HgbA1c (hemoglobin A1c) predicts prediabetes better than glucose

HgbA1c predicts prediabetesHgbA1c (hemoglobin A1c) is hemoglobin that has been ruined by glycation (bonding with sugar). It has long been recognized as a biomarker for average glucose over an approximately three month time span as well as a metric for the degree of damaging glycation occurring throughout the body. Now further evidence for its superior value as a predictor for prediabetes is presented in a study just published in The Lancet Diabetes & Endocrinology.The authors…

“…compared the risk of future outcomes across different prediabetes definitions based on fasting glucose concentration, HbA1c, and 2 h glucose concentration during over two decades of follow-up in the community-based Atherosclerosis Risk in Communities (ARIC) study. We aimed to analyse the associations of definitions with outcomes to provide a comparison of different definitions.”

HgbA1c compared to fasting and 2 hour glucose

They compared several prediabetes definitions in their ability to predict major long-term health problems. They analyzed data from over seven thousand subjects drawn from four communities across the USA who participated in the Atherosclerosis Risk in Communities (ARIC) study. HgbA1c was pitted against fasting and 2 hour postprandial glucose:

“Fasting glucose concentration and HbA1c were measured at visit 2 and fasting glucose concentration and 2 h glucose concentration were measured at visit 4. We compared prediabetes definitions based on fasting glucose concentration (American Diabetes Association [ADA] fasting glucose concentration cutoff 5·6–6·9 mmol/L and WHO fasting glucose concentration cutoff 6·1–6·9 mmol/L), HbA1c (ADA HbA1ccutoff 5·7–6·4% [39–46 mmol/mol] and International Expert Committee [IEC] HbA1c cutoff 6·0–6·4% [42–46 mmol/mol]), and 2 h glucose concentration (ADA and WHO 2 h glucose concentration cutoff 7·8–11·0 mmol/L).”

HgbA1c better identifies those at risk for diabetes and serious complications

Chronic kidney disease, cardiovascular disease and death were more accurately predicted by HgbA1c than by fasting glucose:

“After demographic adjustment, HbA1c-based definitions of prediabetes had higher hazard ratios and better risk discrimination for chronic kidney disease, cardiovascular disease, peripheral arterial disease, and all-cause mortality than did fasting glucose concentration-based definitions (all p<0·05). The C-statistic for incident chronic kidney disease was 0·636 for ADA fasting glucose concentration clinical categories and 0·640 for ADA HbA1c clinical categories. The C-statistics were 0·662 for ADA fasting glucose clinical concentration categories and 0·672 for ADA HbA1c clinical categories for atherosclerotic cardiovascular disease, 0·701 for ADA fasting glucose concentration clinical categories and 0·722 for ADA HbA1c clinical categories for peripheral arterial disease, and 0·683 for ADA fasting glucose concentration clinical categories and 0·688 for ADA HbA1c clinical categories for all-cause mortality. Prediabetes defined using the ADA HbA1c cutoff showed a significant overall improvement in the net reclassification index for cardiovascular outcomes and death compared with prediabetes defined with glucose-based definitions.”

Clinical Significance

HgbA1c study reviewed in Medscape Family Medicine

Medscape Family Medicine remarks:

“The researchers found that using an HbA1c-based definition, those identified as having prediabetes were 50% more likely to develop kidney disease, twice as likely to develop CVD, and 60% more likely to die from any cause compared with those with normal HbA1c.”

The authors, quoted in Medscape Family Medicine, comment on the practical significance of their findings:

“When someone is told they have prediabetes, we hope it will cause them to make changes to their habits in order to prevent the development of diabetes and its complications,” added the study’s senior author, Elizabeth Selvin, PhD, MPH, a professor in the Bloomberg School’s department of epidemiology.

“Being identified as having prediabetes can also make it easier to receive weight-loss and nutritional counseling as well as reimbursement for these services. Intensive lifestyle changes and weight loss can reduce the risk of diabetes, so it is critically important we identify those persons who are at high risk.

At the same time, we also don’t want to overdiagnose people. Using the hemoglobin A1c test allows us to more accurately identify those persons at highest risk,” she added.

This is important information for physicians and it is also important information for professional organizations. Coming to a global consensus on how to define and diagnose prediabetes would really help move the field forward — and help patients all over the world,” she concluded.”

The authors conclude:

“Our results suggest that prediabetes definitions using HbA1c were more specific and provided modest improvements in risk discrimination for clinical complications. The definition of prediabetes using the ADA fasting glucose concentration cutoff was more sensitive overall.”

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.”

