Sulfonylureas and Ischemic Preconditioning?


From Google Image

In UGDP study (universal group diabetic programme) study published in the 1970s, it was revealed that patients taking tolbutamide had higher cardiovascular mortality.

Since then, it was hypothesized that sulfonylureas by blocking potassium channel, can impair ischemic preconditioning, causing an increase in CV events & mortality.

Let’s understand a few terms:

Ischemic preconditioning:

  • Repeated short episodes of ischaemia protect the myocardium against a subsequent ischaemic insult.
  • Basically, during ischemia, substances like adenosine and bradykinin are released. They cause the opening of potassium channel which lead to release of different mediators which end up protecting the heart from ischemic necrosis.

The detail mechanism is here:

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F
rom Google Image

How does sulfonylurea work?

  • To understand this, need to understand how insulin is secreted.
  • Glucose metabolism (by glycolysis, Krebs cycle) produces ATP. ATP closes the potassium channels located on B-cells.
  • No efflux of potassium leads to depolarization. This opens up the calcium channels, leading to Ca2+ influx.
  • Calcium activates insulin gene expression, insulin synthesis and finally secretion.


From Google Image

  • Sulfonylureas block K channels, so the B-cells are always in depolarization and more insulin can be released.


From Google Image

Ok, so how does sulfonylurea impair ischemic preconditioning (theoretically)?

  • If you notice, potassium channels are integral in the process of ischemic proconditioning. Its opening leads to release of cardioprotective mediators.
  • BUT sulfonylurea blocks this channel. Therefore, this relationship theoretically exist.

But is it true?

There were experiments done on humans (though indirectly) to prove this relationship.

  • And by and large, they indeed proved this relationship.

How about large randomized prospective trials?

Well, so far, only UGDP and UKPDS have targeted the associated between sulfonylureas and CV mortality.

  • Well, UGDP was critisized for its methadology. Worthwhile to note that “all the aberrant results for tolbutamide, for example, came from 4/12 participating centres, in which there was an excess of cardiovascular disease or abnormal ECGs in the tolbutamide arm”.
  • UKPDS on the other hand, investigated glibenclamide and found no significant effect on mortality/CV events.

Another retrospective study looked at CK-MB levels of DM patients who underwent CABG and took their routine diabetic medicines up to the day of surgery compared with non-DM patients who underwent CABG.

  • In the study, only 112 of the 360 DM patients took sulfonylureas (about 30 percent).
  • There was no difference between the CK-MB levels between DM and non-DM patients.
  • Importantly, no difference was also observed after correction for different diabetic medications use.
  • Well, this study was not perfect, and CK-MB was not as predictive as troponin for future CV events.

However, it showed to us that sulfonylureas do not increase the risk of myocardial ischemia. The theory of impairing ischemic preconditioning may well be theory at best.

If glycemic control is controlled appropriately (not going into hypoglycemia), sulfonylureas are okay to be used in acute myocardial ischemia.

References:

  1. The University Group Diabetes Program
    http://www.diapedia.org/introduction-to-diabetes-mellitus/the-university-group-diabetes-program
  2. An analysis of the University Group Diabetes Study Program: data results and conslusions.
    B. Leibel Can Med Assoc J. 1971 Aug 7; 105(3): 292–294.
  3. The effect of diabetic medications on creatine kinase-myocardial band levels in patients undergoing coronary artery bypass surgery.
    Engoren M, Zacharias A, Habib RH, Schwann TA, Riordan CJ, Durham SJ, Shah A.
    Interact Cardiovasc Thorac Surg. 2009 Nov;9(5):793-6
  4. Is impairment of ischaemic preconditioning by sulfonylurea drugs clinically important?
    J J Meier, B Gallwitz, W E Schmidt, A Mügge, and M A Nauck
    Heart. 2004 Jan; 90(1): 9–12.
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