SGLT-2 inhibitors and increased lower extremity amputation

​A recent retrospective cohort study from a large commercial claims database assessed the relationship between the newer diabetes meds and the incidence of lower extremity amputations (see see dm sglt2 inhib and lower extrem amputation jamaintmed2018 in dropbox, or doi:10.1001/jamainternmed.2018.3034)

Details:

-- 2.0 million commercially-insured non-insulin using adults in the Truven Health Market Scan Commercial Claims and  Encounters database, from 2012-2015.

-- 953906 people (516046 women and 437860 men); mean age 52, 89% with lowest rating on Diabetes Complications Severity Index, 60% with baseline hypertension/6% ischemic heart disease/all other comorbidities were <5%, 60% on ACE-I or ARBs/36% statins

-- 39869 new users of SGLT-2 inhibitors (4.2%) [28036 on canagliflozin, 8647 on dapagliflozin and 3186 on empagliflozin], 105023 new users of DPP-4 inhibitors (11.0%), and 39120 new users of GLP-1 agonists (4.1%). Users of multiple newer agents were excluded, though those just on the older agents were included

-- about 30% of those on the newer agents were also on sulfonylureas, 60% on metformin, and 1% on glitazones

-- the study compared new use of SGLT-2 inhibitors alone, DPP-4 inhibitors alone, GLP-1 agonists alone, or other antidiabetic agents (sulfonylurea, metformin, or thiazolidinediones) to assess foot and leg amputation rates

--there were some baseline differences between the groups: new users of SGLT-2 inhibitors and DPP-4 inhibitors were less likely to be female (45%) than those on GLP-1 agonists (61%);  there was more hypertension in those new users of SGLT-2 inhibs (60%) vs DPP4 inhibs (56%) vs GLP-1 agonists (52%); and more on SGLT-2 inhibs were on statins (36%) vs DPP-4's (34%) and GLP-1's (32%)

-- median observation time ranged from 99 days for new users of GLP-1 agonists to 127days for those using metformin, sulfonylureas, and thiazolidinediones

-- outcomes: foot and leg amputations, peripheral arterial disease, critical limb ischemia, osteomyelitis, and ulcer

Results:

--crude incidence rates of amputations:

    -- metformin, sulfonylureas, and thiazolidinediones: 4.90/10K person-yrs

    -- SGLT-2 inhibitors: 10.5/10K person-yrs (with 10.0/10K for canagliflozin); 8.5/10K person-yrs for DPP-4 inhibitors and 7.10 person-yrs for GLP-1 agonists.

-- After propensity score weighting (to balance baseline differences) and adjustment for demographics, severity of diabetes, comorbidities (cerebrovascular disease, heart failure, ischemic heart diseae, hypertension, retinopathy, nephropathy, neuropathy, atrial fibrillation, renal disease, and eye disease), and medications, the risk of lower extremity amputation:

    -- SGLT-2 inhibitors compared with DPP-4 inhibitors: a 50% increase, adjusted HR 1.50 (0.85-2.67), though not statistically significant

    -- SGLT-2 inhibitors compared with GLP-1agonists: a 47% increase, adjusted HR 1.47 (0.64-3.36), though not statistically significant

    -- SGLT-2 inhibitors compared with sulfonylureas, metformin, or thiazolidinediones (glitazones): more than twice the rate, adjusted HR 2.12 (1.19-3.77).

-- These results persisted in sensitivity analyses, including lumping together those on DPP-4 inhibitors plus GLP-1 agonists. BUT including patients with prior amputation, there was a statistically significant 73% increase with SGLT-2 vs DPP-4 inhibitors, adjusted HR 1.73 (1.01-2.98), p=0.048

-- SGLT-2 inhibitors were also associated with a 34% higher rate of vascular ulcers, 44% higher osteomyelitis, and 11% higher critical limb ischemia, as compared to the older meds; and these were all statistically significant

Commentary:

--approx 23 million diabetics in the US, and approx 1.5 million new ones annually (ie, a really important public health issue, as we all know only too well)

--the Truven Health Market Scan Commercial Claims and  Encounters database has information on 25 million privately-insured people in the US, including demographics and medical/pharmacy services provided

--the concern leading to this study was that canagliflozin has been associated with increased lower extremity amputations: canagliflozin vs placebo was associated with 6.3 vs 3.4 people per 1000 person-yrs getting lower extremity amputations (see reference to blog on this study below) . it should be noted that these studies on SGLT-2 inhibitors were not powered to assess this pretty rare outcome

