Diabetes Assn update: dapagliflozin and icosapent ethyl

the Am Diabetes Association just updated their (quite recent) 2019 standards of care for diabetes, with 2 notable additions (see http://www.diabetes.org/newsroom/press-releases/2019/ada-issues-critical-updates-to-2019-standards-of-care.html ):

-- from the REDUCE-IT trial, consider adding icosapent ethyl to statins to reduce cardiovascular risk in diabetic patients with high triglycerides and atheroscleroitic cardiovasc disease, or other risk factors, but who have controlled LDL levels and fasting triglycerides of 135-499,
-- from the DECLARE-TIMI 58 trial, dapagliflozin (an SGLT-2 inhibitor) has been shown to decrease risk of hospitalization for heart failure and reduce in progression of chronic kidney disease; and it can be used down to eGFR of 45

will give briefer-than-usual reviews of these trials below
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The REDUCE-IT trial (see triglycerides REDUCE-IT trial nejm2019 in dropbox, or DOI: 10.1056/NEJMoa1812792):

-- 8179 patients with established cardiovascular disease or with diabetes and other risk factors, already on a statin and low LDL levels, and who had fasting triglycerides of 135-499, were randomized to either 2g of icosapent ethyl twice a day vs placebo, and followed them 4.9 years.
-- icosapent ethyl is a highly purified and stable EPA (eicosapentanaenic acid, an n-3 fatty acid/fish oil)
-- median age 64, 71% male, 90% white, BMI 31, 58% with diabetes, median TG level 216 mg/dL, HDL 40, LDL 75, median baseline EPA level 26 mcg/ml
-- icosapent ethyl led to a 18.3% decrease in triglycerides vs 2.2% increase with placebo, a 3.1% increase in LDL vs 10.2% increase with placebo, and HDL increased from 40 to 41vs from 40 to 42 with placebo 
-- primary endpoint: composite of cardiovasc death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina:
    -- 17.2% of patients on icosapent ethyl and 22.0% on placebo, 25% reduction, HR 0.75 (0.68-0.83), p<0.001
-- secondary endpoint: composite of cardiovascular death, nonfatal MI or nonfatal stroke:
    -- 11.2% of patients on  icosapent ethyl and 14.8% on placebo, 26% reduction, HR 0.74 (0.65-0.83), p<0.001
-- also, rate of cardiovasc death by itself decreased 20%, HR 0.80 (0.66-0.98), p=0.03
-- curves showed that the clinical outcome differences began to appear after 1-2 years of treatment
-- subgroup analyses found that there was benefit for icosapent ethyl for almost all of the subgroups (the only ones not reaching statistical significance had too few people in the groupings, such as those few on ezetimibe)
    -- also, the initial triglyceride level (<150, 150-200, >200) did not matter much
-- adverse events: 
    -- more atrial fib or flutter with icosapent ethyl (3.1% vs 2.1%), p=0.004)
    -- more bleeding with icosapent ethyl (2.7% vs 2.1%), p=0.06

-- these medication benefits were more impressive than in prior studies of fish oils.  ?because this was only EPA and not a combo of EPA with docosahexaenoic acid (DHA), or this was a higher dose, or a more purified and stable form of EPA, or the fact that the LDL was much lower in this study, or because there was a difference in LDL levels between the groups by active treatment. 
    -- since the benefit of icosapent ethyl seemed to be independent of the baseline triglyceride level, perhaps its benefit is actually independent of triglycerides.  perhaps a cardioprotective effect was from the LDL differences (7.1% difference), and lowering LDLs even further seems to confer benefit without much harm: see http://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html ; and which may mean that more aggressive LDL lowering, perhaps by using rosuvastatin 40 over atorvastatin, might itself confer some of the benefit of icosapent ethyl, and without the noted adverse events]
    -- another issue adding to this is LDL size.  Diabetics in general have small, dense and highly atherogenic LDLs, about 3-fold more atherogenic than larger LDL particles
        -- fish oils transform these small, dense LDL particles to the larger, less-atherogenic ones (see https://www.ncbi.nlm.nih.gov/pubmed/7775859 ). this transformation might explain the slight increase in total LDL levels with icosapent ethyl yet the cardioprotection
        -- so, even though the usual cardiovascular risk protection is that a 1 mmol/L decrease in LDL (38.7 mg/dL) is associated with a 25+% decrease in major cardiovascular events, the 7.1 mg/dL difference found in the above study might really understate the actual atherosclerotic benefit from the icosapent ethyl because of the likely shift to larger LDL particles.        

