Less mortality and cardiovascular risk with metformin than other diabetes drugs

Posted on April 11, 2011 by Dr. Jonathan

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

Posted on February 25, 2011 by Dr. Jonathan

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

Posted on January 21, 2011 by Dr. Jonathan

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

Posted on December 18, 2010 by Dr. Jonathan

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

Posted on October 4, 2010 by Dr. Jonathan

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

Posted on September 22, 2010 by Dr. Jonathan

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

Posted on September 7, 2010 by Dr. Jonathan

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

Posted on May 20, 2010 by Dr. Jonathan

A 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.”

Even mild anemia has a big impact

Posted on March 21, 2010 by Dr. Jonathan

Because anemia degrades the ability of the blood to carry oxygen to every cell in the body it has a profound and global affect on function, especially for the brain. Sadly, this is often ‘written off’ in older folks who miss out on the care they need.

Haematologica 0109 Here’s a paper published in the journal Haematologica that opens with…

“Mild anemia is a frequent laboratory finding in the elderly usually disregarded in everyday practice as an innocent bystander.”

They took over three years to investigate the association of mild anemia with hospitalization and mortality in 7,536 subjects. Here’s what their data showed:

“The risk of hospitalization in the 3 years following recruitment was higher among the mildly anemic…Mortality risk in the following 3.5 years was also higher among the mildly anemic elderly…Similar results were found when slightly elevating the lower limit of normal hemoglobin concentration to 12.2 g/dL in women and to 13.2 g/dL in men.”

They conclude with this statement:

“After controlling for many potential confounders, mild grade anemia was found to be prospectively associated with clinically relevant outcomes such as increased risk of hospitalization and all-cause mortality.”

A study published not long ago in the journal Medicine also highlights the fact that even borderline anemia can have a big effect. First they note:

“The occurrence of anemia in older adults has been associated with adverse outcomes including functional decline, disability, morbidity, and mortality.”

In their study…

“Anemia was defined as hemoglobin <13 g/dL for men or <12g/dL for women.”

These levels are almost always ignored by most doctors. Here’s what their data showed:

“Anemia was associated with greater fatigue, lower handgrip strength, increased number of disabilities, and more depressive symptoms. Multivariate regression analysis…demonstrated strong associations for reduced hemoglobin, even within the “normal” range, and poorer health-related quality of life across multiple domains.”

Leading to the conclusion:

“Thus, anemia was independently associated with clinically significant impairments…Mildly low hemoglobin levels, even when above the World Health Organization (WHO) anemia threshold, were associated with significant declines in quality of life among the elderly.”

Another paper published in Current Opinion in Hematology begins with the familiar observation:

“Anemia is common in older adults and is an independent predictor for increased morbidity and mortality in several disease states. Older persons with anemia suffer hospitalization, physical decline, and disability at higher rates than those people without anemia.”

In their study they found that a third of the cases were due to nutritional deficiencies (!), a third from chronic disease, and a third were unexplained (more on that in a future post). They too found that it predicted diminished physical performance and mobility, and reported the same finding that clarifies how we should understand ‘low’:

“The data suggest that the risk of mortality and loss of mobility even extends to levels of hemoglobin normally considered low normal by WHO criteria….”

Practitioners take note of their parting comment:

“Anemia is a common modifiable predictor of poor medical outcome in older adults and, as such, should be actively managed.”

I’ll introduce one more paper published in the Public Library of Science (PLoS One) that focuses on the damage to cognition and mood caused by mild anemia. In this study mood (depression), cognition, attention, memory and quality of life were all quantified for 4,068 individuals. Here’s what their data showed:

“In univariate analyses, mild anemic elderly persons had significantly worse results on almost all cognitive, functional, mood, and QoL (Quality of Life) measures. In multivariable logistic regressions…mild anemia remained significantly associated with measures of selective attention and disease-specific QoL.”

As in other studies, when the reference range was narrowed to a more precise ‘functional’ level, the deleterious effect of mild anemia was clear:

“When the lower limit of normal hemoglobin concentration according to WHO criteria was raised to define anemia (+0.2 g/dL), differences between mild anemic and non anemic elderly persons tended to increase on almost every variable.”

Here’s the bottom line: mild anemia has a profoundly negative impact on every aspect of function and should be investigated diligently as to its cause and treated accordingly.

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

Posted on March 7, 2010 by Dr. Jonathan

Archives of Internal Medicine 0210 RDW 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.”

Another 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 0210.2 This 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.”

And 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.”

And 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.”

Lastly, 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 (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