SGLT2s decrease gout risk??

SGLT2s decrease gout risk??

G

Geoff A. Modest, M.D.

Wed 1/29/2020 7:44 AM

• Geoff A. Modest, M.D.

 

A large population-based cohort study found that sodium-glucose co-transporter-2 inhibitors (SGLT2) in patients with diabetes decrease the risk for gout (see dm sglt2 dec gout AIM2020 in dropbox, or doi:10.7326/M19-2610)

Details:

-- data from IBM MarketScan, a US nationwide commercial insurance database of healthcare claims, largely reflecting those people with health coverage through an employer-based health plan

-- people with type II diabetes who were prescribed an SGLT2 inhibitor were compared with those prescribed a GLP-1 agonist, from 2013-2018

    -- 295,907 adults with diabetes were newly prescribed one of these medications (151,949 on SGLT2 inhibitors, 143,958 on GLP-1 agonists)

    -- 52% women, mean age 54, mean A1c 8.7, mean creatinine 0.89, 11% with diabetic neuropathy/68% hypertension/67% dyslipidemia/5% smoking/12% OSA/26% overweight or obese/2% CKD

-- meds: 63% metformin, 32% sulfonylurea, 17% DPP4 inhibitor, 25% insulin; 59% on statin, 19% on NSAIDs

-- propensity score matching was used to adjust the measured confounders, since those on GLP-1 agonists were more likely to be women, on insulin, and have a diagnosis related to CKD or obesity. As a result of doing this statistical manipulation, about 80% of all patients were included

-- primary outcome: new diagnosis of gout, either inpatient (based on diagnosis) or outpatient (based on diagnosis plus a claim for medication)

-- mean follow-up 302 days for those on SGLT2, 261 days for GLP-1

-- almost 50% of those on either medicine stopped meds, largely because of adverse effects

Results:

-- the gout incidence was 36% lower in those on SGLT2, HR 0.64 (0.57-0.72)

-- the absolute rate difference was 2.9 cases per 1000 person-years, 4.9 vs. 7.8 events per 1000 person-years

Commentary:

-- gout affects nearly 10 million adults across North America, and is associated with an approximately 30% higher rate of cardiovascular disease and all-cause mortality

-- SGLT2 inhibitors block the reabsorption of glucose at the proximal convoluted tubule, and the attendant high levels of glycosuria causes uric acid excretion into the urine [which could, by the way, increase the formation of uric acid stones, not studied here]

-- studies do suggest that serum uric acid level is lower in those on SGLT2 inhibitors: 

    -- empagliflozin decreases serum uric acid (SUA) levels by about 30 µmol/L (translating to 0.5 mg/dL), and a recent meta-analysis found a decrease of 37 µmol/L (0.62 mg/dL).

    -- but, GLP-1 agonists do not affect SUA

--unfortunately, we have no information on what the baseline SUA level was, or what the changes were per SGLT-2 vs GLP-1 therapy

--I do have lots of patients on GLP-1’s and there really are very few of patients who do not tolerate them. For some of them, they have minor GI discomfort. But when explained that these are really great meds and help prevent heart disease (the major cause of diabetic mortality), only a few have stopped them. So their 50% dropout rate in this study is quite high given my pretty large sample of patients (I think that tolerability of adverse effects may be quite different depending on how the medication is presented to the patient: see http://gmodestmedblogs.blogspot.com/2012/08/nocebo.html)

--also, it should be noted that the NNT (number-needed-to-treat) in this study is quite high, since the occurrence of gout was low overall. In fact, if it is the lowering of SUA being associated with decreased gout, the actual lowering in the other studies (0.5 mg/dL) is not so much and on the order achievable by dietary interventions (I have had a few patients stop drinking sodas that have high levels of fructose, with an associated 1 mg/dL decrease in SUA)

--limitations of the study:

    --a huge data-mining study without much granular information about comorbidities/alcohol consumption/other dietary measures or any changes over the course of the study, baseline/achieved SUA levels, psychosocial issues...

    --the use of propensity scoring is helpful in trying to mathematically equalize the 2 groups of patients, there are some people in each group who cannot be matched and are not included: hence, a distorted comparison that could lead to distorted results (?perhaps significant that those on GLP-1's had more baseline CKD, which is associated with hyperuricemia??)

    --so, the overall results of the study reveal an interesting association between SGLT-2's and decreasing gout incidence, but there need to be rigorous studies to confirm any real benefit

So, interesting study, but a few issues:

--there are many reasons to suggest that GLP-1 agonists are better drugs than SGLT-2 antagonists, including that the GLP-1's re-establish a normal physiologic mechanism that goes awry in diabetics (the "incretin effect") vs distorting the function of the glomeruli leading to massive glycosuria (and uricosuria), there are many fewer serious adverse effects with GLP-1s (SGLT2's being associated with fractures/amputation, urosepsis, ketoacidosis at low glucose levels, Fournier's gangrene, and severe mycotic infections (see some former blogs on them, as below), and much more impressive A1c reductions with GLP-1's

--the achievable decreases in SUA levels by using SGLT-2's is achievable by lifestyle changes (diet, decreasing intake of fructose, decreasing alcohol, ...)

--there are arguments that high SUA levels by themselves lead to more cardiovascular disease and that lowering them is cardioprotective (eg see http://gmodestmedblogs.blogspot.com/2017/07/hyperuricemia-and-cardiometabolic.html and the embedded links); and there will be a blog soon on a proposed uric acid threshold for CAD mortality

There are lots of prior blogs on the problems with SGLT-2 inhibitors:

-- http://gmodestmedblogs.blogspot.com/2016/06/canagliflozin-decreases-macrovasc.html for eval/critique of the CANVAS trials which had significant design problems but found a decrease in cardiovascular and renal endpoints though twice the number of amputations and 71% increase in fractures

-- http://gmodestmedblogs.blogspot.com/2016/05/another-fda-alert-about.html for an FDA alert on amputations

-- http://gmodestmedblogs.blogspot.com/2018/09/sglt-2-inhibitors-and-increased-lower.html for a large-scale analysis showing the risk of amputations was high for all of the SGLT-2 inhibitors

-- http://gmodestmedblogs.blogspot.com/2019/05/sglt-2-inhibitors-and-fourniers-gangrene.html a newer analysis finding increases in Fournier’s gangrene with SGLT-2 inhibitors

-- http://gmodestmedblogs.blogspot.com/2015/05/sglt2-inhibitors-for-diabetes-may-cause.html for a blog on SGLT-2 inhibitors causing ketoacidosis, even with blood sugars <200 mg/dL

-- https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about for FDA alert on serious UTIs/urosepsis with SGLT-2’s

and, even the purported cardiovascular benefits are challenged in a large data-mining study comparing SGLT-2's and GLP1's, finding fewer heart failure admissions with the former, but a 23% increase in composite of MI or stroke, mortality and heart failure hospitalizations in those without known cardiovascular disease (see https://diabetes.diabetesjournals.org/content/6d8/Supplement_1/247-OR , not yet published, though i will review in detail when it is)

geoff​

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