Liraglutide also decreases adverse renal outcomes

Right after I sent out blog (http://gmodestmedblogs.blogspot.com/2017/08/liraglutide-new-indication-for.html ) on the FDA including cardiovascular protection as indication for liraglutide, an article reviewed renal protection in the same LEADER study, extending the finding in the original article, which had noted a 22% reduction in renal events. (see Mann JFE, N Engl J Med 2017;377:839-48.)

Will reprint/append my blog below from 6/22/16, which reviewed the original article leading to this indication, and my commentary (see below)

Details:

--for details of the study, see the 6/22/16 blog below

--this new analysis is of the prepecified secondary renal outcomes from this study, a composite of new-onset persistent macroalbumenuria (>300mg albumin in 24h urine), persistent doubling of the serum creatinine level and an estimated GFR of <45, the need for continuous renal-replacement therapy with no reversible cause of renal disease, or death from renal disease

--at the beginning of the study, 26.3% had microalbuminuria and 10.5% macroalbuminuria

Results:

--as noted, there were 22% fewer renal outcomes in those on liraglutide vs placebo (268 patients = 5.7% vs 337 = 7.2%), HR 0.78 (0.67-0.92), p=0.003); this benefit was evident at the first followup visit at 12 months, and increased some over time. There were small  differences in decline of eGFR, though it was significant (p=0.01 for trend over 36 months). The differences in urinary albumin-to-creatinine ratio (17% lower on liraglutide, p<0.001) were evident at 12 months, did not change over the course of the study, and were independent of baseline eGFR or baseline albuminuria

--this decrease was predominantly from new onset of persistent macroalbuminuria, occurring in 161 patients =3.4% on liraglutide vs 215 = 4.6% on placebo, a 26% decrease, HR 0.74 (0.60-0.91), p=0.004

--no difference in doubling of creatinine or development of end-stage renal disease [though this was a pretty short study, so not very surprising]

--rates of renal adverse events were similar (15.1/1000 patient-yrs in liraglutide vs 16.5/1000), including rate of acute kidney injury (7.1 vs 6.2/1000 patient-yrs)

--in prespecified subgroups, assessing composite renal outcome:

    --3422 patients with baseline micro- or macro-albuminuria: significant 19% decrease (p=0.02) in those with any albuminuria vs nonsignificant 31% decrease in those without

    --2158 patients with baseline eGFR <60: nonsignificant 16% decrease, though there was a significant 32% decrease in those with eGFR >60

    --and, for those with eGFR>60 and or no albuminuria, significant 30% decrease vs those with both eGFR<60 and albuminuria, nonsignificant 19% decrease

--there was a 13% decrease in the development of microalbuminuria with liraglutide (not a prespecified endpoint)

Commentary:

--the biggest outcome difference above was a decrease in the development of persistent macroalbuminuria with liraglutide. It is important to emphasize that in a short-term study like this one, it is quite unlikely to see changes in other renal outcomes (especially progressive decreases in eGFR, which typically happens years after developing progressive microalbuminuria), though as macroalbuminuria increases, it does portend poorly for the struggling kidneys)

--many studies have found that improved glycemic control (decreased A1c) is associated with improved renal outcomes, including the occurrence of early diabetic nephropathy, so the 0.4 percentage point decrease of A1c  in the liraglutide group may be part of the renoprotective effect.  In this study, however, statistical adjustment for A1c did not affect the results

--in addition, there was more weight loss and lower systolic blood pressure in the liraglutide group, though statistical adjustment for these differences also did not affect the results

--a proposed mechanism for the benefit of liraglutide includes that it decreases inflammation (at least in rats) and 5 inflammatory biomarkers in humans, including TNF-a (see DOI: 10.1111/dom.12884 )

--one other uncontrolled variable is that patients on placebo did have more concomitant medications added, which could have affected the results

so, this does add to the list of potential positives of the GLP-1 agonists.

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will append my blog below from 6/22/16, which reviewed the original article leading to this indication, and my commentary:

there was a recent article from a paper at the Am Diabetes Assn annual meeting finding decreased cardiovascular events in patients on the glucagon-like peptide 1 (GLP-1) agonist liraglutide (see DOI: 10.1056/NEJMoa1603827). 

details:

--9340 patients with type 2 diabetes and high cardiovascular risk, randomized to liraglutide vs placebo, with mean follow-up 3.8 yrs. Drug-company sponsored study begun in 2010, in 410 sites in 32 countries

--65% male, mean age 64, duration of diabetes 13 yrs, 35% North America/30% Europe/8% Asia, A1c 8.7, BMI 33, BP 136/77, 18% with heart failure, 81% prior MI, 16% prior stroke/TIA, 25% chronic kidney disease CKD with eGFR<60, 35% with normal renal function.

--76% were on lipid lowering meds, with 72% of them on statins; 67% on antiplatelet drugs of which 64% on aspirin; 93% on BP meds, of whom 57% on b-blocker, 84% on ACE/ARB.

