colchicine decreases cardiovasc events if diabetes and recent MI

 A recent study found that patients with type II diabetes and a recent myocardial infarction had impressive decreases in a composite of cardiovascular events by being randomized to colchicine (see colchicine helps if MI and DM DiabCare2024 in dropbox, or doi.org/10.2337/dc23-1825

 

Details:

-- this current analysis was a prespecified analysis from the Colchicine Cardiovascular Outcomes Trial (COLCOT), a Canadian with patients enrolled from December 2015 to July 2019

    -- the original COLCOT study involved 4745 patients who had an MI in the prior 30 days and were randomized to colchicine 0.5 mg a day versus placebo, finding a 23% reduction of the cardiovascular composite outcomes (death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization) over a median follow-up of 22.6 months: see (see cad colchicine postMI nejm2019 in dropbox, or  DOI: 10.1056/NEJMoa191238, or https://gmodestmedblogs.blogspot.com/2019/12/colchicine-benefits-post-mi.html)

    -- there were many exclusions in this study including patients with severe heart failure or LVEF <35%, stroke within the prior 3 months, inflammatory bowel disease or chronic diarrhea, clinically significant hematologic abnormalities or severe renal disease, severe hepatic disease, long-term steroid therapy, as well as a slew of other less prominent exclusions

-- this current study is a prespecified subgroup analysis of the 959 of the patients in the original COLCOT study who had type II diabetes, comprising 462 who had been randomized to colchicine 0.5mg and 497 receiving placebo

-- mean age 62, 22% female, BMI 30

-- current smokers 26%, hypertension 75%, history of MI 26%/percutaneous coronary intervention (PCI) 25%/heart failure 4%/stroke or TIA 5%

-- time since index MI: 14 days (with 90% having a PCI)

-- medications: aspirin 98%, other platelet agent 97%, statin 99%, beta blocker 92%

-- diabetic meds: Metformin 75%, insulin 30%, GLP-1 agonists 8%, SGLT-2 inhibitors 17%, DPP-4 inhibitors 21%, sulfonylurea 20%

-- primary efficacy outcome: a composite of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization, in a time-to-event analysis

 

Results:

-- primary outcome by intention-to-treat (ITT) analysis:

    -- colchicine group: 8.7%

    -- placebo group: 13.1%

        -- 35% reduction with colchicine, HR 0.65 (0.44-0.96), p=0.03

-- in the per-protocol analysis (i.e. those who completed the study on their assigned medication), there was a 37% benefit from colchicine, HR 0.63 (0.42-0.95),p=0.03

 

-- the total numbers of primary endpoint events and their event rates:

    -- colchicine group: 50 patients, primary endpoint event in 0.48 per 100 patient-months

    -- placebo group: 93 patients, primary endpoint event in 0.86 per 100 patient-months

        -- 47% reduction with colchicine, HR 0.53 (0.33-0.87), p=0.01

 

-- Incidence of any adverse events considered to be related to the study drug:

    -- colchicine group: 14 6% of patients

    -- placebo group: 12.8% of patients

       -- this difference was not statistically significant

    -- gastrointestinal events: 15.3% with colchicine, 16.1% with placebo (more with placebo!!!)

    -- diarrhea, flatulence, decreased appetite, gastrointestinal hemorrhage, anemia, leukopenia, and thrombocytopenia had no statistical difference between the groups; the only one with a significant statistical finding was nausea in 12 patients on colchicine and 4 on placebo, p=0.03

 

-- incidence of serious adverse events:

    -- 20.4% with colchicine and 18.9% with placebo, not statistically significantly different

    -- the only serious event, which was more prominent with colchicine, was pneumonia in 11 patients, and 2 on placebo, p=0.008

    -- there was no statistical difference in serious gastrointestinal events, infection, severe infection, septic shock, hospitalization for heart failure, or cancer

 

Commentary:

-- 30 to 40% of patients with an MI have type II diabetes or metabolic syndrome

-- conversely, cardiovascular disease is extremely prominent in those with diabetes, and is the major cause of death

    -- in the original COLCOT trial, patients with type II diabetes had a 1.86-fold higher risk of a cardiovascular event

-- the LoDoCo2 study, another big colchicine study with 5522 patients but having chronic coronary disease, found a 31% decreased risk of the primary composite endpoint of cardiovascular death, spontaneous MI, ischemic stroke, or ischemia-driven coronary revascularization in those randomized to colchicine 0.5mg (https://www.nejm.org/doi/full/10.1056/nejmoa2021372 )

-- there is also evidence that colchicine may decrease the risk of cardiovascular events in patients without a history of cardiovascular disease: https://gmodestmedblogs.blogspot.com/2016/10/colchicine-may-lower-cardiac-risk-in.html

    -- the putative mechanism by which colchicine might decrease cardiovascular events is through its down-regulation of inflammatory cytokines and neutrophil chemotaxis, and decreasing inflammation. And it does have clinical benefit in several inflammatory conditions including recurrent pericarditis, Familial Mediterranean Fever, …  And, we know that diabetes is an inflammatory condition