Less mortality and cardiovascular risk with metformin than other diabetes drugs

It’s by far best to prevent type 2 diabetes by acting on the earliest signs of metabolic syndrome with appropriate lifestyle changes and evidence-based support for genetic and epigenetic needs based on objective laboratory data. All too often, however, this isn’t accomplished and the case advances to type 2 diabetes as insulin resistance mounts and insulin production can no longer compensate. When we enter the realm of pharmaceuticals for T2DM there are choices. A huge study just published in the European Heart Journal offers valuable evidence that metformin is associated with much less risk of cardiovascular disease and all-cause mortality. The authors state:

“The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study.”

The authors examined the data for all Danish residents over 20 years old who starting taking an a single-agent insulin secretagogue (medication that provokes the secretion of insulin, ISs) or metformin between 1997 and 2006, a total of 107,806 subjects. They were followed for up to 9 years (3.3 years on average) for all-cause mortality, cardiovascular mortality, and the combination of myocardial infarction (MI), stroke, and cardiovascular mortality. This was correlated with the use of individual ISs. What did their data show?

Compared with metformin, glimepiride: 1.32, glibenclamide: 1.19, glipizide: 1.27, and tolbutamide: 1.28 were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30, glibenclamide: 1.47, glipizide: 1.53 (1.23–1.89), and tolbutamide: 1.47. Results for gliclazide and repaglinide and were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint.”

In other words, for example, patients (who had never had a heart attack) taking glimepiride had a 32% increased chance of dying compared with taking metformin. The authors conclude by stating:

Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.”

This outcome is not unexpected when we consider that, in addition to suppressing hepatic glucose production, metformin acts to increase insulin receptor sensitivity. The authors of an editorial published in the same journal comment on the gravity of this study:

“While this is not the first study to evaluate outcomes with these drug classes comparatively, the observations are among the most robust published based on the very large sample of patients with drug choices largely free of selection bias, sufficient numbers of events ascertained to yield substantial statistical power to analyse outcomes for each insulin secretagogue individually, with additional stratification by history of previous myocardial infarction.”

Important: metformin is known to interfere with vitamin B12 absorption (see previous posts). Patients should be followed carefully for indications of suboptimal vitamin B12 levels, preferably by urine or serum methylmalonic acid assays.

Statins do not decrease mortality in primary prevention

A systematic review just published in the journal Evidence-Based Medicine adds more clarity to the proper use of statin medications. Clinicians reading this are likely aware of the controversy raised by the  extensive JUPITER trial. The authors note:

“Low-density lipoprotein (LDL) cholesterol (LDL-C) is a risk factor for cardiovascular disease (CVD). Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) lower LDL-C concentrations by about 30–50% and have been shown to reduce mortality in patients with prevalent CVD. However, it is not clear whether statin treatment is beneficial in a primary prevention setting, that is in people without prevalent CVD who are at relatively lower risk. The recent results of the JUPITER trial have fueled an intense debate whether statins should be given for primary prevention of CVD.”

They performed a comprehensive analysis of studies published in the MEDLINE and Cochrane Collaboration databases involving trials of statin use whose subjects were without prevalent CVD at baseline. They performed a detailed meta-analysis employing sophisticated statistical methods with all-cause mortality as the primary outcome of interest. In all, 11 studies involving 65,229 patients met their inclusion criteria, comprising 244,000 person-years of observation. An interesting picture emerged when the numbers were crunched:

“…LDL-C concentration was not predictive of mortality. Statin therapy was not associated with a significant survival benefit…The exclusion of the two trials comprising only patients with diabetes did not substantively change these results. Furthermore, the authors did not find a correlation between mortality reduction and baseline LDL-C concentration or with relative LDL-C reduction in the treatment arm.”

In other words, in this large cohort of patients without already active cardiovascular disease, statin therapy showed no benefit in mortality reduction. The authors state in their conclusion:

“This investigation is by far the largest analysis of statin therapy in a purely primary prevention setting…the authors observed a consistent null result (for statin benefit) independent of mean baseline LDL concentration and mean LDL-C reduction in the treatment arm and without evidence of relevant heterogeneity across cohorts…This study therefore questions the widespread practice of prescribing statins to middle-aged patients with an average cardiovascular risk profile who do not have overt CVD…The inference can be made that individuals with lower cardiovascular risk are likely to benefit even less from statin therapy.”

Statin therapy is not without serious risks and must be pondered carefully for each individual patient. It should not be simply employed as a surrogate for a thorough analysis of the underlying causes promoting dyslipidemia, and most importantly, vascular inflammation—the driving pathological process in cardiovascular disease. The authors further conclude:

“Taken together, the study is the first to meta-analyse statin therapy in a purely primary prevention setting. Its conclusive null result (for statin benefit on all-cause mortality) raises important questions about the current practice of widespread use of statins for primary prevention of CVD in individuals with average cardiovascular risk.”

