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.”


DHEA predicts coronary heart disease risk

Journal of the American College of CardiologyDHEA (dehydroepiandosterone) an adrenal steroid hormone also produced in the brain, is associated with many inflammatory and other disorders. A study recently published in the Journal of the American College of Cardiology shows that low DHEA can predict coronary heart disease in older men. This is especially important because there is still a high incidence of sudden cardiac death in individuals who do not have the traditional risk factors. The authors state:

“The adrenal sex hormone dehydroepiandrosterone (DHEA), which is present in serum mainly as the sulfate DHEA-S, is the most abundant steroid hormone in human blood. Its levels decline dramatically with age. Despite the great amount of literature on vascular and metabolic actions of DHEA/-S, evidence for an association between DHEA/-S levels and cardiovascular events is contradictory.”

To test predictive value for major coronary heart disease (CHD) and/or cerebrovascular disease (CBD) events, they measured  baseline levels in a large cohort of men aged 69-81 and correlated this with a 5-year follow-up for complete cardiovascular clinical outcomes.

DHEA predicts coronary heart disease but not stroke

The predictive accuracy persisted even when traditional cardiovascular risk factors were adjusted for :

“During the 5-year follow-up, 302 participants experienced a CHD event, and 225 had a CBD event. Both DHEA and DHEA-S levels were inversely associated with the age-adjusted risk of a CHD event; the hazard ratios and 95% confidence intervals per SD increase were 0.82 (0.73 to 0.93) and 0.86 (0.77 to 0.97), respectively. In contrast, DHEA/-S showed no statistically significant association with the risk of CBD events. The association between DHEA and CHD risk remained significant after adjustment for traditional cardiovascular risk factors, serum total testosterone and estradiol, C-reactive protein, and renal function, and remained unchanged after exclusion of the first 2.6 years of follow-up to reduce reverse causality.”

Changing the assessment of cardiovascular risk

The authors of an editorial in the same issue of JACC assert:

Everything we once thought we knew about the therapeutic use of estrogen for the prevention of cardiovascular disease (CVD) in women is wrong. Everything we once knew about the role of sex in CVD is still right; men are affected a decade earlier than women. We are still enamored with the idea that sex steroids, particularly androgens, have, if not a causal role in CVD development, at least an association. We simply cannot get the notion out of our heads that androgens (or relative lack of estrogen) drive endothelial dysfunction and atherogenesis, and potentially, even plaque fracture. In this light, new studies that assess the risk associated with low levels of a particularly abundant sex steroid (dehydroepiandrosterone [DHEA] and its sulfated congener [DHEA-S], which can serve as the precursor substrate for either testosterone or estradiol) are of particular interest.”

They note an important difference between the two forms:

“Furthermore, this study measured both DHEA and DHEA-S, and showed a more pronounced negative relationship between mortality and DHEA than that with DHEA-S. This suggests that DHEA could be a more important predictor of outcomes, despite low plasma DHEA concentrations relative to DHEA-S. This has significant implications, because most previous negative studies examined only DHEA-S levels.”

A new arrow in the quiver

Cardiovascular disease is complex and multi-causal…

“Despite advances in primary and secondary prevention of CHD events, there is still a high incidence of death due to CHD, including sudden cardiac death in individuals who do not have traditional coronary disease risk factors…An ideal solution might be the use of weighted patterns of biomarkers, which would take into consideration typical biochemical interactions and provide a personalized biochemical fingerprint to more exactly define an individual’s risk of future events. DHEA may represent a new arrow in the quiver of biomarkers…The findings reported here should, at the least, spur further interest in understanding DHEA as a biomarker of CVD risk.”

Clinical Note

It is, of course, never desirable to recommend or take any hormone, OTC or not, without measuring free-fraction hormone levels comprehensively at baseline and after appropriate intervals. Clinicians, however, can add DHEA levels to CHD risk assessment in older men.

The authors conclude:

Low serum levels of DHEA and its sulfate predict an increased risk of CHD, but not CBD, events in elderly men.

