cystatin c: better predictor of bad outcomes than creatinine

Another study assessed the role of a sodium-glucose co-transporter 2 inhibitor, this time 

canagliflozin, and its effects on cardiovascular and renal outcomes in patients with type II diabetes (see
dm canagliflozin dec macrovasc dz NEJM2017 in dropbox or DOI: 10.1056/NEJMoa1611925 ). A drug company supported study.

Details:

-- this report involved 2 trials with 10,142 participants with type II diabetes and high cardiovascular risk, randomized to canagliflozin vs placebo, followed a mean of 188.2 weeks. All had HgbA1c between 7 and 10.5%, had a history of symptomatic atherosclerotic cardiovascular disease, or were at least 50 years old and had 2 or more risk factors (which included diabetes of at least 10 years duration). Patients were from 667 centers in 30 countries. 96% participants completed the trial.

-- mean age 63, 36% women, mean duration of diabetes 13.5 years, 78% white/13% Asian/3% black, 18% current smoker, 90% history of hypertension/14% heart failure/56% CAD/19% cerebrovascular disease/21% peripheral vascular disease (66% overall had a history of cardiovascular disease), 2% amputation, BMI 32, blood pressure 137/78, A1c 8.2%, 70% with normal albuminuria/22% microalbuminuria/8% macroalbuminuria

-- baseline diabetes therapy: 50% insulin/43% sulfonylurea/77% metformin/4% GLP-1 inhibitors/12% DPP-4 inhibitors

-- the 2 studies overall were similar, though in one study patients received canagliflozin 300 mg vs canagliflozin 100 mg vs placebo, the other canagliflozin 100 mg with an optional increase to 300 mg vs placebo

-- primary outcome: composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.

Results:

-- for those on canagliflozin (vs placebo):

    -- the use of other antihyperglycemic agents was 9.3% lower.

    -- HgbA1c -0.58%, BMI -1.60, blood pressure -4/-1 mmHg (p<0.001 for all comparisons). LDL and HDL were higher with canagliflozin, though the ratio was similar

-- the primary outcome was lower with canagliflozin, 26.9 vs 31.5 per 1000 patient-years, a 14% decrease with HR 0.86 (0.75-0.97), p<0.001 for noninferiority, p=0.02 for superiority

-- these outcomes were broadly consistent across prespecified subgroups, though those on baseline diuretics did significantly better (34%, HR 0.66, p<0.001) and those not on diuretics had a trend to doing worse

-- the pre-specified secondary renal outcomes (progression of proteinuria with >30% increase and a change from either normoalbuminuria to microalbuminuria or from micro to macroalbuminuria) overall were not statistically significant, however there seemed to be a possible benefit of canagliflozin in terms of progression of albuminuria, HR 0.73 (0.67-9): regression of albuminuria with HR 0.60, as well as for the composite outcome of the sustained 40% reduction in eGFR plus need to renal replacement therapy plus death renal causes, HR 0.60 (0.47-0.77)

-- adverse reactions: overall 7% less common in those on canagliflozin, but of note there were twice the number of amputations, 6.3 vs 3.4 participants per 1000 patient-years, HR 1.97 (1.41-2.75), in 71% at the level of the toe or metatarsal, and especially those with a prior history of amputation or peripheral vascular; fracture risk was also higher, occurring in 15.4 vs 11.9 per thousand patient years, p=0.02; and, as per prior studies of SGLT-2 inhibitors, there were more cases of osmotic diuresis, volume depletion, and mycotic genital infections in women in those on canagliflozin, though not urinary tract infections.

Commentary:

--reviewing their graphs, there were several major differences in the groups:

    --the HgbA1c was significantly lower, was down to 7.5 by week 26, slowly increased to 7.8 by week 150, and ultimately to around 8.0 by week 300. placebo was pretty consistently around 8.2-8.3

    --mean weight decreased to 87kg with canagliflozin but remained around 89-90 kg with placebo

    --blood pressure was 131/74 with canagliflozin but 136/76 with placebo

--the graphs for cardiovascular events:

    --deaths from cardiovascular causes, nonfatal MI or nonfatal stroke: curves separated at around 52 weeks of treatment, then paralleled after 104 weeks

    --death from cardiovascular causes: nonsignficant. curves initially separated favoring canagliflozin then merged together after 260 weeks

    --nonfatal stroke: also nonsignificant and similar to cardiovascular deaths

    --nonfatal MI: also nonsignificant, though did separate after 104 weeks and remained separate

--other outcomes:

    --death from any cause: nonsignificant

    --heart failure hospitalizations: signficantly better with canagliflozin, HR 0.67 (0.52-0.87) with separation early, by 26 weeks

    --renal: clear benefit beginning by 78-104 weeks for progression of albuminuria and the composite of 40% reduction in eGFR, requirement for renal replacement therapy or death from renal causes [though it seems that lowering A1c itself seems to be renoprotective from many studies, and those on canagliflozin had lower A1c levels!!!]

--it is unclear how much of the benefit from canagliflozin is related to the protective effects of this drug, given the substantial differences in HgbA1c, weight and blood pressure. the change in renal outcomes would largely be expected from these differences, as per many prior studies (unfortunately the authors did not compute the expected effect attributable to these A1c changes, but they would certainly go a long way to explaining the differences). and the differences in macrovascular outcomes (their primary outcomes) similarly may be explained largely by these differences in the constellation of better A1c, blood pressure, and weight loss in the canagliflozin group

--also, there is no comment in the article or the supplementary materials about the differences in treatment in the placebo group: they comment that the use of other antihyperglycemic agents was 9.3% lower with canagliflozin but do not comment on what additional meds were used in the placebo group. was it potentially harmful agents (eg rosiglitazone)? more sulfonylureas (which do not seem to help and may hurt cardiovascular outcomes)? more GLP-1 agonists (which would make their results more impressive, given that these do seem to be cardioprotective)

--and it is concerning about the increase in both amputations and fractures with canagliflozin.  Bones do not seem to fare well.

--also, see prior blogs on another SGLT2 inhibitor empaglifozin, where I found the study also quite flawed (see http://blogs.bmj.com/ebm/2015/12/21/primary-care-corner-with-geoffrey-modest-md-empaglifozin-the-good-and-the-bad/ ). And, it is important to remember, these SGLT-2 trials were both drug-company sponsored. and, it would not be so surprising to find that these trials are designed to achieve the results that the drug companies would like....  for example, they could have designed this canagliflozin trial so that the A1c levels in both the drug and placebo groups matched!!!! we could then sort out how much of the problem was related to the A1c differences and how much to the drugs used (they would also need to describe what drugs were used....)

so, how to proceed?

--these SGLT2 inhibitors possibly do decrease cardiovascular events (at least this has been shown for 2 different ones, though I think both studies are pretty flawed, as above). it should be kept in mind that  the FDA does warn about ketoacidosis and severe urosepsis with these drugs (see https://www.fda.gov/Drugs/DrugSafety/ucm475463.htm​ ), and there are reports of acute kidney injury as well as a pretty high incidence of genital mycotic infections.​

--i personally am still more impressed with the studies on GLP-1 agonists. they seem to be cardioprotective, I am consistently shocked at how well they work in lowering A1c levels, and they are quite targeted (the most common problem I have seen is GI, though a few cases of itchy rash/apparent allergy to one of them, though subsequent use of another was well-tolerated). And, they have been around for a long time ( exenitide has been used in Europe for >10 years).

geoff

link: https://www.dropbox.com/sh/0bmvtita8mzms11/XDTwHySFFg

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