low LDL and diabetes risk

as is evident in several studies, there is a relationship between the use of statins and the development of diabetes (approx 9% increase in diabetes incidence). A recent study looked at the relationship between LDL levels themselves and the development of diabetes (see dm risk and low LDL diabetologia 2015 in dropbox or DOI 10.1007/s00125-015-3762-x​). details:

--data from the Framingham Heart Study offspring cohort, with 6011 people and 14120 person-observations (mean age 50, 56% women, mean LDL 125 mg/dl) who were not on any lipid-modifying or antihypertensive medication, followed a mean of 4.5 years

--assess the development of diabetes (fasting glucose >125 mg/dl or put on glucose-lowering meds), comparing that to their LDL levels as well as a genetic risk score (GRS) --different genetic changes in single-nucleotide polymorphisms (SNPs) which affect LDL levels

--results:

    ​--312 people (2.2%) developed diabetes

    --a higher LDL level was associated with a lower risk of diabetes in a graded fashion [OR per SD decrement was 0.81 (0.70-0.93, p=0.004)]

    --the GRS was similarly associated with incident diabetes, both in direction and in magnitude [OR per SD decrement was 0.85 (0.76-0.96, p=0.009)]

    --the increased risk of diabetes was similar across age, sex, BMI, fasting glucose, HDL, or triglyceride levels

a few background issues:

--it may be more than a coincidence that 2 drugs (niacin and statins) that lower LDL levels are both associated with the development of diabetes

--other studies have also found that the GRS for LDL was also associated with diabetes

--3 observational studies have found lower LDL levels in people with insulin resistance and diabetes 

--A large Danish database of patients with familial hypercholesterolemia and very high LDL levels (86% of whom had LDL receptor mutations) has found a lower incidence of diabetes (overall OR of 0.45 for those with LDL receptor mutations), with a graded association: the more severe the mutation (assoc with higher LDL levels), the lower the risk of diabetes (see JAMA 2015;313:1029), raising the question that the issue is not statins per se, but the role of the upgraded LDL receptor in predisposing people to diabetes, and raising further the issue of that receptor's role in glucose homeostasis (see JAMA 2015;313:1016).

--patients having variants of the HMG Co-A reductase gene, the enzyme targeted by statins, have increased blood sugar and diabetes risk (ie, both in those on statins and those with this genetic variant, both of which increase the expression of LDL receptors). the authors postulate that pancreatic β​-cells, in the setting of familial hypercholesterolemia, have decreased cholesterol uptake (genetic impairment of LDL receptors) and therefore improved β​-cells function and survival (there are a slew of animal studies and some human tissue culture ones supporting the conclusion that those with enhanced LDL receptor activity and the resulting cholesterol-laden pancreatic β​-cells​ have impaired function of the β​-cells, see JAMA 2015;313:1029).

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so, what does this all mean?? it raises a few issues: perhaps it is not the statins that are causing diabetes, but the lower LDL levels themselves. and, if it turns out that this is mediated through the increased LDL receptors as is likely, and this increase is augmented by statins as well as some mutations, then perhaps developing other drugs which lower LDL levels but do not affect the LDL receptors might be more beneficial (by the way, the PCSK9 inhibitors increase LDL receptor concentrations even more than statins). but at this point, all analyses suggest that lowering of LDL is still beneficial overall, despite the potential development of diabetes.  see http://gmodestmedblogs.blogspot.com/2013/10/statin-safety.html  for a review of statin adverse effects.