Women’s heart risk lower with exercise 2-3x/week than daily

CirculationExercise is a measured stress applied to the body to exploit a desirable genetic, cardiometabolic, endocrine and immune response. Like almost every other physiological intervention there is a dose-response curve: too little doesn’t elicit a sufficient reaction while the benefits degrade and harm can accrue with too much (over-training). A large study using data from 1.1 million women recently published in the journal Circulation offers evidence that strenuous physical activity 2-3 times per week significantly lowered their coronary heart disease risk while more frequent strenuous exercise actually increased it. The authors state:

“Although physical activity has generally been associated with reduced risk of vascular disease, there is limited evidence about the effects of the frequency and duration of various activities on the incidence of particular types of vascular disease…We describe here the relationships of the frequency, duration, and type of physical activity with incident CHD, cerebrovascular disease (overall and separately for hemorrhagic and ischemic stroke), and VTE (venous thromboembolism, overall and separately for those with and without pulmonary embolism), excluding the first 4 years of follow-up from recruitment into the study to limit the possible effects of reverse causation attributable to preclinical disease.”

They note the findings of a previous study on cardiovascular mortality in both sexes and running frequency:

“A recent prospective study of men and women aged 44 years on average at baseline, suggested a U-shaped association between running frequency and cardiovascular mortality. Although the lowest risk appeared to be among those reporting running 3 times per week, the confidence intervals were large.”

The low central portion of the ‘U’ corresponds to decreased mortality with exercise of moderate frequency.

Less cardiovascular disease with strenuous exercise 2-3 times per week

Absolute risks and 95% group-specific confidence intervals (gsCI) for incident vascular diseases, by strenuous and any physical activity, excluding the first 4 years of follow-up.

Absolute risks and 95% group-specific confidence intervals (gsCI) for incident vascular diseases, by strenuous and any physical activity, excluding the first 4 years of follow-up.

The authors analyzed data on physical activity an exercise for 1.1 million women without prior vascular disease along with and many other personal characteristics in including time spent walking, cycling, gardening, and housework each week. This was linked to National Health Service (UK) cause-specific hospital admissions and death records. The adjusted relative risks were calculated for first vascular events in relation to physical activity:

“During an average of 9 years follow-up, 49 113 women had a first coronary heart disease event, 17 822 had a first cerebrovascular event, and 14 550 had a first venous thromboembolic event. In comparison with inactive women, those reporting moderate activity had significantly lower risks of all 3 conditions. However, women reporting strenuous physical activity daily had higher risks of coronary heart disease, cerebrovascular disease, and venous thromboembolic eventsthan those reporting doing such activity 2 to 3 times per week.”

They comment on these results:

“Results from this prospective study of 1.1 million UK women showed that women who engaged in physical activity had a lower incidence of CHD, cerebrovascular disease, and VTE than women who were inactive. Overall, the main difference in risk was between those doing some activity versus none, with the lowest risks being observed among women doing moderate amounts of activity. These associations were evident for different pathological types of stroke and of VTE, and across analyses using different measures of physical activity, including the frequency of any or strenuous activity, excess MET-hours expended, and durations of specific types of activity. Among active women, there was little evidence of progressive reductions in risk with more frequent activity, and some evidence of an increase in risk for CHD, cerebrovascular disease, and VTE in the most active group, compared to those who were moderately active.”

Keep up the moderate exercise, no need to push harder

The data suggests that pushing past moderation goes over the hump of the dose-response curve into over-training with degraded outcomes. The authors conclude:

“Moderate physical activity is associated with a lower risk of coronary heart disease, venous thromboembolic event, and cerebrovascular disease than inactivity. However, among active women, there is little to suggest progressive reductions in risk of vascular diseases with increasing frequency of activity.”

Strenuous endurance exercise promotes inflammation

PLOS ONEChronic inflammation, the common denominator of aging and most chronic diseases, is promoted by an imbalance between proinflammatory Th17 cells that drive autoimmunity and the anti-inflammatory Treg cells (regulatory T cells). An important study published in PLOS One reveals one of the mechanisms by which more than moderate strenuous exercise can increase cardiovascular risk. The authors state:

“Endurance, marathon-type exertion is known to induce adverse changes in the immune system. Increased airway hyper-responsiveness and airway inflammation are well documented in endurance athletes and endurance exercise is considered a major risk factor for asthma in elite athletes. Yet, the mechanisms underlying this phenomenon are still to be deduced. We studied the effect of strenuous endurance exercise (marathon and half-ironman triathlon) on CD4+ lymphocyte sub-populations and on the balance between effector and regulatory CD4+ lymphocytes in the peripheral blood of trained athletes.”

