Prediabetes, chronic inflammation and hemoglobin A1c

PrediabetesPrediabetes, blood glucose is slightly higher than normal but not enough to qualify for diabetes, is associated with an increased systemic burden of inflammation and elevated risk for cardiovascular, cancer, dementia and other diseases. The first study described in this post, published in the European Journal of Nutrition, highlights the link between prediabetes, chronic inflammation and mortality from a range of diseases tied to HgbA1c (hemoglobin A1c, glycosylated hemoglobin), the key biomarker for glucose regulation. The authors state:

Chronic inflammation is associated with increased risk of cancer, cardiovascular disease (CVD), and diabetes. The role of pro-inflammatory diet in the risk of cancer mortality and CVD mortality in prediabetics is unclear. We examined the relationship between diet-associated inflammation, as measured by dietary inflammatory index (DII) score, and mortality, with special focus on prediabetics.”

Pro-inflammatory diet plus prediabetes (increased HgbA1c)

Of great significance is the effect they reveal when a pro-inflammatory diet, measured by the dietary inflammatory index (DII) score, is consumed when there is elevated HgbA1c. They categorized 13,280 subjects between the ages 20 of and 90 years according to whether or not they were prediabetic, which they defined as a HgbA1c percentage of 5.7–6.4. Their data highlighted this connection between all-cause mortality, a pro-inflammatory diet and prediabetes:

“The prevalence of prediabetes was 20.19 %. After controlling for age, sex, race, HgbA1c, current smoking, physical activity, BMI, and systolic blood pressure, DII scores in tertile III (vs tertile I) was significantly associated with mortality from all causes (HR 1.39, 95 % CI 1.13, 1.72), CVD (HR 1.44, 95 % CI 1.02, 2.04), all cancers (HR 2.02, 95 % CI 1.27, 3.21), and digestive-tract cancer (HR 2.89, 95 % CI 1.08, 7.71). Findings for lung cancer (HR 2.01, 95 % CI 0.93, 4.34) suggested a likely effect.”

The authors conclude:

“A pro-inflammatory diet, as indicated by higher DII scores, is associated with an increased risk of all-cause, CVD, all-cancer, and digestive-tract cancer mortality among prediabetic subjects.”

 Prediabetes and cardiovascular risk

Research published in The BMJ (British Medical Journal) focusses on the substantial impact of prediabetes on the risk of heart attack and ischemic stroke. The authors set out to…

“…evaluate associations between different definitions of prediabetes and the risk of cardiovascular disease and all cause mortality…”

…by analyzing 53 prospective cohort studies with 1,611,339 individuals that passed the screening tests for validity. In this study they applied several definitions of prediabetes:

“Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6-6.9 mmol/L = 101-124 mg/dL), the WHO expert group (IFG-WHO; fasting glucose 6.1-6.9 mmol/L = 110-124 mg/dL), impaired glucose tolerance (2 hour plasma glucose concentration 7.8-11.0 mmol/L = 141-198 mg/dL during an oral glucose tolerance test), or raised haemoglobin A1c (HbA1c) of 39-47 mmol/mol [5.7-6.4%] according to ADA criteria or 42-47 mmol/mol [6.0-6.4%] according to the National Institute for Health and Care Excellence (NICE) guideline.”

Their data show that prediabetes with a ‘mildly’ elevated HgbA1c was clearly associated with increased cardiovascular risk:

“Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA1c to 39-47 mmol/mol [5.7-6.4%] or 42-47 mmol/mol [6.0-6.4%] were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality.”

Interestingly, risk of stroke does not emerge from these data, suggesting other factors promoting vascular inflammation. The authors conclude:

“…we found that prediabetes defined as impaired fasting glucose or impaired glucose tolerance is associated with an increased risk of composite cardiovascular events, coronary heart disease, stroke, and all cause mortality. There was an increased risk in people with fasting plasma glucose as low as 5.6 mmol/L [100 mg/dL]. Additionally, the risk of composite cardiovascular events and coronary heart disease increased in people with raised HbA1c. These results support the lower cut-off point for impaired fasting glucose according to ADA criteria as well as the incorporation of HbA1c in defining prediabetes.”

