Liraglutide: new indication for cardiovascular risk reduction

​​Per the manufacturer, liraglutide just received a new indication by the FDA: "to reduce the risk of major adverse cardiovascular (CV) events, heart attack, stroke and CV death, in adults with type 2 diabetes and established CV disease". see http://press.novonordisk-us.com/2017-08-25-Victoza-R-liraglutide-is-approved-in-the-US-as-the-only-type-2-diabetes-treatment-indicated-to-reduce-the-risk-of-three-major-adverse-cardiovascular-events 

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 original empagliflozin study finding potential cardiovascular benefit. [Will also add reference for blog on canagliflozin, another SGLT-2 inhibitor with a more recent study, where i am also concerned about their methodology (see https://mail.google.com/mail/u/0/#label/clinical/15cc034d05181307 )]

​