Crucial Th17/Treg balance

There is a wealth of scientific evidence for the importance of the Th17 and Treg interplay in autoimmunity and chronic inflammation. The authors of this study note:

T helper (h)17 cells are CD4+ lymphocytes that produce Interleukin (IL)-17, a cytokine that play a crucial role in allergic inflammation and are known as powerful pro-inflammatory cells that promote autoimmunity. On the other end of the spectrum CD4+CD25+ regulatory T cells (Tregs) are differentiated T lymphocytes actively involved in control of peripheral immunity. The identification of these cells has led to new insights into mechanisms of tolerance breakdown in human diseases, including those resulting from allergic, autoimmune, or infectious causes.”

Endurance exercise induced a significant increase in Th17 cells and a sustained decline in peripheral blood Tregs population. These alterations in CD4+ T cell sub-populations may be attributed to changes in TGFβ, IL-6 and IL-2 serum levels.

Endurance exercise induced a significant increase in Th17 cells and a sustained decline in peripheral blood Tregs population. These alterations in CD4+ T cell sub-populations may be attributed to changes in TGFβ, IL-6 and IL-2 serum levels.

They examined the effect of strenuous exercise on the balance between pro-inflammatory effector and anti-inflammatory regulatory CD4+ lymphocytes in the blood of trained athletes who performed in the Emek-Hayarden Half Ironman triathlon or the 2009 Tiberia marathon and documented a marked pro-inflammatory shift:

Endurance exercise induced a significant increase in Th17 cells and a sustained decrease in peripheral blood regulatory T cells (Tregs). While interleukin (IL)-2 levels remained undetectable, post-race serum IL-6 and transforming growth factor (TGF) β levels were significantly elevated. Treg levels in sedentary controls’ decreased in vitro after incubation with athletes’ post-exercise serum, an effect that was attenuated by supplements of IL-2 or anti IL-6 neutralizing antibodies.”

Bottom line

Patients at risk for ‘sedentary death syndrome’ should be enthusiastically encouraged to have a dose of HIIT exercise 2-3 times per week, a fundamental life-style factor that reduces risk across the whole spectrum of chronic disease. HIIT (high intensity interval training) in particular efficiently yields desired cardiometabolic and other benefits with reduced risk for injury. The authors conclude:

“Our data suggest that exercise-induced changes in serum cytokine levels promote alterations in Tregs and Th17 cell populations, which may divert the subtle balance in the immune system towards inflammation. This may explain allergic and autoimmune phenomena previously reported in endurance athletes and contribute to our understanding of exercise-related asthma.”

Blood pressure treated aggressively increases heart disease risk

Diabetes Care Vol 36 No 5Blood pressure management must be done judiciously with respect for the fact that driving blood pressure too low with medication results in worse outcomes. Is this surprising if we consider that blood pressure can increase to compensate for peripheral resistance (associated with diminished vascular elasticity and sympathetic nervous system dominance that typically occurs with aging) in order to get oxygen into the tissues (perfusion)? A study just published in the journal Diabetes Care adds more to the large body of evidence* that 120/80 should not be the target. The authors investigated specifically the association of blood pressure levels and heart disease risk in diabetic patients:

“Blood pressure control can reduce the risk of coronary heart disease (CHD) among diabetic patients; however, it is not known whether the lowest risk of CHD is among diabetic patients with the lowest blood pressure level.”

So they looked into this by examining data for 17,536 African American and 12,618 white diabetic patients, using Cox proportional hazards regression models to gauge the association of blood pressure with CHD risk. They found a U-shaped curve:

“During a mean follow-up of 6.0 years, 7,260 CHD incident cases were identified. The multivariable-adjusted hazard ratios of CHD associated with different levels of systolic/diastolic blood pressure at baseline (<110/65, 110–119/65–69, 120–129/70–80, and 130–139/80–90 mmHg [reference group]; 140–159/90–100; and ≥160/100 mmHg) were 1.73, 1.16, 1.04, 1.00, 1.06, and 1.11 (P trend <0.001), respectively, for African American diabetic patients, and 1.60, 1.27, 1.08, 1.00, 0.95, and 0.99 (P trend<0.001) for white diabetic patients, respectively. A U-shaped association of isolated systolic and diastolic blood pressure at baseline as well as blood pressure during follow-up with CHD risk was observed among both African American and white diabetic patients (all P trend <0.001). The U-shaped association was present in the younger age-group (30–49 years), and this U-shaped association changed to an inverse association in the older age-group (≥60 years).”

