase plasma glucose.19,46–48 Hypothesis A+B=C is denoted in Figure 1. However, several challenges remain for this hypothesis, including the incompleteness of experimental evidence that hypokalemia in the range measured in these patients actually decreases insulin secretion as shown in Figure 2. Download figureDownload PowerPointFigure 1. Hypothesis for the relationship between thiazide-induced hyperglycemia and hypokalemia.Download figureDownload PowerPointFigure 2. Alternative pathways by which thiazides may cause hyperglycemia.Insulin and PotassiumPotassium infusions increase insulin secretion,42,43 and removal of potassium by insulin from the extracellular fluid (ECF) compartment may help protect against hyperkalemia after a meal.42,49 However, insulin is not required for potassium movement from the ECF into the intracellular fluid, as shown by the demonstration that potassium exits from the ECF of dogs with pancreatectomy and clamped insulin infusion.50 The mechanism for that effect is not known, but the removal of potassium from the ECF is facilitated by insulin.The more relevant question in the context of this hypothesis is whether potassium controls insulin release. Here, the evidence is not as clear, particularly regarding the potential for decreased plasma potassium to decrease insulin.47,48 Most studies have focused on the effects of increased potassium to stimulate insulin, but there has not been consistent evidence that physiological increases in plasma potassium, on the order of 1 to 2 mmol/L, can stimulate insulin secretion, even in studies that have demonstrated stimulation by larger increases.42,43,49 However, if basal insulin is decreased with somatostatin, then low-dose potassium infusions that have minimal effects on plasma potassium in intact conditions have been shown to cause significant hyperkalemia.42 The effect of decreased potassium in impairing insulin secretion has not been studied as extensively. Although dietary potassium deprivation has been shown to decrease plasma insulin levels,47,48,51 others have shown that potassium deprivation impairs insulin-mediated potassium uptake in skeletal muscle without affecting glucose uptake.52 Remarkably, the significant hypokalemia that accompanies chronic hyperaldosteronism is not associated with hyperglycemia.53–55 However, insulin resistance and an impaired glucose response to an oral glucose load have been reported in such patients.53–55Thus, the effect of elevated potassium in stimulating insulin is well supported, but whether the 1- to 2-mmol/L changes in plasma potassium that are most relevant physiologically are significant controllers of insulin secretion is not established. It is possible that there is a multiplicative interaction between potassium and glucose in the control of insulin secretion, just as has been described for the effects of potassium and angiotensin II on aldosterone secretion.56 This is particularly intriguing given the role of KATP channels in glucose-mediated control of insulin secretion, but it also makes the study of potassium-regulated insulin secretion more difficult.Other Possible MechanismsThere are other potential mechanisms or covariables that should be considered as intermediaries in the relationship among diuretic therapy, hypokalemia, and hyperglycemia, including hypomagnesemia.57,58 In addition, it has been proposed recently that increases in free fatty acids (related to increased serum triglycerides) may damage pancreatic β-cells.59,60 The sympathetic nervous and renin angiotensin systems are stimulated by diuretic-induced decreases in BP, and Figure 2 shows potential mechanisms through which they could be linked to increased blood glucose. Interestingly, the sympathetic nervous system actually could contribute to the hypokalemic response to diuretic treatment, because it is known to be a powerful driving force for moving potassium from the ECF to the intracellular fluid and minimizing hyperkalemia during exercise.61 Importantly, Figure 2 shows potential ways that hypokalemia could induce insulin resistance and hyperglycemia independent of a direct effect to decrease insulin secretion. Although there are data to support each of the individual relationships depicted in Figures 1 and 2, it is important to highlight that there is no integrative evidence to construct a mechanistic causal chain that links diuretics to hyperglycemia, whether it be potassium dependent or not.Minimizing Dysglycemia by Preventing Hypok
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