prediabetes and cardiovascular risk: a lower cutpoint?

A recent systematic review/meta-analysis assessed the association between prediabetes by different definitions and all-cause/cardiovascular mortality (see dm prediabetes lower defn bmj2016 in dropbox, or doi.org/10.1136/bmj.i5953)

Details:
-- 53 prospective cohort studies with 1,611,339 individuals were followed a median of 9.5 years.
-- The researchers assessed different criteria for defining glucose intolerance:
    --impaired fasting glucose
        -- IFG – ADA (American Diabetes Association): 100 to 126 mg/dL
        -- IFG – WHO (World Health Organization): 110 to 126 mg/dL
    -- impaired glucose tolerance: 140 to 200 mg/dL, which is consistent across guidelines, based on 2-hour plasma glucose during an oral glucose tolerance test
    -- raised hemoglobin A1c:
        -- ADA: 5.7 to 6.4%
        -- NICE guidelines (UK): 6.0-6.4%
-- they specifically looked for the following endpoints: composite cardiovascular events (combination of coronary heart disease, stroke, or "other type of cardiovascular disease"), coronary heart disease, stroke, and all-cause mortality.

results:
-- as compared to normoglycemia (only statistically significant associations are reported below),
    -- risk for composite cardiovascular disease was increased 13% for IFG – ADA, 26% for IFG– WHO and 30% for impaired glucose tolerance
    -- risk for coronary heart disease was increased 10% for IFG – ADA, 18% for IFG– WHO, and 20% for impaired glucose tolerance
    -- risk of stroke was increased 6% for IFG– ADA, 17% IFG– WHO, and 20% for impaired glucose tolerance
    -- all cause mortality was increased 13% for IFG– ADA, 13% for IFG– WHO, and 32% for impaired glucose tolerance
    -- note: the observed increased risk occurred with fasting glucose as low as 100 mg/dL
-- in terms of A1c: 
    -- those in the 5.7 to 6.4% range had an increase of the composite cardiovascular disease of 25% and coronary heart disease 28%
    ​-- note: they found that the risk of composite cardiovascular events and coronary heart disease were higher in people with an A1c in the 5.7 - 6.4% vs. the 6.1 - 6.4% group (ie, the lower numbers mattered)


commentary:
-- overall, the study found that there was an increased risk of cardiovascular disease and all-cause mortality with fasting glucose as low as 100 mg/dL or a hemoglobin A1c of 5.7%. So, they strongly support the ADA definitions of prediabetes, which have not been accepted at this point by the European Society of Cardiology, the European Association for the Study of Diabetes, or the European Diabetes Epidemiology Group.
-- this review is useful given that individual published studies have found mixed results on the actual cutpoint of impaired fasting glucose associated with increased cardiovascular disease.
-- However, this study did not have data on the future development of diabetes during the follow-up period, and other data suggest that diabetes increases cardiovasc outcomes more than prediabetes
-- They did find that the risk of all-cause mortality was actually significant higher in the impaired glucose tolerance group than in the groups with other definitions of prediabetes, suggesting that impaired glucose tolerance may be a stronger risk factor for all-cause mortality than other definitions of prediabetes, though not for cardiovascular disease
-- other studies have suggested that impaired glucose tolerance is associated with increased risk of cancer mortality in Australia as well as in Mauritius
-- of considerable importance is that the more aggressive definition by the ADA includes lots more people, 36.2% of those in the US and 50.1% in China, for example. ie, this is a huge public health issue
-- the ADA does now recommend considering pharmacologic therapy in patients with impaired glucose tolerance and impaired fasting glucose as well as at least one of: age <60, BMI >35, family history of diabetes in first-degree relative, high triglycerides, decreased HDL, hypertension, and hemoglobin A1c >6.1%

so, the main reason I bring up this issue is to make sure we're all aware of the significant increase in cardiovascular and all-cause mortality associated with glucose intolerance, even at the remarkably common A1c level of 5.7% (and this raises the issue of what the lower limit really is, in terms of cardiovascular outcomes. And, about 80% of diabetics die ultimately die from CVD, even though those with this level of A1c only very slowly progresses to diabetes, if at all). Basically, I do think it is really important for us to aggressively pursue nonpharmacologic therapies to decrease both the glucose intolerance and these adverse consequences. In addition, I think the increased risk for cardiovascular disease at lower levels of glucose intolerance should be factored into our overall preventive strategies around atherosclerotic disease, including not just more aggressive nonpharmacologic therapies (eg, strongly reinforcing managing the other cardiovascular risk factors, BMI, etc, esp through diet, exercise....), but also perhaps an earlier initiation of statins and perhaps aspirin.