-- consistent with this postulate that the main mechanism of colchicine benefit is through its being anti-inflammatory, an exploratory analysis of LoDoCo2 also found that colchicine decreased the need for hip and knee replacements https://gmodestmedblogs.blogspot.com/2023/12/colchicine-decreases-hip-and-knee.html

-- this current analysis of the COLCOT study confirms rather profound benefit of colchicine in those who have diabetes and a recent MI

    -- reviewing the graph above, it is clear that the benefit began after about 3 months and that benefit increased over time (the curves splaying apart)

-- the adverse effects found were really not much different in the colchicine versus placebo group (only 2 of them reached statistical significance); a few comments here:

    -- the increase in pneumonia, a quite serious adverse event is really not clear. The somewhat larger LoDoCo2 study found pneumonia hospitalizations in 1.7% in those on colchicine and 2.0% in those on placebo

        -- it is certainly possible that the issue is an altered immunologic response in those on colchicine: colchicine's blunting the inflammatory response to infection could potentially interfere with the body’s natural protective response against infection

    – the increase in nausea with colchicine is not so surprising. Colchicine (which itself is associated with nausea and other GI symptoms) is being added to several meds associated with nausea (aspirin, other anti-platelet drugs) as well as perhaps other gastrotoxins (there is no mention of NSAID use, for example)

-- on June 20, 2023, the FDA approved the lower dose of colchicine 0.5 mg (to be sold as LoDoCo) for decreasing cardiovascular events . However, it should not come as a shock that it costs around $531 for a 30-tablet supply, versus about $29.71 for a 30-tablet supply of colchicine 0.6 mg. No doubt, the former will involve getting prior approvals, larger out-of-pocket expense to the patients, and larger costs for the overall care system. 

    – i could not find any data on the benefit in adverse events by using the lower dose pill, though there was an article assessing the clinical benefits and pharmacodynamics of colchicine: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688259/ 

 

I can't help myself, but i do need to make what i think is an important diversion:

-- one very curious, and perhaps not-so-well-known, issue is how diabetes is defined: 

    -- the A1c 6.5% cutpoint differentiating the definition of diabetes vs prediabetes is based on the A1c level at the inflection point for the increase of retinopathy  (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453668/ )

         -- and, though retinopathy is not such a great thing to have, the major cause of death in patients with diabetes is cardiovascular!!! (and not retinopathy!!!)

    -- and there are many studies finding that “pre-diabetes” with A1c levels down to 5.7% are associated with a major increase in cardiovascular disease

        -- a 2020 updated meta-analysis assessed the association between prediabetes and the risk of all-cause mortality as well as cardiovascular disease (see dm prediabetes inc risk CVD mortality BMJ2020 in dropbox, or doi.org/10.1136/bmj.m2297), finding: 

            -- 129 studies identified, all having adjusted for other risk factors in these numbers: more than 10 million individuals followed for a median of 9.8 years; comparing prediabetes versus normoglycemia found (the relative risks were calculated over a follow-up of 9.8 years; absolute risk follow-up of 3.2 years): 

            -- all-cause mortality: 13% increased risk, RR 1.13 (1.10-1.17) 

                -- absolute risk: 7.36 per 10,000 person-years 

            -- composite cardiovascular disease: 15% increased risk, RR 1.15 (1.11-1.18) [composite cardiovascular disease was not defined and ??may have varied by the different individual studies ]

                -- absolute risk: 8.75 per 10,000 person-years 

            -- coronary heart disease: 16% increased risk, RR 1.16 (1.11-1.21) 

               -- absolute risk: 6.59 per 10,000 person-years 

            -- stroke: 14% increased risk, RR 1.14 (1.08-1.20) 

                -- absolute risk: 3.68 per 10,000 person-years 

        -- in patients with pre-existing atherosclerotic cardiovascular disease, prediabetes was associated with: 

            -- all-cause mortality: 36% increased risk, RR 1.36 (1.21-1.54) 

               -- absolute risk: 66.19 per 10,000 person-years 

            -- composite cardiovascular disease: 37% increased risk, RR 1.37 (1.23-1.53) 

                -- absolute risk: 189.77 per 10,000 person-years 

            -- coronary heart disease: 15% increased risk, RR 1.15 (1.02-1.29) 

                -- absolute risk: 8.54 years per 10,000 person-years 

            -- stroke: 3.68: no significant difference 

    -- and, there have been a few studies finding significant increases in cardiovascular disease in those with even lower A1c's: eg a European study found that in men, compared to an A1c <5%, those with A1c of 5-5.4% had a 56% increase in coronary heart disease, those 5.5-5.9% had relative risk RR 2.00, 6-6.4% had RR 2.13, 6.5-6.9% RR 3.44, >7% RR 7.07 (see dm A1C and cardiovasc dz annals 2004 in dropbox, or Khaw K, AnnInternMed 2004; 141: 413-420)