HgbA1c and risk of all-cause and cause-specific mortality without diabetes

Similar results were obtained in a study published in Scientific Reports. Here the authors concluded:

“We found evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer in this meta-analysis. The dose-response curves were relatively flat for HbA1c less than around 5.7%, and rose steeply thereafter. This fact reveals a clear threshold effect for the association of HbA1clevels with mortality. In addition, from the perspective of mortality benefit and health care burden, it suggests that the most appropriate HbA1c level of initiating intervention is approximately 5.7%…higher HbA1c level is associated with increased mortality from all causes, CVD, and cancer among subjects without known diabetes. However, this association is influenced by those with undiagnosed diabetes or prediabetes .Because of limited studies, the results in relation to cancer mortality should be treated with caution, and more studies are therefore warranted to investigate whether higher HbA1c level is associated with increased cancer mortality.”


Nuts reduce inflammation and all-cause mortality

Asia Pacific Journal of Clinical NutritionNuts have been shown to confer multiple health benefits, so it’s disconcerting to see  some apparently popular paleo diet plans that forbid them. In the absence of a nut allergy it’s a shame to forgo the benefit of such a healthful and convenient food. The intent of the paleo diet is to reduce inflammation, so it’s worth considering a paper published in the Asia Pacific Journal of Clinical Nutrition offering evidence that nuts reduce inflammation. The authors note:

“Several large epidemiological studies have associated the frequency of nut consumption with reduced risk of coronary heart disease (CHD), CVD, myocardial infarction, sudden death, and all causes of mortality, Type 2 diabetes (T2D) and other chronic disease.

Nuts are anti-inflammatory

Key inflammatory markers including CRP and IL-6 are reduced by nut consumption:

“Epidemiological and clinical studies suggest that some dietary factors, such as n–3 polyunsaturated fatty acids, antioxidant vitamins, dietary fiber, L-arginine and magnesium may play an important role in modulating inflammation. The relationship observed between frequent nut consumption and the reduced risk of cardiovascular mortality and type 2 diabetes in some prospective studies could be explained by the fact that nuts are rich in all of these modulator nutrients. In fact, frequent nut consumption has been associated with lower concentrations of some peripheral inflammation markers in cross-sectional studies. Nut consumption has also been shown to decrease the plasma concentration of CRP, IL-6 and some endothelial markers in recent clinical trials.”

Nuts also benefit cholesterol and lipids

“In the last two decades, a considerable number of clinical trials have consistently demonstrated beneficial effects on blood lipids and lipoproteins, primarily a decrease in Low-density lipoprotein (LDL) cholesterol, a classical CHD risk factor. This effect has been demonstrated consistently in different population groups, using different types of nuts (walnuts, hazelnuts, almonds, pecan, pistachio and macadamia nuts) and study designs. The favourable effects of tree nuts or tree nut oils on plasma lipid and lipoprotein profiles is a mechanism that appears to account for some of the cardio protective effects observed in the epidemiological studies.”

Nuts and olive oil are a great combination for cardiovascular risk:

“…in a cross-sectional study we evaluated the association between components of the Mediterranean diet and circulating markers of inflammation in a large cohort of asymptomatic subjects with high risk of cardiovascular disease. Subjects with the highest consumption of nuts and virgin olive oil showed the lowest concentrations of VCAM-1, ICAM-1, IL-6 and CRP; although this difference was statistically significant for ICAM-1 only in the case of nuts and for VCAM-1 in the case of olive oil.”

After reviewing several other studies documenting improvements in inflammation and endothelial function the authors conclude:

“In conclusion, nuts are complex food matrices containing diverse nutrients and other chemical constituents that may favourably influence human physiology. These sub- stances may inhibit the activation of the innate immune system, probably by decreasing the production of proinflammatory cytokines such as CRP, IL-6, TNF-α or IL-18, and increase the production of antiinflammatory cytokines such as adiponectin. This may improve the proinflammatory milieu, which in turn ameliorates endothelial dysfunction at the vascular level, and ultimately decreases the risk of insulin resistance, type 2 diabetes and coronary heart disease. The capacity of nuts to modulate inflammation may explain at least in part why frequent nut consumption is associated with reduced risk of diabetes and cardiovascular disease in epidemiological studies.”