        --the prior studies on n-3 fatty acids also found a small increase in LDL levels (see fish oils and CAD AHRQ2017 in dropbox, or https://effectivehealthcare.ahrq.gov/sites/default/files/related_files/fatty-acids-cardiovascular-disease_executive.pdf )

-- see http://gmodestmedblogs.blogspot.com/2018/11/omega-3-pill-decreases-cardiac-events.html for more details on the REDUCE-IT trial

-- see https://blogs.bmj.com/bmjebmspotlight/2016/09/01/primary-care-corner-with-geoffrey-modest-md-omega-3-fatty-acids-and-cardiovascular-disease/ for the AHRQ systematic review of omega-3 fatty acids and cardiovascular disease

so, all of the above does suggest the fish oils are probably an important adjuvant to treating diabetics, emphasized by the quite favorable effects of the pretty high dose of purified EPA via icosapent ethyl.  but, it could be that eating more fatty fish, or taking higher doses of omega-3 supplements, or perhaps taking supplements that have a much higher EPA/DPA ratio would do just as well as this medication supplementation.  and the wholesale price of 2 grams twice a day of icosapent ethyl is $364 per month…. and, perhaps we should just be pushing statins more in the attempt to maximize cardioprotection: eg, more routinely prescribing rosuvastatin 40mg in high risk patients such as diabetics, the most potent one we have.

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The dapagliflozin study (see dm dapagliflozin dec cardiac events nejm2018 in dropbox, or DOI: 10.1056/NEJMoa1812389 ):

-- 17,160 diabetic patients at risk for ASCVD (41% known ASCVD, 59% multiple risk factors) randomized to dapagliflozin vs placebo, and followed 4.2 years
-- no difference in major adverse cardiovascular events, but those on meds did have a lower rate of the combo of cardiovascular death or hospitalization (4.9% vs 5.8%, 17% decrease, HR 0.83 (0.73-0.95), p=0.005)
    -- this really represented just a lower rate of hospitalization for heart failure: 27% decrease, HR 0.73 (0.61-0.88). 
-- also a 24% decrease in renal events (defined largely as >40% decrease in eGFR) on dapagliflozin

-- but DKA was more common with dapagliflozin (0.3% vs 0.1%, p=0.02); and there were more genital infections or other adverse effects leading to dapagliflozin discontinuation (0.9% vs 0.1%, p<0.001). notably, there was no difference in amputation or fractures.
    -- as a placebo-controlled study, the patients on dapagliflozin had a lower A1c (0.42%) throughout the trial, 10% received GLP-1 agonists, and 5% open-label SGLT-2 antagonists. also those on dapagliflozin had a 1.8 kg decrease in weight, and 2.7/0.7 mmHg decrease in BP; these differences might explain some part of the observed cardiovascular and renal benefits from dapagliflozin
    --though dapagliflozin decreased only the rate of hospitalization for heart failure, empagliflozin did so as well, but also decreased cardiac death rates. And canagliflozin also decreased heart failure hospitalizations, though no other specific cardiac outcome was significantly improved
-- though this study did not find an increase in  amputation or fractures, a large Swedish/Danish study did: seehttp://gmodestmedblogs.blogspot.com/2018/11/sglt-2-inhibitors-twice-risk-of.html.

-- this brings up another issue: SGLT-2 inhibitors are effective loop diuretics, which perhaps explains why fewer people developed heart failure. but is this the best approach? or should we follow diabetic patients more closely, since such a large number do develop heart failure (eg, one study found heart failure prevalence in those >65yo to be 22.3% and subsequent increases of new cases at 12.6%/yr, others estimate the rate around 30%.  see see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107260/ or Bertoni AG. Diabetese Care 2004; 699). And then give them the more tried-and-true loop diuretics (eg torsemide or furosemide), that are titratable and have lots of studies supporting their use, and have been around for a long time so patients and us may not be blind-sided by a really bad adverse effect that does not manifest itself for awhile, and do not cause fractures/amputations, DKA, urosepsis, genital mycotic infections, etc
--see http://gmodestmedblogs.blogspot.com/2018/11/sglt-2-inhibitors-twice-risk-of.html for a critique of SGLT-2 inhibitors overall and the review of dapagliflozin study

so, as with many studies, more questions are raised than the narrow answers found. the dapagliflozin study did find less heart failure (as did the other SGLT-2 inhibitors) and less renal deterioration (as do the other SGLT-2's). The ADA does extend its use down to eGFR of 45, but that is the cutpoint for the other SGLT-2 inhibitors. so i'm not sure what the big deal is here. The ADA does not modify their guidelines when yet another ACE inhibitor becomes available...

geoff

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