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  1. Dr. Jordan Weinstein
  2. Verified UKidney Expert
  3. Fluid & Electrolyte
  4. Tuesday, 14 October 2014
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I don't understand why it can cause hyperkalemia. Even more... from my point of view... it could cause hypokalemia... Do you have an explanation.

Sylvie Bertrand MD, CSPQ, FRCP(c)
Endocrinologist
Montreal
Responses (4)
Accepted Answer Pending Moderation
Hello,

Firstly, sorry for the delay in this reply.

I agree with you; the mechanism of hyperkalemia is not well understood and counterintuitive. The impact on patients with preserved renal function is only very mild. Important hyperkalemia appears to be limited to those with more advanced renal failure, a group that would not commonly be treated with an SGLT2 inhibitor for diabetes care, based on the current label. 

Here is a summary of the findings with Invokana:

  • Mean percent changes from baseline in blood potassium were 0.5% and 1.0% for INVOKANA™ 100 mg and 300 mg, respectively, compared to 0.6% for placebo. Episodes of elevated serum potassium (> 5.4 mEq/L and 15% above baseline) were seen in 4.4% of patients treated with INVOKANA™ 100 mg, 7.0% of patients treated with INVOKANA™ 300 mg, and 4.8% of patients treated with placebo.
  • In a trial in patients with moderate renal impairment (eGFR 30 to < 50 mL/min/1.73 m2), increases in serum potassium to > 5.4 mEq/L and 15% above baseline were seen in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA™ 100 mg, and INVOKANA™ 300 mg, respectively. Elevations to ≥ 6.5 mEq/L occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA™ 100 mg, and INVOKANA™ 300 mg, respectively.

It is not clear whether this effect (which was seen more-so in patients with impaired renal function) was independent in small changes in GFR or volume status. One possibility therefore, is that a slight reduction in volume status led to a reduction in sodium delivery to the cortical collecting duct in the distal nephron, resulting in less sodium exchanged for potassium. However, this would be speculation. 
I have reviewed this finding with one of our local potassium experts (he's an internationally recognized authority), and he was similarly surprised by the finding of hyperkalemia.

Perhaps the lesson here is to repeat electrolytes and renal function shortly after starting the medication, a practice that is likely common irrespective of this finding. One could consider a low potassium diet for those with more borderline renal function. You can download an example diet here:

Low Potassium Diet
 
 
  1. more than a month ago
  2. Fluid & Electrolyte
  3. # 1
Accepted Answer Pending Moderation
It is also known two other adverse effects namely, orthostatic hypotension and dehydration. Thus, it's very reasonable to understand why there is hyperkalemia and not hypokalemia as I first thought.

Seems like the glucose and sodium exerts it's osmotic effect and results in dehydration, which would cause hyper kalemia.
  1. more than a month ago
  2. Fluid & Electrolyte
  3. # 2
Accepted Answer Pending Moderation
But wouldnt the dehydration cause a low volume state and with it a decrease in renal plasma flow and activation of the RAAS sodium rabsorption and potasium secretion.
  1. more than a month ago
  2. Fluid & Electrolyte
  3. # 3
Accepted Answer Pending Moderation
But wouldnt the dehydration cause a low volume state and with it a decrease in renal plasma flow and activation of the RAAS sodium rabsorption and potasium secretion.


If a patient is pre-renal and distal sodium delivery is low as a result (to conserve volume), then even if aldosterone acts, there is little sodium to participate in potassium exchange. If this physiology didn't occur, we would be come hypokalemic whenever volume contracted.

Dr. Jordan Weinstein
  1. more than a month ago
  2. Fluid & Electrolyte
  3. # 4
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