Old Doc, New Drug: Gliflozins

Quick confession: I have never read or seen anything about Harry Potter in my life.  It isn’t because I am opposed to the Rowling machine.  I just grew up at the time before Harry and then had kids who missed the last few episodes…  I guess I have a lot to look forward to, one day when my boys go wizard-crazy?  Anyway, the reason that I bring this up is that I imagine that if J.K. Rowling was going to name a class of drugs then she would choose the title “Gliflozins”.  Awesome name for a magical potion, weird name for an actual drug.  As an ED doctor, I know about as much about these gliflozins as I do about Hogwarts’ pupils. They are a mysterious new entity that has started turning up on medication lists in recent years.  So I am going to take a look at this class of drugs and try to work out where they fit into the diabetes oeuvre.

The ‘gliflozins’ are SGLT2-inhibitors. The sodium-glucose co-transporter is a protein that lives on the proximal convoluted tubules in one’s kidneys (presumably the 2 means ‘the later model’?)  The main job of the SGLT2 protein is to reabsorb glucose that has been excreted in the glomerulus and hence bring it back into the plasma.  It also pumps sodium back into the circulation.  Now in diabetics, who are already hyperglycemic, the SGLT-2 protein is upregulated to cope with all the sugar hitting the tubules.  As the little pumps try to reabsorb the excess glucose they also bring back sodium and water, therefore contributing to hypertension and possibly fluid overload.  Hence this is a neat target for the treatment of diabetes.  Importantly the SGLT protein is not dependent on insulin.  So it works and can be inhibited without affecting or being affected by the pancreatic hormones.

The actual molecule upon which the gliflozins are based, phlorizin,  has been known about for a long time ( first isolated in 1835!) However, the current generation of molecules was not released onto the market until the last few years.  There was a lot of effort to try and find drugs that specifically inhibited the SGLT2 protein. Turns out that inhibiting the SGLT1 protein gives the patient iatrogenic, choleriform diarrhoea which is much tougher to market!

The current crop of SGLT2-inhibitors includes ertugliflozin, canagliflozin, empagliflozin and dapagliflozin.  Since these are all tough to say and sell the creative folk in the Pharma companies decided to give them names that sound exactly like a list of Trump’s wives eg.  Invokana, Jardiance, Stegaltro, Melania and Forxiga (one of those is a joke).  Canagliflozin (Invokana) got a divorce from the PBS in 2015 and is no longer available in Australia.

The mechanism of action of SGLT2-inhibitors is reasonably straightforward.  They stop you kidneys reabsorbing the glucose that gets filtered and you end up passing it into the urine and out into the world.  This tends to reduce the plasma glucose load and decreases the stimulation of the pancreatic beta-cells to produce more insulin.  It also means that your body is getting rid of calories via the urine.  So the urine is now sweeter and a little saltier, voila, your patient is now peeing margaritas!  Of course, this does have a few downsides. Let’s look at those.

The most common side effect of SGLT2 inhibitors is urogenital infections.  All that extra sugar provides a happy medium for bacteria and fungi.  There is a risk of UTIs, vulvovaginitis, candida and rarely Fournier’s necrosis of the perineum (aka necrotizing fasciitis… very unpleasant).

All of the extra excreted sugar (and salt) tends to create an osmotic drag which can lead to dehydration. There is also the problem of urinary frequency and the need to get up at night to empty the bladder, orthostatic hypotension and possibly falls.  The risk of acute kidney failure is also increased – likely as a result of relative hypovolemia in patients with vulnerable beans to begin with.  In our hot Australian climate, this might be a big issue. 

Now there are a few very serious potential effects of SGLT2 inhibitors.

The first one to mention is the recent post-marketing association with increased risk of toe and lower limb amputations.  The FDA placed a black box warning on canagliflozin for amputation risk.  A recent study [Kmietowicz, BMJ, 14 Nov 2018] showed that the risk was roughly doubled compared to patients taking other diabetic meds.  This appears to be a class effect as this study included patients taking gliflozins other than canagliflozin.

The gliflozins can also produce euglycemic diabetic ketoacidosis. That is ketoacidosis in the presence of a normal blood glucose level.  This is an important factoid for the Emergency doctors out there.  We need to be checking the fingerprick BSL AND ketones in patients who are prescribed gliflozins.  Don’t be reassured by a normal sugar.

OK, so now the big question… Do they actually work… ie. are they saving lives?  That is really what we want to know when we decide to use these drugs.  As with any new drug, the trials that try to answer this question are all conducted by the drug companies that manufacture them.  So these trials need to be taken with a pinch of salt e.g. the amount that might frost the rim of your margarita.

There are three big pharma-run trials EMPA-REG, CANVAS and DECLARE-TIMI58 looking at 3 different gliflozins.  Just last week the Lancet published a metanalysis and systematic review by  Zelniker et al (free PDF)  which combined all the data from these trials (34,322 patients followed for between 2 – 4 years) into one big punch-bowl of data.  So you can get a pretty good overview of the effects by reading that paper… or you can trust me and I will give you the headline outcomes.  They are broken down into primary and secondary prevention.

OK, here we go:

All-cause mortality was better in patients taking an SGLT2i.  About 15% reduction if you take all comers.

  • In patients with an atherosclerotic cardiovascular disease, the HR was 0·83 (0·75–0·92)
  • and in those with pre-disease risk factors, it was 0·90 (0·77–1·05) i.e not significant

For the composite outcome [a bit statistically naughty] of MI, stroke or cardiovascular death:

  • There was a benefit in patients with diagnosed cardiovascular disease (i.e. secondary prevention)
  • NO benefit for patients with no known cardiovascular disease (primary prevention)

For “hospitalisation for heart failure” or cardiovascular death – the same was observed.  A benefit in people with a disease, no benefit in folk without diagnosed diseases of the vessels.  Physiologically, this makes sense. We would expect a reduction in heart failure on these drugs.

You may be seeing a theme here…. SGLT2 inhibitors seem to work in people with actual diagnosed heart disease.  The data for primary prevention is really not showing a benefit.

The only outcome which seemed to show the most benefit to all patients was for reduction of renal failure, progress to ESRF and renal death.  Nearly a 50% effect size by this measure. Sothe kidneys are one area where these drugs may be more useful.

The authors of this metanalysis conclude, somewhat counterintuitively, that we ought to consider SGLT2 inhibitors in all diabetics regardless of the actual presence of established cardiovascular disease.  For me, that is a bridge too far.  Like all things in medicine, there is a balance between harms and benefits. The side effects are not insignificant and with time the “real world” harms will start to be reported.  The pre-market evidence always underestimates the downsides

For me, the current data would suggest these drugs are best used in patients with established cardiovascular complications.  They may also be useful if folk with heart failure and progressing renal disease.

OK, that’s a wrap.  I am off to the cocktail bar for a lime margarita!






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