    --in 2017, the FDA issued a warning on the use of canagliflozin based on the increased risk of lower extremity amputations in the CANVAS studies (see http://gmodestmedblogs.blogspot.com/2016/05/another-fda-alert-about.html ​ )

--the above Truven database study has some significant potential deficiencies which might affect the generalizability of the results:

    --i am somewhat surprised that only 60% of the diabetics were on metformin when the newer agents were added (and only 37% if on older drugs alone). metformin has been considered the first line drug for years, and the baseline comorbidity of nephropathy which could have precluded metformin was only in the 2% range (metformin was considered the top choice by the Am Diabetic Assn back in the 2012-2015 years of this study). And metformin has a pretty good track record for decreasing macrovascular events 

    --also a bit surprising that only 36% were on statins and only 60% on ACE-I/ARBs [though the increased use of statins in the SGLT-2 group may have led to an underestimation of the risk of amputations, since statins may be protective]. 

    --was there a difference in who got older drugs vs new ones in this observational study, which was not accounted for in their mathematical matching by propensity scoring? for example, it was notable that all of the newer agents were associated with higher amputation rates than the older agents (over twice as many with SGLT-2 inhibitors than with the newer ones). Were those put on the newer agents sicker, have harder-to-control diabetes, more prone to vascular complications? 

    --and, perhaps most significantly, there was a really short follow-up period of only a few months in this study.  these patients seemed to be pretty healthy diabetics (very low diabetes complications, and also pretty low numbers on statins, ACE-I/ARBs: though even then the ADA recommendations should have resulted in many more on statins). and it is not so surprising that the combo of healthier patients with only a few months of followup would lead to very few amputation events.​ So, pretty surprising that they still found about 50% more amputations in the SGLT-2 group than the other newer agents, though these events were not formally statistically significant. But if one includes those with prior amputations (who likely were sicker and had higher risk for further amputations), SGLT-2 inhibitors were statistically significantly associated with more amputations than those on the DPP-4 inhibitors

    --also, this patient population is derived from a database of privately-insured patients, and this may not be generalizable to non-employed people (ie: the "healthy worker bias", whereby workers overall tend to be healthier than those not working, where there is more disability etc)

-- unclear what the mechanism for increased amputations might be.  ?SGLT-2 inhibitors lead to more volume depletion/hemoconcentration from the glycosuria 

-- also, it is notable that in this short study, there was a significant increase in SGLT-2 inhibitors being associated with the other outcomes of vascular ulcers, osteomyelitis, and critical limb ischemia

--relevant prior blogs on concerns about the SGLT-2 inhibitors:

    -- http://gmodestmedblogs.blogspot.com/2015/12/empagliflozin-good-and-bad.html   is a blog which critiques the first study on empagloflozin, raising the question whether there was insufficient information in the study to support its claim of decreasing cardiovascular events

    -- http://gmodestmedblogs.blogspot.com/2016/06/canagliflozin-decreases-macrovasc.html  which critiques the canagliflozin study, including highlighting many of its adverse events (eg amputations) and also insufficient info to draw conclusions (one potentially important concern in both this and the emaglifozin study is that those not in the SGLT-2 intervention groups had a higher use of glitazones, and it was not mentioned which was used: was it rosiglitazone??)

    -- http://gmodestmedblogs.blogspot.com/2015/05/sglt2-inhibitors-for-diabetes-may-cause.html  is an FDA warning about all of the SGLT-2 meds and ketoacidosis even in those with type 2 diabetes

    -- http://gmodestmedblogs.blogspot.com/2017/07/another-study-assessed-role-of-sodium.html reviews the two CANVAS studies of canagliflozin and its effects on cardiovascular and renal outcomes, also finding the higher risk of lower extremity amputations as well as fracture risk

so, it may well be that these SGLT-2 inhibitors do decrease macrovascular events, though the pivotal primary studies were pretty flawed (as noted above).  And it is pretty clear that at least with canagliflozin, there does appear to be more lower extremity amputations, both in the original CANVAS studies and as confirmed in this new study with only a few months of follow-up in a healthy diabetic population (!!!). My main concern is that these studies did allow for the possibility of no cardioprotection og SGLT-2 inhibitors given their design and missing information, there are pretty clear very serious adverse events associated with the SGLT-2 inhibitors (worse for canagliflozin, leading to the FDA warning), and that we do have a few meds which have largely been shown to decrease macrovascular events (metformin, probably GLP-1 agonists, probably pioglitazone) and do not seem to have such bad adverse effects.

geoff

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