In other words, there is a U-shaped curve in patients with type 2 diabetes with rates of coronary heart disease (CHD) increasing at both the lower and upper ends of blood pressure. Moreover, in folks over 60 the association becomes inverse—patients with lower blood pressure had a higher CHD risk across the board.

As reported on Medscape Family Medicine, study coauthor Gang Hu, MD, PhD comments…

“We should pay attention not only to the harm of uncontrolled blood pressure but [also to] aggressively controlled blood pressure.”

He added…

“My advice for individual clinicians is the idea of ‘the lower, the better’ should pass away… Patients need individualized or tailored treatment for their hypertension.”

While there may be comorbidities associated with the lowest blood pressure, it stands to reason that diminished oxygen delivery to tissues—hypoperfusion—is an important factor. Dr. Hu further comments:

Low blood pressure might increase cardiovascular risk by the underperfusion of vital organs. Elderly patients with type 2 diabetes represent a population that is highly enriched with underlying coronary artery disease and may be more prone than others to display the harm of underperfusion.”

The authors conclude:

“Our study suggests that there is a U-shaped or inverse association between blood pressure and the risk of CHD, and aggressive blood pressure control (blood pressure <120/70 mmHg) is associated with an increased risk of CHD among both African American and white patients with diabetes.”

* Those with particular interest in the topic of blood pressure management should see these earlier posts:

Data shows high intake of omega-6 fatty acids is not advised for cardiovascular health

BMJ 9 Feb 2013Research recently published in BMJ (British Medical Journal) examines accumulated data to reveal that advice given by the American Heart Association to increase consumption of omega-6 fatty acids, particularly linolenic acid found in corn, sunflower, safflower, and soybean oils, is misguided for cardiovascular health. The author of an accompanying editorial notes that linolenic acid…

“…is the most prevalent PUFA and omega 6 PUFA in most Western diets. As a result of the effects of linoleic acid on cholesterol concentrations, lowering intake of saturated fat and increasing that of PUFAs has been a cornerstone of dietary advice, with the aim of decreasing the risk of cardiovascular disease (CVD).”


“The American Heart Association recently repeated advice to maintain, and even to increase, intake of omega 6 PUFAs. This advice has caused some controversy, because evidence that linoleic acid lowers the risk of CVD is limited—most trials that claimed to investigate the effect of exchanging saturated fat for linoleic acid involved multiple dietary changes or multiple interventions (or both).”

As it turns out…

The impact on CVD risk or mortality of replacing saturated fat with linoleic acid without changes in other fatty acids has rarely been investigated, and no large randomised controlled trial has recently explored this important question.”

Therefore, in their paper the authors set out…

“…to evaluate the effectiveness of replacing dietary saturated fat with omega 6 linoleic acid, for the secondary prevention of coronary heart disease and death.”

To do so they recovered data from the Sydney Diet Heart Study, a randomized controlled trial conducted in 1966-73 using 458 men aged 30-59 years with a recent coronary event (myocardial infarction, acute coronary insufficiency, or angina) as study subjects. In fact, death from cardiovascular disease specifically was not even reported in the original paper describing the Sydney Diet Heart Study. This updated meta-analysis included previously missing data. As described in the editorial:

“Participants were randomised to a diet rich in linoleic acid or continuation of their habitual diet. Both groups were treated the same in other respects and received the same advice. Baseline dietary intake data showed an average linoleic acid intake of about 6% of energy and an average saturated fatty acid intake of about 16% of energy. The linoleic acid group was instructed to increase PUFA intake to 15% of energy and to reduce saturated fatty acid intake to less than 10% of energy; participants were provided with liquid safflower oil and a safflower oil based margarine to be used instead of animal fats for cooking, baking, and spreading. Safflower oil is 75% linoleic acid and does not provide other PUFAs. Follow-up was a median of 39 months. Total cholesterol was lowered by an average of 13% in the linoleic acid group.”