Nut consumption reduces total and cause-specific mortality

New England Journal of MedicineA paper published earlier this year in The New England Journal of Medicine add more extensive data presenting evidence that eating nuts reduces death from cancer, heart disease, respiratory disease and ‘all causes’.

“Observational and intervention studies of nut consumption have also shown reductions in various mediators of chronic diseases, including oxidative stress, inflammation, visceral adiposity, hyperglycemia, insulin resistance, and endothelial dysfunction. In prospective cohort studies, increased nut intake has been associated with reduced risks of type 2 diabetes mellitus, the metabolic syndrome, colon cancer, hypertension, gallstone disease, diverticulitis, and death from inflammatory diseases.”

To extend the data to encompass the effects of eating nuts and all causes of death the authors:

“…examined the association of nut consumption with total and cause-specific mortality in two large, independent cohort studies of nurses and other health professionals. These studies provide repeated measures of diet (including separate data on peanuts and tree nuts), extensive data on known or suspected confounding variables, 30 years of follow-up, and data on more than 27,000 deaths for analysis.”

Their data suggest that nuts are among the healthiest foods to eat:

“In two large prospective U.S. cohorts, we found a significant, dose-dependent inverse association between nut consumption and total mortality, after adjusting for potential confounders. As compared with participants who did not eat nuts, those who consumed nuts seven or more times per week had a 20% lower death rate. Inverse associations were observed for most major causes of death, including heart disease, cancer, and respiratory diseases. Results were similar for peanuts and tree nuts, and the inverse association persisted across all subgroups.”

Some nuts every day was the best:

“Our results are consistent with the findings in previous, smaller studies. The Adventist Health Study showed that, as compared with nut consumption less than once per week, consumption five or more times per week was associated with reduced total mortality among whites, blacks, and elderly persons, with hazard ratios ranging from 0.56 to 0.82. Similarly, a study of a U.K. cohort, the Iowa Women’s Health Study, the Netherlands Cohort Study, and an earlier analysis of the NHS all showed significant inverse associations between nut intake and total mortality. Finally, in a recent secondary analysis within the PREDIMED (Prevención con Dieta Mediterránea) trial, a hazard ratio for death of 0.61 (95% CI, 0.45 to 0.83) was found for consumption of more than three servings of nuts per week, as compared with no nut consumption.”

Bottom line: ‘paleo’ and ‘autoimmune’ paleo diets can be fine healing diets for many, but like everything else should not be applied dogmatically or in a ‘rubber stamp’, ‘one-size-fits-all’ manner. In the absence of allergy, the evidence supports the consumption of nuts as wholesome foods with anti-inflammatory and metabolic benefits, exactly what paleo diets intend to accomplish.

Low ‘normal’ free T3 thyroid hormone predicts death in older patients even without overt hypothyroid

Journal of Clinical Endocrinology & MetabolismLow free T3 thyroid hormone (triiodothyronine, FT3), even without overt hypothyroid and still within most ‘normal’ reference ranges, predicts death from cardiovascular disease and all causes in people over 65 according to a study just published in The Journal of Clinical Endocrinology & Metabolism. The authors state:

“Several alterations in thyroid function test (TFT) results have been associated with mortality in elderly patients…Our aim was to investigate the relationship between TFT results and all-cause and cardiovascular (CV) mortality in aged hospitalized patients.”