Low cholesterol associated with higher mortality

Most readers here are aware that cholesterol is the substrate for all steroid hormones and a component of all cell membranes, so that when too low it is a contributing factor to a range of disorders. A study just published in the Journal of Epidemiology provides more evidence for the association between low cholesterol and death from all causes. The authors state:

“We investigated the relationship between low cholesterol and mortality and examined whether that relationship differs with respect to cause of death.”

They conducted their study using 12,334 healthy adults from 12 rural areas in Japan. They correlated serum total cholesterol with total mortality, noting sex and cause of death. The average follow-up period was 11.9 years. What did their data show?

As compared with a moderate cholesterol level (4.14-5.17 mmol/L)[161.5-201.5 mg/dL], the age-adjusted hazard ratio (HR) [risk] of low cholesterol (<4.14 mmol/L)[161.5 mg/dL] for mortality was 1.49 [50% increase in mortality]High cholesterol (≥6.21 mmol/L)[≥242 mg/dL] was not a risk factor. This association was unchanged in analyses that excluded deaths due to liver disease… The multivariate-adjusted HRs [hazard ratios = risks]…of the lowest cholesterol group for hemorrhagic stroke, heart failure (excluding myocardial infarction), and cancer mortality [were] significantly higher than those of the moderate cholesterol group, for each cause of death.”

Numerous lines of reasoning, documented in a broad accumulation of scientific evidence (of which a small ‘taste’ is reported in this venue) converge on the assertion that inflammation, rather than cholesterol per se, is the primary villain in cardiovascular disease. Clinicians and patients alike should bear in mind the authors’ conclusion:

Low cholesterol was related to high mortality even after excluding deaths due to liver disease from the analysis. High cholesterol was not a risk factor for mortality.

Bioelectrical phase angle predicts quality of life and mortality with cancer

Bioelectrical phase angle, which we easily and non-invasively measure in the clinic by bioelectrical impedance analysis, has been validated by numerous studies as a prognostic indicator for a variety of medical conditions. A study recently published in The American Journal of Clinical Nutrition offers evidence for its accuracy in predicting life quality, nutritional status and mortality for patients with cancer. The authors state:

“The bioelectrical phase angle has shown predictive potential in various diseases…This study evaluated the prognostic value of the fifth percentile of sex-, age-, and body mass index–stratified phase angle reference values in patients with cancer with respect to nutritional and functional status, quality of life, and 6-mo mortality.

They then examined how the standardized phase angle and its deviation from population averages (‘z score’) on these life and mortality variables. They tested phase angle with bioelectical impedance analysis, muscle strength by handgrip and peak expiratory flow, employed assessments for quality of life and nutritional status, and documented survival after 6 months for 399 patients. What did the data show?

Patients with a phase angle of less than the fifth reference percentile had significantly lower nutritional and functional status, impaired quality of life, and increased mortality. The standardized phase angle emerged as a significant predictor for malnutrition and impaired functional status in generalized linear model regression analyses. It was also a stronger indicator of 6-mo survival than were malnutrition and disease severity in the Cox regression model…”

Having an accurate, easy and inexpensive instrument to objectively evaluate the effectiveness of therapeutic case management in cancer in respect to mortality, function, quality of life and nutritional status is a resource that should not be overlooked by clinicians. The authors conclude:

“The standardized phase angle is an independent predictor for impaired nutritional and functional status and survival. The fifth phase angle reference percentile is a simple and prognostically relevant cutoff for detection of patients with cancer at risk for these factors.”

Note: This refers to bioelectrical impedance analysis measured by a professional clinical-grade instrument.

NSAID use associated with increased cardiovascular death

An important study recently published in the journal Circulation: Cardiovascular Quality and Outcomes alerts us to a serious hazard associated with non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (Voltaren®), rofecoxib (Vioxx®, now withdrawn), and even ibuprofen to a lesser degree. The authors state:

“Studies have raised concern on the cardiovascular safety of nonsteroidal antiinflammatory drugs (NSAIDs). We studied safety of NSAID therapy in a nationwide cohort of healthy individuals.”

They analyzed data for 1,028,437 individuals drawn from the entire Danish population by the appropriate selection criteria. By crunching 8 years’ worth of numbers they found:

“Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death. There was a trend for increased risk of fatal or nonfatal stroke associated with ibuprofen treatment, but naproxen was not associated with increased cardiovascular risk.”

