{"id":890,"date":"2015-11-16T16:10:27","date_gmt":"2015-11-16T16:10:27","guid":{"rendered":"http:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/?p=890"},"modified":"2017-08-21T11:16:28","modified_gmt":"2017-08-21T11:16:28","slug":"primary-care-corner-with-geoffrey-modest-md-potassium-sparing-diuretics-and-metabolic-changes","status":"publish","type":"post","link":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2015\/11\/16\/primary-care-corner-with-geoffrey-modest-md-potassium-sparing-diuretics-and-metabolic-changes\/","title":{"rendered":"Primary Care Corner with Geoffrey Modest MD: Potassium Sparing Diuretics and Metabolic Changes"},"content":{"rendered":"<p><strong>By Dr. Geoffrey Modest<\/strong><\/p>\n<p>There has been a lot of controversy about the role of diuretics in the treatment of hypertension, with their\u00a0not being in the first line therapy list of NICE (National Institute for Health and Care Excellence in the UK) and sometimes not used in the US as the initial agent\u00a0because of adverse effects (hyperglycemia, hypokalemia, etc.). In this context, there was a short-term\u00a0but quite impressive study in\u00a0Lancet Diabetes&amp;Endocrinology looking at their adverse effects in hypertensive patients assigned to hydrochlorothiazide, amiloride, or the combination\u00a0in a government-supported study\u00a0(see\u00a0doi.org\/10.1016\/S2213-8587(15)00377-0).<\/p>\n<p>Details:<\/p>\n<ul>\n<li>Patients were 18-80 yo, withclinic systolic\u00a0BP (SBP)\u00a0&gt;140 mmHg\u00a0or home SBP\u00a0&gt;130 mmHg, and at least one other component of the metabolic syndrome, and\u00a0excluding\u00a0patients with known diabetes.<\/li>\n<li>441 patients were enrolled (mean age 62;\u00a042% female; 89 kg;\u00a0BMI 31;\u00a09% smokers;\u00a0clinic BP 155\/91;\u00a0home BP 150\/86;\u00a089% on ACE-I\/ARB, 15% b-blocker, 42% calcium channel blocker, with\u00a0mean of 1.5 BP meds;\u00a033% with impaired glucose tolerance;\u00a0serum potassium 4.1 mmol\/L;\u00a0and\u00a099% had central obesity as a component of the metabolic syndrome,\u00a0defined as men with waist circumference &gt; 94 cm and\u00a0women &gt;80\u00a0cm)<\/li>\n<li>For the modified intention-to-treat analysis\u00a0132 patients were randomized to\u00a0amiloride 10mg, 134 to\u00a0hydrochlorothiazide (HCTZ) 25mg, and 133 to amiloride\/HCTZ combo pill with 5mg amiloride\/12.5mg\u00a0HCTZ for 12weeks, then double the initial\u00a0dose of the meds for each group\u00a0for another 12 weeks.<\/li>\n<\/ul>\n<p>Results:<\/p>\n<ul>\n<li>(Primary outcome):\u00a02-hr results of <strong>oral glucose challenge test<\/strong>.\u00a0Mean changes from baseline were\n<ul>\n<li>\u200bamiloride: -0.35 mmol\/L (6.3 mg\/dL) [i.e. got better]<\/li>\n<li>amiloride and HCTZ: -0.22 mmol\/L (4 mg\/dL) [i.e. got better]<\/li>\n<li>HCTZ: +0.20 mmol\/L (+3.6 mg\/dL) [i.e.\u00a0got worse], so the net increase in those on\u00a0HCTZ vs amiloride\/HCTZ combo was 0.42 mmol\/L (7.6 m\/dL) higher<\/li>\n<\/ul>\n<\/li>\n<li>Other outcomes:\n<ul>\n<li><strong>Clinic SBP<\/strong>: amiloride &#8211;baseline 153.8,\u00a0at 12 weeks 140.8, at 24 weeks 135.4; combo baseline 156.2,\u00a0at 12 weeks 136.7, at 24 weeks 133.4; HCTZ\u00a0baseline 154.4,\u00a0at 12 weeks 140.3, at 24 weeks 135.8\u00a0(difference of about 4.0 mm Hg lower SBP\u00a0with\u00a0combo over HCTZ, and significant at p=0.018 at 24 weeks<\/li>\n<li><strong>Home SBP<\/strong>: amiloride &#8211;baseline 149.3,\u00a0at 12 weeks 138.3, at 24 weeks 134.4; combo\u00a0baseline 150.6,\u00a0at 12 weeks 136.1, at 24 weeks 132.3; HCTZ\u00a0baseline 148.8,\u00a0at 12 weeks 138.5, at 24 weeks 135.0\u00a0(difference of\u00a0about 3.5\u00a0mmHg lower with\u00a0combo over\u00a0HCTZ, and significant at p=0.011 at 24 weeks<\/li>\n<li>\u200bP<strong>otassium<\/strong>:\u00a0with amiloride increased from 4.09 baseline\u00a0\u00a0to\u00a04.55 at 12 weeks and 4.61 at 24 wks, with combo increased from 4.16 baseline to 4.31 at 12 weeks, then back down to 4.14 at 24 weeks, and with\u00a0HCTZ decreased from 4.21 baseline to 3.97 at 12 weeks then to 3.79 at 24 weeks (so, diff between combo and HCTZ was 0.46 on average, p&lt;0.0001, though note that the combo did not lead to much of a change at 24 weeks when people were on double dose of the med)<\/li>\n<li>\u200bU<strong>ric acid<\/strong>: overall essentially no change with amiloride, and equivalent changes with either HCTZ or the combo, increasing from a baseline of approx\u00a0345 mmol\/L\u00a0(5.88 mg\/dL) to approx 385\u00a0mmol\/L\u00a0(6.47\u00a0mg\/dL)<\/li>\n<li><strong>LDL <\/strong>did\u00a0not change significantly with either HCTZ or the combo (which actually differs from prior studies finding some increase in LDL with thiazides)<\/li>\n<\/ul>\n<\/li>\n<li>\u200bAdverse events (overall numbers were not different,\u00a0around 65%, between groups), but for hyperkalemia: 4.8% with amiloride (highest K was 5.8 mmol\/L), and 2% with the combo (most in the 5.0-5.3 range, though they did not give the specifics). Most common adverse events were dizziness in 6% amiloride,\u00a010% in combo, 11% HCTZ; muscle spasms in 9% amiloride,\u00a09% of combo and 7% of HCTZ, and rest were &lt;9%.