Primary Care Corner with Geoffrey Modest MD: Potassium Sparing Diuretics and Metabolic Changes

Posted on by

By Dr. Geoffrey Modest

There has been a lot of controversy about the role of diuretics in the treatment of hypertension, with their not 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 because of adverse effects (hyperglycemia, hypokalemia, etc.). In this context, there was a short-term but quite impressive study in Lancet Diabetes&Endocrinology looking at their adverse effects in hypertensive patients assigned to hydrochlorothiazide, amiloride, or the combination in a government-supported study (see doi.org/10.1016/S2213-8587(15)00377-0).

Details:

  • Patients were 18-80 yo, withclinic systolic BP (SBP) >140 mmHg or home SBP >130 mmHg, and at least one other component of the metabolic syndrome, and excluding patients with known diabetes.
  • 441 patients were enrolled (mean age 62; 42% female; 89 kg; BMI 31; 9% smokers; clinic BP 155/91; home BP 150/86; 89% on ACE-I/ARB, 15% b-blocker, 42% calcium channel blocker, with mean of 1.5 BP meds; 33% with impaired glucose tolerance; serum potassium 4.1 mmol/L; and 99% had central obesity as a component of the metabolic syndrome, defined as men with waist circumference > 94 cm and women >80 cm)
  • For the modified intention-to-treat analysis 132 patients were randomized to amiloride 10mg, 134 to hydrochlorothiazide (HCTZ) 25mg, and 133 to amiloride/HCTZ combo pill with 5mg amiloride/12.5mg HCTZ for 12weeks, then double the initial dose of the meds for each group for another 12 weeks.

Results:

  • (Primary outcome): 2-hr results of oral glucose challenge test. Mean changes from baseline were
    • ​amiloride: -0.35 mmol/L (6.3 mg/dL) [i.e. got better]
    • amiloride and HCTZ: -0.22 mmol/L (4 mg/dL) [i.e. got better]
    • HCTZ: +0.20 mmol/L (+3.6 mg/dL) [i.e. got worse], so the net increase in those on HCTZ vs amiloride/HCTZ combo was 0.42 mmol/L (7.6 m/dL) higher
  • Other outcomes:
    • Clinic SBP: amiloride –baseline 153.8, at 12 weeks 140.8, at 24 weeks 135.4; combo baseline 156.2, at 12 weeks 136.7, at 24 weeks 133.4; HCTZ baseline 154.4, at 12 weeks 140.3, at 24 weeks 135.8 (difference of about 4.0 mm Hg lower SBP with combo over HCTZ, and significant at p=0.018 at 24 weeks
    • Home SBP: amiloride –baseline 149.3, at 12 weeks 138.3, at 24 weeks 134.4; combo baseline 150.6, at 12 weeks 136.1, at 24 weeks 132.3; HCTZ baseline 148.8, at 12 weeks 138.5, at 24 weeks 135.0 (difference of about 3.5 mmHg lower with combo over HCTZ, and significant at p=0.011 at 24 weeks
    • ​Potassium: with amiloride increased from 4.09 baseline  to 4.55 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 HCTZ 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<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)
    • ​Uric acid: overall essentially no change with amiloride, and equivalent changes with either HCTZ or the combo, increasing from a baseline of approx 345 mmol/L (5.88 mg/dL) to approx 385 mmol/L (6.47 mg/dL)
    • LDL did not change significantly with either HCTZ or the combo (which actually differs from prior studies finding some increase in LDL with thiazides)
  • ​Adverse events (overall numbers were not different, around 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, 10% in combo, 11% HCTZ; muscle spasms in 9% amiloride, 9% of combo and 7% of HCTZ, and rest were <9%.

So, synthesis of all of these numbers above:

  • 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 potassium was rarely elevated 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)
  • ​Why does this happen: for the blood pressure, it is not unexpected to get some synergy between HCTZ and amiloride: thiazides cause sodium excretion in the distal tubule, and potassium-sparing diuretics prevent sodium reabsorption in the cortical collecting tubules. And, there 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).
  • 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 lacks robust data confirming benefit in preventing clinically-relevant outcomes  (see doi:10.1016/j.jacc.2010.07.053).  It may also be of significance that there are no clinical outcome data that I know 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)
  • ​In the past, I have usually prescribed the 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 for 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 <55yo and white. Unless there are other reasons to use a diuretic). And the potassium-sparing effect are also magnesium sparing (i.e. one loses less magnesium in the urine)
(Visited 4 times, 1 visits today)