But despite the reduction in cholesterol the outcome for cardiovascular mortality worsened significantly with the high omega-6 fatty acid diet:

“The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% v 11.8%, hazard ratio 1.62; cardiovascular disease 17.2% v 11.0%, 1.70; coronary heart disease 16.3% v 10.1%, 1.74. Inclusion of these recovered data in an updated meta-analysis of linoleic acid intervention trials showed non-significant trends toward increased risks of death from coronary heart disease (hazard ratio 1.33 and cardiovascular disease 1.27.”

The editorialist for BMJ brings these findings in to focus:

“The authors then used the new data generated from the Sydney Diet Heart Study to update an earlier meta-analysis. Two other linoleic acid intervention trials that reported CHD and CVD mortality were included. This updated analysis reported an increased risk of death from CHD and CVD, although the results were not significant. These findings argue against the “saturated fat bad, omega 6 PUFA good” dogma and suggest that the American Heart Association advisory that includes the statement “higher [than 10% of energy] intakes [of omega-6 PUFAs] appear to be safe and may be even more beneficial” may be misguided. The more cautious UK dietary recommendations on fat and fatty acids, which include the statement, “There is reason to be cautious about high intakes of omega 6 PUFAs,” seem fully justified in the light of the current study’s findings.”

The authors of the research study themselves conclude:

“Advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for coronary heart disease risk reduction. However, clinical benefits of the most abundant polyunsaturated fatty acid, omega 6 linoleic acid, have not been established. In this cohort, substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These findings could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats.”

Bottom line: the data offer no evidence for clinicians to advise increasing the ratio of omega-6 fatty acids (such as linolenic acid in corn, sunflower, safflower, and soybean oils) to saturated fats for cardiovascular health.

GGT is an important predictor of diabetes and cardiovascular risk

I always include GGT (Serum γ-Glutamyltransferase) in our basic screening blood panel, but find often that this is not included in lab work that patients bring from elsewhere. A study recently published in the journal Obesity shows that, besides being associated with fatty liver,  GGT is an important metric for predicting metabolic syndrome, diabetes and hypertension. The authors state:

“Serum γ-glutamyltransferase (GGT) is associated with oxidative stress and hepatic steatosis. The extent to which its value in determining incident cardiometabolic risk (coronary heart disease (CHD), metabolic syndrome (MetS), hypertension and type 2 diabetes) is independent of obesity needs to be further explored in ethnicities.”

They examined a cohort of 1,667 adults from a general population age 52 to 63 with 4 year’s follow-up, measuring GGT activity in association with metabolic syndrome (identified by Adult Treatment Panel-III criteria modified for male abdominal obesity) and multiple markers for cardiovascular disease. Their data bolsters the use of GGT for case management:

“Median GGT activity was 24.9 U/l in men, 17.0 U/l in women…while smoking status was not associated, (male) sex, sex-dependent age, alcohol usage, BMI, fasting triglycerides and C-reactive protein (CRP) were significant independent determinants of circulating GGT. Each 1-s.d. increment in (= 0.53 ln GGT) GGT activity significantly predicted in each sex incident hypertension (hazard ratio (HR) 1.20), and similarly MetS, after adjustment for age, alcohol usage, smoking status, BMI and menopause. Strongest independent association existed with diabetes (HR 1.3) whereas GGT activity tended to marginally predict CHD independent of total bilirubin but not of BMI.”


“Higher serum total bilirubin levels were protective against CHD risk in women.”

While not any stronger a risk predictor for coronary heart disease (CHD) than body mass index (BMI), GTT is a valuable and underutilized marker to use for the case management of cardiometabolic disorders. The authors conclude:

“We conclude that elevated serum GGT confers, additively to BMI, risk of hypertension, MetS, and type 2 diabetes but only mediates adiposity against CHD risk.”