<\/li>\n<\/ul>\n<p>So,\u00a0synthesis of all of these numbers above:<\/p>\n<ul>\n<li>The combo pill was associated with improved blood pressure control over HCTZ (by systolic of about 4 mmHg), there was slight improvement in 2 hr glucose (difference with HCTZ of 7.6 mg\/dL), and\u00a0potassium was rarely\u00a0elevated and only mildly so from an average baseline of 4.1 (though, remember that these were nondiabetic patients. the glucose effect may be more in diabetics)<\/li>\n<li>\u200bWhy does this happen: for the blood pressure, it is\u00a0not unexpected to get some synergy between HCTZ and amiloride: thiazides cause sodium excretion in the distal tubule, and potassium-sparing diuretics prevent sodium reabsorption\u00a0in the cortical collecting tubules. And,\u00a0there are old experimental data showing that hypokalemia is associated with impaired insulin secretion by the b-cells of the pancreas (purported mechanism that b-cells have an ATP-dependent K channel, and that with higher K levels, more gets into the cells, leading to enhanced calcium-mediated release of insulin).<\/li>\n<li>This study used a higher dose of HCTZ than we often use in the US, with its attendant increase in metabolic disarray. However, as I have pointed out in other blogs, there is an argument that the more-commonly prescribed 12.5 mg dose has inferior 24-hour effectiveness and\u00a0lacks robust data confirming benefit in preventing clinically-relevant outcomes\u00a0\u00a0(see\u00a0doi:10.1016\/j.jacc.2010.07.053). \u00a0It may also be of\u00a0significance\u00a0that there\u00a0are no clinical outcome data that I\u00a0know of\/remember on the HCTZ\/amiloride type combo drugs (though I doubt that outcomes would be worse, given the decrease in several potentially bad adverse events, such as hypokalemia or hyperglycemia)<\/li>\n<li>\u200bIn the past, I have usually prescribed\u00a0the combination pill when patients have baseline potassium in the mid 3 range or lower. This study shows that not only does it seem safe to use the combo pill at higher potassium levels, but that there seem to be better outcomes (lower blood pressure and fewer metabolic sequelae). This study is pretty short-term (24 weeks), but does add to the argument for the combo pill over HCTZ alone\u00a0for many patients (though, personally I still tend to follow the NICE guidelines of using a dihydropyridine calcium channel blocker for older and non-white patients, and use ACE-I in those who are &lt;55yo and white. Unless there are other reasons to use a diuretic). And the potassium-sparing effect\u00a0are\u00a0also magnesium sparing (i.e. one loses less magnesium in the urine)<\/li>\n<\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Primary Care Corner with Geoffrey Modest MD: Potassium Sparing Diuretics and Metabolic Changes [&#8230;]<\/p>\n<p><a class=\"btn btn-secondary understrap-read-more-link\" href=\"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2015\/11\/16\/primary-care-corner-with-geoffrey-modest-md-potassium-sparing-diuretics-and-metabolic-changes\/\">Read More&#8230;<\/a><\/p>\n","protected":false},"author":148,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[14283],"tags":[],"class_list":["post-890","post","type-post","status-publish","format-standard","hentry","category-archive"],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"_links":{"self":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts\/890","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/users\/148"}],"replies":[{"embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/comments?post=890"}],"version-history":[{"count":0,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts\/890\/revisions"}],"wp:attachment":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/media?parent=890"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/categories?post=890"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/tags?post=890"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}