The risk was almost doubled for Voltaren and Vioxx. For ibuprofen the risk for stroke was increased by about 30%. Of special note is that the average duration of treatment with these medications was only 14 days. The authors sum up their results:

“In the present nationwide study of healthy individuals, we found that most NSAIDs are associated with increased cardiovascular mortality and morbidity. In particular, the use of the nonselective NSAID diclofenac and the selective COX-2 inhibitor rofecoxib was associated with a similarly increased risk of cardiovascular mortality and morbidity among healthy individuals. Our results suggest that naproxen could be a safer alternative when NSAID treatment is required.”

In other words, ibuprofen is not innocent, but Voltaren is as bad as Vioxx. These risks make sense if we consider that NSAIDs also increase intestinal permeability, an aggravating factor for autoimmunity, and recall the autoimmune aspect of cardiovascular disease. They further exhort doctors and public health officials with a stern warning:

“Diclofenac is widely used in the general population worldwide, and it is also accessible as over-the-counter medication in various countries. Our study suggests that this pharmaceutical strategy represents a major public health issue, potentially exposing a substantial number of individuals to risk of cardiovascular adverse events. Physicians initiating NSAID treatment should always make an individual assessment of cardiovascular risk and carefully consider the balance between benefit and risk before starting treatment with any NSAID.

Carbohydrates and death from inflammatory disease

As the authors of research just published in the American Journal of Clinical Nutrition state:

“Several studies suggest that carbohydrate nutrition is related to oxidative stress and inflammatory markers.”

The proceeded to examine whether dietary glycemic index (GI), dietary fiber, and carbohydrate-containing food groups were associated with death due to non-cardiovascular, non-cancer inflammatory disease in 1490 postmenopausal women and 1245 men. What did their data show?

“Over a 13-y period, 84 women and 86 men died of inflammatory diseases. Women in the highest GI tertile had a 2.9-fold increased risk of inflammatory death…Increasing intakes of foods high in refined sugars or refined starches and decreasing intakes of bread and cereals or vegetables other than potatoes also independently predicted a greater risk. In men, only an increased consumption of fruit fiber and fruit conferred an independent decrease in risk of inflammatory death.”

In other words, for postmenopausal women the high glycemic index diet almost tripled the risk of death from inflammatory disease.

The tape measure: a powerful predictive ‘instrument’ for mortality

More research recently published in the Archives of Internal Medicine further validates the power of waist circumference measurements to predict death from all causes. This study provides evidence that its accuracy is far superior to body mass index (BMI).

Waist circumference (WC), a measure of abdominal obesity, is associated with higher mortality independent of body mass index (BMI). Less is known about the association between WC and mortality within categories of BMI or for the very high levels of WC that are now common.”

The authors examined the association between WC and mortality among 48 500 men and 56 343 women between 1997 and 2006, during which 9315 men and 5332 women died. Considering the adverse metabolic and hormonal activity of visceral (intra-abdominal versus subcutaneous) fat, their data is not surprising:

“After adjustment for BMI and other risk factors, very high levels of WC were associated with an approximately 2-fold higher risk of mortality in men and women…The WC was positively associated with mortality within all categories of BMI.”

Very high levels of WC means 47 inches for men and 43 inches for women. Waist circumference is a more reliable indicator than weight or BMI. If you’re losing weight without your WC getting smaller, you’re probably losing more muscle than fat. As the authors state in their conclusion:

“These results emphasize the importance of WC as a risk factor for mortality in older adults, regardless of BMI.”

Higher estrogen predicts mortality in older women

Journal of the American Geriatrics SocietyA study published not long ago in the Journal of the American Geriatrics Society is a reminder that even natural estrogen at higher levels than the proper physiological range is detrimental. The authors aimed…

“To investigate the relationship between total estradiol (E2) levels and 9-year mortality in older postmenopausal women not taking hormone replacement therapy (HRT).”

The study participants were a representative sample of 509 women aged 65 and older living the Chianti region of Italy. What did their data show?

Higher E2 levels were associated with a greater likelihood of death…independent of age, waist:hip ratio, C-reactive protein, education, cognitive function, physical activity, caloric intake, smoking, and chronic disease…The excessive risk of death associated with higher total E2 was not attenuated after adjustment for total testosterone and after further adjustment for insulin resistance…Total E2 was highly predictive of death after more than 5 years and not predictive of death for less than 5 years.”

This study highlights the importance of the functional management of estrogen levels even when HRT is not being used. All the more reason for cautious objective validation with the appropriate lab test (free-fraction bioactive estrogen) if we bear in mind the investigators’ conclusion:

Higher total E2 concentration predicts mortality in older women not taking HRT.”