The highest amounts of calcium intake increase the risk of fracture

Patients are often surprised to learn that osteoporosis is not a calcium deficiency disorder but rather a failure to maintain the microarchitecture of the bone of which the protein matrix is a critical component. Moreover, earlier posts on magnesium and calcium have document the pro-inflammatory potential of calcium supplementation. Now fascinating research just published in the British Medical Journal offers evidence that calcium above the lowest quintile does not improve the risk of fracture of any type, while the highest levels actually increase the risk of fracture. The authors set out to…

“……investigate associations between long term dietary intake of calcium and risk of fracture of any type, hip fractures, and osteoporosis.”

They note that confusion regarding the issue of calcium requirements has been…

“…reflected by the wide range of daily calcium recommendations for individuals older than 50 years: at present 700 mg in the UK, 800 mg in Scandinavia, 1200 mg in the United States, and 1300 mg in Australia and New Zealand.”

The authors investigated 61,433 women born between 1914 and 1948 for 19 years for correlations between dietary intake of calcium and fractures of any type, hip fractures, and osteoporosis. They took into consideration vitamin D consumption, hormonal status, and other pertinent biological and lifestyle factors including physical activity. Perhaps not surprisingly in light of other evidence that has emerged recently about calcium, their data challenges the conventional wisdom:

“These findings show an association between a low habitual dietary calcium intake (lowest quintile) and an increased risk of fractures and of osteoporosis. Above this base level, we observed only minor differences in risk. The rate of hip fracture was even increased in those with high dietary calcium intakes.

In others, amounts higher than the lowest level of calcium intake adequate to avoid gross insufficiency and compromised bone micoarchitecture there were not only no significant benefits, the highest levels of intake increased fracture risk. The authors comment:

“The present results may reflect a situation when a moderate intake of calcium* combined with adequate intake of other micronutrients is sufficient to meet the structural and functional demands of the skeleton. High levels of intake did not further decrease the rate of fracture, and might even increase the rate of hip fractures…Moreover, use of supplemental calcium has been associated with higher rates of hip fracture both in a cohort study and in randomised controlled trials…Furthermore, high calcium doses slow bone turnover and also reduce the number of active bone remodelling sites. This situation can lead to a delay of bone repair caused by fatigue, and thus increase the risk of fractures independent of bone mineral density.”

*Their data indicate that a total dietary intake of 700 mg of calcium per day is sufficient to prevent fracture and osteoporosis. The authors conclude:

“Incremental increases in calcium intake above the level corresponding to the first quintile of our female population were not associated with a further reduction of osteoporotic fracture rate.”

Considering that chronic inflammation can be a primary factor in causing loss of the protein ‘scaffolding’ of bone responsible for strength, resilience, and the matrix to which minerals attach, these findings invoke recollection of the recent evidence that calcium supplementation can increase the inflammation of  cardiovascular disease. In case you missed it, a recent research paper published in the British Medical Journal follows up on earlier reports of this association. The authors’ intent was…

“To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.”

The examined the data from a randomised, placebo controlled trial of calcium alone or with vitamin D in 36,282 postmenopausal women over seven years for myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke. The data told an interesting story:

“In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events…Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P=0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P=0.009).”

Clinicians and patients need to appreciate that inflammation, a fundamental causal factor in both osteoporosis and cardiovascular disease, can be made worse by calcium supplements. The authors conclude:

Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.


Low testosterone increases heart disease mortality in men

More evidence of the importance of testosterone in preventing heart disease for men is offered in a study just published in the journal Heart in which the authors set out to…

“…examine the effect of serum testosterone levels on survival in a consecutive series of men with confirmed coronary disease and calculate the prevalence of testosterone deficiency.”

They followed 930 men with coronary disease for an average of seven years and correlating all-cause mortality and vascular mortality with testosterone deficiency. What did the data show?

“The overall prevalence of biochemical testosterone deficiency in the coronary disease cohort using bio-available testosterone (bio-T) was 20.9%, using total testosterone was 16.9% and using either was 24%. Excess mortality was noted in the androgen-deficient group compared with normal (41 (21%) vs 88 (12%). The only parameters found to influence time to all-cause and vascular mortality in multivariate analyses were the presence of left ventricular dysfunction, aspirin therapy, β-blocker therapy and low serum bio-T.”