--inclusion criteria -- all patients needed initial A1c >7.0% (either treated or untreated), and:

        --were over 50yo, and at least one cardiovascular problem (coronary heart dz, cerebrovasc dz, peripheral arterial dz, chronic kidney dz at least stage 3, or chronic heart failure NYHA class II or III)

        --or, were >60yo with at least one cardiovasc risk factor (microalbuminuria or proteinuria, hypertension and LVH, LV systolic or diastolic dysfunction, ankle-brachial index of <0.9)

--results:

    --A1C was 0.40 percentage points lower in those on liraglutide, though more placebo patients were on metformin, sulfonylureas, TZDs (?which one), glinides, SGLT-2 inhibitors, or the array of insulin preparations

    --liraglutide was also associated with significantly more weight loss (2.3kg), lower systolic blood pressure (1.2 mmHg), but higher diastolic (0.6 mmHg), and higher pulse (3.0 beats/min)

    --primary composite endpoint (first occurrence of death from cardiovasc causes, nonfatal MI, or nonfatal stroke): 608 of 4668 patients on liraglutide (13.0%) vs 694 of 4672 on placebo (14.9%), a13% decrease [HR 0.87 (0.78-0.97), p<0.001 for noninferiority and p=0.01 for superiority]. overall NNT to prevent one event in 3 years was 66

        ​--219 patients died from cardiovascular causes (4.7%) vs 278 on placebo (6.0%), a 22% decrease [HR 0.78 (0.66-0.93),  p=0.007]

        --381 patients died from all causes (8.2%) vs 447 on placebo (9.6%), a 15% decrease [HR 0.85 (0.74-0.97),  p=0.02]; NNT to prevent one death from any cause in 3 years was 98

        --rates of nonfatal MI, nonfatal stroke and hospitalization for heart failure were nonsignificantly lower with liraglutide

    --review of the graphs show that a clear separation (improvement with liraglutide) was seen after about 12-18 months, with perhaps some splaying of the curves over time

    --subgroup analysis revealed: pretty consistent though usually nonsignificant benefit of liraglutide independent of the subgroup, though

        --clear benefit in the 7598 patients in the >50 yo and documented cardiovasc disease group but a trend to doing less well in the >60 yo with only cardiovasc risk factors

        --benefit in those with chronic kidney disease was most evident in those with eGFR <60 (too few in the <30 group to be really evaluable)

        --clearer benefit in those with BMI>30 and those with A1c>8.3 and with duration of diabetes <11 years

    --microvascular outcomes: liraglutide associated with decreased nephropathy events (1.5 vs 1.99/100 patient-yrs, a 22% reduction,p=0.003). nephropathy events were the composite of new onset macroalbuminuria, doubling of creatinine and eGFR <45, need for continuous renal-replacement therapy, or death from renal disease

    ---adverse events:

            --liraglutide assoc with more GI events leading to discontinuation of the med

                --more severe hypoglycemia in the placebo group (153 vs 114 events)

                --more GI events with liraglutide (significantly more acute cholecystitis in 36 vs 21; more nausea, vomiting, diarrhea, abdominal pain, decreased appetite

            ​--the incidence of pancreatitis (found in some prior GLP-1 studies) was nonsignificantly lower with liraglutide

            --no difference in neoplasms, though specifically: more pancreatic (13 vs 5, nonsignificant, and a few recent large analyses have not found increased pancreatic cancer), same numbers for melanoma, but significantly less prostate cancer (26 vs 47 cases in the placebo group)

commentary:

--one reassuring aspect of the study was that it was a large study of a diverse group of patients with long-standing diabetes (mean 13 years, which has been a potential issue because the GLP-1 agonists require a functioning pancreas to secrete insulin, and there has been lingering concern in my mind that patients with such longstanding diabetes might not have much b-cell reserve, though i should note that in this study those with longer-standing diabetes did a bit less well. I had been checking C-peptide levels initially on my patients with long-standing diabetes prior to starting a GLP-1 agonist and was surprised to find no one had low levels)

--the decrease in cardiovascular events in the above study is pretty impressive, especially since it seems that patients were mostly on pretty appropriate cardiac meds (though not as many as i might have expected...)

--some question about generalizability: the benefit was really confined to younger patients who had definite cardiovascular disease. would there have been benefit to older patients just with cardiac risk factors after longer-term followup?? after all, the likelihood of decreasing atherosclerotic events is probably higher in those with more advanced established disease, both because of a higher absolute risk of a CV event in that group and a greater likelihood of an event sooner than later. My guess is that longer followup would show benefit in those with just a cardiovasc risk factor, since 80% of diabetics overall die from carvdiovac causes. and, those on liraglutide in this study did have some possible outcome advantage just because their A1c was lower, lost some weight and their BP was lower. also, as per many prior blogs, i am concerned that short-term studies will tend to understate adverse effects, which may take longer to manifest themselves, and thereby exaggerate the benefit/harm ratio.

--as per prior blogs, i am very impressed clinically with the GLP-1 agonists, because of their often dramatic effects on glucose control, their relative lack of hypoglycemia, their tendency to lead to weight loss and not cause hyperinsulinemia, their apparent ability to supply a very specific peptide (GLP-1) which is part of normal glucose control but deficient in diabetics, and their overall acceptability by most of my patients. 

--and my real concerns about most of the newer meds is that their approval is not based on real clinical outcomes, just A1c effects. So, this study reinforces that these drugs are clinically beneficial. by the way, the FDA just strengthened their warnings about SGLT-2 inhibitors because of increasing numbers of cases of acute renal injury, though they did not include empagliflozin.  for my critique of the methodology of the original http://gmodestmedblogs.blogspot.com/2015/12/empagliflozin-good-and-bad.html  finding potential cardiovascular benefit)​ [Will also add reference for blog on http://gmodestmedblogs.blogspot.com/2017/07/another-study-assessed-role-of-sodium.html, another SGLT-2 inhibitor with a more recent study, where i am also concerned about their methodology]