They measured TSH, free T4, and free T3 (FT3) for 404 patients aged >65 years admitted to the Hospital General, Segovia, Spain for any reason in 2005 and followed the outcomes for seven years, correlating the total survival times, number of deaths, and all-cause and CV mortality with the thyroid function test (TFT) values. The data showed that functionally low free T3 was strongly associated with mortality:

“During the study, 323 patients (80%) died. Kaplan-Meier analysis showed that median survival time for all-cause mortality was significantly lower in patients in the first tertile of serum FT3, in the first tertile of TSH, and in the first tertile of serum free T4 concentrations. Multivariate adjusted Cox regression analysis showed that the history of cancer (hazard ratio, 1.60), age (1.03), and FT3 levels (0.72) were significant factors related to all-cause mortality. The cause of death was known in 202 patients. Of this group, 61 patients (30.2%) died of CV disease. Patients in the first tertile of TSH and FT3 exhibited a significant higher mortality due to CV disease. In the adjusted Cox regression analysis, FT3 was a significant predictor of CV mortality (0.76).”

Medscape Family Medicine quotes from the study:

“Median survival time for all-cause mortality was 3.0, 13.0, and 19.0 months for patients belonging to the first (<3.18 pmol/L), second (3.18> to <3.96 pmol/L), and third (>3.96 pmol/L) tertiles of free T3, respectively (P < .001).”

In the US we use pg/mL to measure free T3. In this study the lowest survival time was associated with less than 3.18 pmol/L which converts to less than 2.1 pg/mL. In my practice I use 3.0-4.5 pg/mL as the desired functional reference range; 2.1 pg/mL is within the ‘normal’ range of most labs. Medscape also quotes the authors:

“Our results clearly show a significant relationship between TFT results and mortality in aged hospitalized patients not only during hospitalization but also long term after hospital discharge,” say Dr. Iglesias and colleagues… The study “confirms this association between low free-T3 levels and all-cause and CV mortality being the most important predictor of 7-year CV mortality in octogenarian patients, even more than age.””

Clinical note: Practitioners should consider not only the effects of suboptimal free T3, but also be diligent in investigating the underlying causes that are making it low. The authors conclude:

“Alterations in TFT results during hospitalization are associated with long-term mortality in elderly patients. In particular, low FT3 levels are significantly related to all-cause and CV mortality.”

High cortisol and low DHEA both predict increased cardiovascular mortality

More evidence for the link between adrenal dysregulation and death from cardiovascular disease is reported in a study recently published in the Journal of Clinical Endocrinology & Metabolism. The authors observe:

“The stress hormone cortisol has been linked with unfavorable cardiovascular risk factors, but longitudinal studies examining whether high levels of cortisol predict cardiovascular mortality are largely absent…The aim of this study was to examine whether urinary cortisol levels predict all-cause and cardiovascular mortality over 6 yr of follow-up in a general population of older persons.”

They studied 861 subjects by assessing 24 hour urinary cortisol levels at the beginning, then followed them for 6 years during which they documented death from all causes and death from ischemic and cerebrovascular disease in particular. What did the data show?

“After adjustment for sociodemographics, health indicators, and baseline cardiovascular disease, urinary cortisol did not increase the risk of noncardiovascular mortality, but it did increase cardiovascular mortality risk. Persons in the highest tertile of urinary cortisol had a five times increased risk of dying of cardiovascular disease. This effect was found to be consistent across persons with and without cardiovascular disease at baseline.”

Their concluding comments express the robustness of their findings and suggest that circulatory damage may be an important mechanism by which high cortisol is so harmful for the brain:

High cortisol levels strongly predict cardiovascular death among persons both with and without preexisting cardiovascular disease. The specific link with cardiovascular mortality, and not other causes of mortality, suggests that high cortisol levels might be particularly damaging to the cardiovascular system.”

Interestingly, we find another paper just published in the same journal that ‘fleshes out’ the connection between adrenal dysregulation and death from cardiovascular disease. The authors state:

“The age-related decline in dehydroepiandrosterone (DHEA) levels is thought to be of importance for general and vascular aging…We tested the hypothesis that low serum DHEA and DHEA sulfate (DHEA-S) levels predict all-cause and cardiovascular disease (CVD) death in elderly men.”

Both cortisol and DHEA, an important androgen for vitality, body composition, mood and immune regulation, are produced in the adrenal glands. Excessive production of cortisol typically depletes the resources to produce DHEA, a phenomenon call the ‘pregnenolone steal’. The authors analyzed baseline levels of DHEA in 2644 Swedish men, then correlated this with mortality data:

Low levels of DHEA-S predicted death from all causes; but not cancer. Analyses with DHEA gave similar results.”