Notice that the bio-available testosterone (free fraction or unbound testosterone, the small percentage that is actually ‘working’) was more revealing than the total testosterone. This is most conveniently measured in a saliva specimen. Clinicians and patients should bear in mind the authors’ conclusion:

In patients with coronary disease testosterone deficiency is common and impacts significantly negatively on survival.

Important: testosterone replacement by gel, cream or patch (transdermal) can easily accumulate to abnormally high (supraphysiologic) levels which ‘back-fires’ by causing testosterone receptor desensitization and pituitary suppression. This may be missed if the correct testosterone test (the bio-active, free fraction portion) is not done.

Nervous system regulation of inflammation, cytokines, and heart rate variability

As readers here know, inflammation is a fundamental factor in chronic disease and accelerated aging (neurodegeneration). A functional approach to treatment requires an objective understanding of how this system is working for each patient. Here are several of the many studies that illustrate how nervous system function and inflammation can be evaluated with heart rate variability (HRV) analysis and cytokine (‘messenger molecules’ of inflammation) levels.

ShockThe practical focus is on restoring parasympathetic nervous system (PNS) activity which inhibits inflammation. (PNS resources decline with disease, stress and age resulting in a state of ‘sympathetic nervous system dominance’.) This paper just published in the journal  Shock shows how autonomic nervous system activity (sympathetic and parasympathetic) as measured by HRV corresponds to inflammatory cytokine activity, in this case when stimulated by endotoxins (poisons produced by bacterial infections):

Autonomic inputs from the sympathetic and parasympathetic nervous systems, as measured by heart rate variability (HRV), have been reported to correlate to the… responses to infectious challenge… In addition, parasympathetic/vagal activity has been shown experimentally to exert anti-inflammatory effects via attenuation of splanchnic tissue TNF-α [cytokine] production. We sought… to determine if baseline HRV parameters correlated with endotoxin-mediated circulating cytokine responses.”

They documented a strong correspondence regardless of gender, body mass index and resting heart rate:

“…we found a significant correlation of several baseline HRV parameters…on TNF-α release after endotoxin exposure.”

Psychosomatic MedicineThis is not a new observation. An interesting study published a few years ago in the journal Psychosomatic Medicine documents the HRV expression of autonomic activity in response to an inflammatory challenge and its correspondence to cytokine production. They begin by noting that:

“…the autonomic nervous system plays a key role in regulating the magnitude of immune responses to inflammatory stimuli. Signaling by the parasympathetic system inhibits the production of proinflammatory cytokines by activated monocytes/macrophages and thus decreases local and systemic inflammation.”

They examined the relationship of HRV to lipopolysaccharide-induced production of the inflammatory cytokines interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-{alpha}, and IL-10. What did the data show?

“Consistent with animal findings, higher derived estimates of vagal activity measured during paced respiration* were associated with lower production of the proinflammatory cytokines TNF-{alpha} and IL-6…These associations persisted after controlling for demographic and health characteristics, including age, gender, race, years of education, smoking, hypertension, and white blood cell count.”

Their conclusion has profound implications for the biological mechanism by which stress causes inflammation:

“These data provide initial human evidence that vagal activity is inversely related to inflammatory competence, raising the possibility that vagal regulation of immune reactivity may represent a pathway linking psychosocial factors to risk for inflammatory disease.”

Brain, Behavior, and ImmunityHow might this show up in heart disease? This paper published not long ago in the journal Brain, Behavior, and Immunity investigates the links between HRV, inflammatory cytokines, coronary heart disease and depression:

“Studies show negative correlations between heart rate variability (HRV) and inflammatory markers [less variability = more inflammation]…We investigated links between short-term HRV and inflammatory markers in relation to depression in acute coronary syndrome (ACS) patients.”

They measured C-reactive protein (CRP), interleukin-6 (IL-6, a cytokine), depression symptoms and heart rate variability determinants of autonomic function. What did their data show?

“…all HRV measures were negatively and significantly associated with both inflammatory markers…HRV independently accounted for at least 4% of the variance in CRP in the depressed, more than any factor except BMI.”

Interestingly, they also noted that:

“Relationships between measures of inflammation and autonomic function are stronger among depressed than non-depressed cardiac patients. Interventions targeting regulation of both autonomic control and inflammation may be of particular importance.”

Journal of Critical CareThe research of another group published in the Journal of Critical Care used sepsis as their model.