-- and a couple of relevant blogs:

    -- a systematic review of the association between prediabetes by different definitions and all-cause/cardiovascular https://gmodestmedblogs.blogspot.com/2016/12/prediabetes-and-cardiovascular-risk.html

    -- a study that found that patients with atrial fibrillation who had prediabetes had a higher incidence of developing heart failure: https://gmodestmedblogs.blogspot.com/2022/11/prediabetes-increases-risk-heart.html

    -- this brings up a few issues in clinical care:

        -- we should all be treating “prediabetes” as a real, important issue, to be addressed with aggressive nonpharmacologic therapy and often meds (eg statins, metformin, GLP-1 agonists…). And  neither us clinicians nor our patients should dismiss this because it is “pre”

        -- it is patently absurd that insurance companies/prescription benefits now seem to be rejecting our treating patients with severe obesity and prediabetes with GLP-1 agonists, and their well-documented benefits (I have had many such patients who initially could get GLP-1’s, lost lots of weight, felt great and had improved self-esteem, were much more motivated to eat healthier and exercise regularly, undoubtedly improved their many cardiovascular and other long-term outcomes, etc. But then there was a recent change to cover only patients who had “diabetes” but not “prediabetes”. This is hugely concerning (though I should state that most of my patients do not have commercial insurances, so I cannot comment on how widespread this retrenchment is)

            -- I assume that this retrenchment is related to 2 factors: the high cost of the meds (which, of course, is itself obscene) but also the realization that many of these patients will not be using the same insurance many years from now when their adverse cardiovascular outcomes become manifest (ie, why “waste” money on people who we will not have to deal with in the future???)

 

Limitations:

-- this study was done 2016-2018, so the above results apply to the clinical situation at that time. For example, very few people were on GLP-1 or SGLT-2 inhibitors, which at this time have changed diabetes and heart disease management substantially. Also, the comorbidities may well have changed in the interim (eg, the current smoking rate in the US has continued to decline from the 26% in this study, which might also reflect some differences in the 2 countries, and those differences might limit the generalizability of their results to other countries)

-- there was relatively limited information on the specifics of the treatment of those with a recent MI that time, which might limit generalizability of the results to the current era

-- we have no information about several important parameters in assessing the study, such as what the actual hemoglobin A1c or lipid levels were. Both of these clearly can affect cardiovascular endpoints, and both in a dose-response manner

-- we do not have much granular information on comorbidities other than a history of a few cardiovascular ones (no info of the level of hypertension, or the type of heart failure and markers of it), nor of other meds taken (some of which could have affected outcomes, such as NSAIDs as noted above)

so, a few issues:

-- studies continue to affirm the role of colchicine in decreasing cardiovascular risk, even in those without known pre-existing cardiovascular disease

-- the 2 major colchicine studies (COLCOT and LoDoCo2) employed colchicine 0.5mg vs the 0.6mg dose we have used in the US.  Does this matter?

    -- we do not have data suggesting that the benefit is the same with the lower dose (though likely it is by its pharmacodynamics), nor that the adverse effects are less. so, should we really change patients to the much more expensive non-generic 0.5mg dose that was recently approved by the FDA??

    -- and, is there similar benefit for colchicine alone vs with aspirin/other anti-platelet meds (in this study a combination of aspirin plus another anti-platelet drug was prescribed to >95% of the patients)?

    -- ie, it would be clinically useful to have good RCT studies assessing:

        --comparison of the colchicine 0.5mg vs 0.6mg dosing on clinical cardiovascular outcomes (an unlikely study to be done: no drug company will pay for a study of their newly patented drug with a cheap generic....they might lose in the competition)

        -- assessment of the effect of colchicine in the absence of antiplatelet drugs. or with just aspirin or one other antiplatelet drug. one would imagine that combining gastrotoxins (which may be a new word i developed??) in the long-term would increase the likelihood of GI bleeds

            -- by the way, there was an interesting study finding that those with H Pylori infections (the most common bacterial infections in the world, with >50% infected globally, and on the order of 30-40% in the US) had a much increased risk of GI bleeds in those people on low-dose aspirin, leading the British to recommend detection of H Pylori and eradication if patients are to be on low-dose aspirin (as well as on NSAIDs): https://gmodestmedblogs.blogspot.com/2013/04/h-pylori-erdication-if-on-aspirin.html , also a strong recommendation from a 2022 RCT to eradicate H Pylori infection as primary prevention in older patients prescribed aspirin (see H pylori eradication to dec risk of aspirin Lancet2022 in dropbox, or Lancet 2022; 400: 1597–606)

--and, per my impassioned diversion above, i really think we should change/discard the current concept of "prediabetes", since it obscures the very real relationship of A1c levels, even down to the 5-5.5% levels, with the increasing, dose-response relationship with cardiovascular disease, the most important clinical outcome associated with dysglycemia...

geoff

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