It was particularly interesting to note that…

The association between low DHEA-S and CVD death remained after adjustment for C-reactive protein and circulating estradiol and testosterone levels. When stratified by the median age of 75.4 yr, the mortality prediction by low DHEA-S was more pronounced among younger  than older men.”

The discerning clinician will recognize that for cardiovascular risk assessment to be complete, cortisol and DHEA levels should be evaluated—ideally by salivary hormone collections that delineate the important diurnal cortisol rhythm.

Two new studies confirm statins do not help in primary prevention of cardiovascular disease

Archives of Internal MedicineAlthough there is evidence that pharmacological lowering of lipids with statins may reduce mortality when coronary heart disease has already been established, there is a massive accumulation of data that confirm they do not reduce mortality when used for prevention. The authors of a study just published in Archives of Internal Medicine observe:

“…it remains uncertain whether statins have similar mortality benefit in a high-risk primary prevention setting. Notably, all systematic reviews to date included trials that in part incorporated participants with prior cardiovascular disease (CVD) at baseline. Our objective was to reliably determine if statin therapy reduces all-cause mortality among intermediate to high-risk individuals without a history of CVD.”

The authors synthesized data from 11 studies including 65,229 participants encompassing 244,000 person-years. What did the data show?

The use of statins in this high-risk primary prevention setting was not associated with a statistically significant reduction in the risk of all-cause mortality.”

To fully appreciate the significance of their findings, consider the editorial statement in the same issue:

“Ray and colleagues present what is to date the cleanest and most complete meta-analysis of pharmacological lipid lowering for primary prevention. Limiting the analysis to patients without existing coronary disease is critical because studies that include both groups of patients may appear to show benefit for all patients, when all the benefit accrues to those with existing disease. The patients in their analysis reduced their average levels of low-density lipoprotein cholesterol from 139 to 98 mg/dL and are therefore representative of those being treated in primary care today.”

This puts the authors’ conclusion in perspective:

“This literature-based meta-analysis did not find evidence for the benefit of statin therapy on all-cause mortality in a high-risk primary prevention set-up.”

And this same issue of Archives includes a critical reappraisal of the evidence for the use of statins for prevention from the much-touted JUPITER ((Justification for the Use of Statins in Primary Prevention) study. Their forthright conclusion is consonant with the rest of the evidence:

“The results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors.”

IMHO: I consider elevated lipoprotein phospholipase A2 (Lp-PLA2) as evidence of already existing vascular disease even when the person has not suffered a heart attack or stroke. I then seriously consider recommending a natural statin with the appropriate co-factors and customized supports until we confirm that the condition has been brought under control.

RDW is an inexpensive but powerful indicator often overlooked on your routine blood test

Archives of Internal Medicine 0210RDW stands for Red (Blood Cell) Distribution Width, an index for the degree of variability in the size and shape of your red blood cells. Recent studies are showing it to be a powerful indicator of overall health and the risk of death from multiple causes. RDW is always included in the standard Complete Blood Count (CBC), one of the most routine lab tests in modern medicine, but there’s evidence that the usual lab reference range is too broad and it’s value is not widely appreciated. It has been established for some time that RDW predicts mortality form cardiovascular disease, but this study recently published in the Archives of Internal Medicine is particularly interesting because it shows that RDW predicts mortality in the general population independent of cardiovascular disease. The authors state:

“Higher RDW values were strongly associated with an increased risk of death…Even when analyses were restricted to nonanemic participants or to those in the reference range of RDW (11%-15%) without iron, folate, or vitamin B12 deficiency, RDW remained strongly associated with mortality. The prognostic effect of RDW was observed in both middle-aged and older adults for multiple causes of death.”

Two weeks later the another paper was published in the same journal on the same topic that begins with this observation:

“Red blood cell distribution width (RDW), an automated measure of red blood cell size heterogeneity (eg, anisocytosis) that is largely overlooked, is a newly recognized risk marker in patients with established cardiovascular disease (CVD).”