“The aim of the study was to investigate possible associations between different heart rate variability (HRV) indices and various biomarkers of inflammation in 45 septic patients.”

They examined the correlation between HRV, C-reactive protein, and the cytokines  interleukin 6 and interleukin 10:

“Our data suggest that low HRV and sympathovagal balance during septic shock are associated with both an increased hyperinflammatory and antiinflammatory response.”

The antiinflammatory response corresponds to high HRV and interleukin-10, the cytokine that is also increased by vitamin D.

Journal of Internal MedicineHow can we reduce inflammation by increasing HRV and reducing inflammatory cytokines? There are numerous methods; one is to increase cholinergic activity in the nervous system (parasympathetic activity mediated by the neurotransmitter acetylcholine). We can increase this with natural precursor support for acetylcholine. This study published recently in the Journal of Internal Medicine shows the connection between vagal parasympathetic function (as shown by HRV), inflammatory cytokines, cholinergic activity and rheumatoid arthritis:

The central nervous system regulates innate immunity in part via the cholinergic anti-inflammatory pathway, a neural circuit that transmits signals in the vagus nerve that suppress pro-inflammatory cytokine productionVagus nerve activity is significantly suppressed in patients with autoimmune diseases, including rheumatoid arthritis (RA). It has been suggested that stimulating the cholinergic anti-inflammatory pathway may be beneficial to patients…”

They found that increasing cholinergic signaling in stimulated whole blood cultures suppressed cytokine production in rheumatoid arthritis patients whose vagal activity was deficient:

“These findings suggest that it is possible to pharmacologically target the α7nAChR dependent control of cytokine release in RA patients with suppressed vagus nerve activity.”

In a functional medicine practice, of course, we use natural acetylcholine precursors.

Brain, Behavior, and Immunity 2This is a drop in the bucket, but here’s one more fascinating paper published recently in the journal Brain, Behavior, and Immunity that shows how acetylcholine activity in the brain (the upper level of autonomic regulation) controls systemic cytokine levels through vagal function:

The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the “cholinergic anti-inflammatory pathway,” defined as neural signals transmitted via the vagus nerve that inhibit cytokine releaseVagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks…Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF [cytokine] production during endotoxemia.”

They demonstrated that inhibiting the breakdown of acetylcholine† markedly reduced proinflammatory serum TNF levels through the resulting increasing vagus nerve signaling which prevented inflammatory damage. What do they conclude from their research?

“These findings show that inhibition of brain acetylcholinesterase [that breaks down acetylcholine] suppresses systemic inflammation through a central…mediated and vagal…dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor† can be utilized to suppress abnormal inflammation to therapeutic advantage.”

* There are numerous therapies to reduce inflammation by increasing parasympathetic function. Breathing is a powerful stimulus to the autonomic nervous system. We train breathing with biofeedback while simultaneously monitoring for CO2 (capnography) and coherence in HRV to hit the physiological “sweet spot”.

† Agents that inhibit the breakdown of neurotransmitters including reuptake inhibitors do not restore the body’s ability to make its own. Precursor therapy provides the natural ingredients that have been depleted or are insufficient to meet genetic needs so neurotransmitters can be increased naturally.

More reasons to go nuts for heart disease

Archives of Internal MedicineA paper just published in the Archives of Internal Medicine analyzes the evidence from 25 intervention trials on the effect of eating nuts on blood lipid levels and heart disease. The authors begin by noting:

Epidemiological studies have consistently associated nut consumption with reduced risk for coronary heart disease…The objectives of this study were to estimate the effects of nut consumption on blood lipid levels and to examine whether different factors modify the effects.”

They pooled the data from 25 trials in 7 countries for cholesterol, LDL, ratio of LDL to HDL, and triglycerides. Improvements were documented in all of these factors. The data also showed that:

“The effects of nut consumption were dose related, and different types of nuts had similar effects on blood lipid levels…the lipid-lowering effects of nut consumption were greatest among subjects with high baseline LDL-C and with low body mass index and among those consuming Western diets.”

In other words, eating more nuts improved the lipid-lowering effect. Hence their conclusion:

Nut consumption improves blood lipid levels in a dose-related manner, particularly among subjects with higher LDL-C or with lower BMI.”