They set out to investigate

“the association of RDW with all-cause mortality and with CVD, cancer, and chronic lower respiratory tract disease mortality in 15,852 adult participants.”

Their conclusion:

“Higher RDW is associated with increased mortality risk in this large, community-based sample, an association not specific to CVD.”

Journals of GerontologyAnother paper just published in The Journals of Gerontology confirms these findings with an analysis of seven community-based studies of older adults. Their conclusion:

“RDW is a routinely reported test that is a powerful predictor of mortality in community-dwelling older adults with and without age-associated diseases.”

Diabetes Care 0210.2This paper just published in the journal Diabetes Care reports on the link between RDW, metabolic syndrome and cardiovascular disease: “A possible explanation for the observed association between RDW and MetS is that high RDW reflects an underlying inflammatory state that leads to impaired erythrocyte (red blood cell) maturation and anisocytosis (size variation), as suggested previously (1–3). In fact, MetS exacerbates oxidative and inflammatory stress in obese adults, which is a potential mechanism for the increased cardiovascular risk in this condition.”

European Journal of Heart FailureAnd as you would expect, the European Journal of Heart Failure recently published a study on heart failure that compares RDW with N-terminal brain natriuretic peptide (NT-proBNP) in which the authors conclude:

“Red cell distribution width is a readily available test in the HF-population with similar independent prognostic power to NT-proBNP across the first to third quartiles. Prognostic models in HF (heart failure) should include RDW.”

Digestive Diseases and SciencesAnd the ‘plot thickens’. In this paper published in the journal Digestive Diseases and Sciences the investigators observe:

“Impaired iron absorption or increased loss of iron was found to correlate with disease activity and markers of inflammation in inflammatory bowel disease (IBD). Red cell distribution width (RDW) could be a reliable index of anisocytosis with the highest sensitivity to iron deficiency.”

Their compelling conclusion:

“Among the laboratory tests investigated, including fibrinogen, CRP, ESR, and platelet counts…analysis indicated RDW to be the most significant indicator of active UC [ulcerative colitis]. For CD [Crohn’s disease], CRP was an important marker of active disease.”

Archives of Pathology & Laboratory MedicineLastly, you’ll appreciate the broadest statement yet about the value of this inexpensive and readily available marker. In a recent paper published in the Archives of Pathology & Laboratory Medicine. The authors begin by chiming in with the neighborhood chorus:

“A strong independent association has been recently observed between elevated red blood cell distribution width (RDW) and increased incidence of cardiovascular events;”

but they aim to

“assess whether RDW is associated with plasma markers of inflammation.”

Their conclusion:

“To our knowledge, our study demonstrates for the first time a strong, graded association of RDW with hsCRP and ESR independent of numerous confounding factors.”

In other words, RDW is inexpensive, easily obtained, and a powerful marker for inflammation in general, the common denominator of most chronic disease.

Here’s the ‘take home’ message (if you’ve gotten this far): If you have almost any blood work done at all it’s likely to include RDW automatically. Make good use of it, keeping in mind that laboratory reference ranges do not reflect the latest research and your doctor may not be aware of this. Functional medicine doctors want RDW to be no more than 13%.

A possible explanation for the observed association between RDW and MetS is that high RDW reflects an underlying inflammatory state that leads to impaired erythrocyte maturation and anisocytosis, as suggested previously (13). In fact, MetS exacerbates oxidative and inflammatory stress in obese adults, which is a potential mechanism for the increased cardiovascular risk in this condition

Lower Vitamin D again linked to earlier death

In yet another study, this one just published in the journal Clinical Endocrinology, lower levels of vitamin D were associated with (30.6 nm/L) associated with a 124 increased risk of  all-cause mortality [death from all diseases] and a 378 per cent  increased risk from cardiovascular mortality. The researchers additionally state: “Apart from the maintenance of muscular and skeletal health, vitamin D may also protect against cancer, infections, autoimmune and vascular diseases, suggesting that vitamin D deficiency might contribute to a reduced life expectancy.”