Vitamin B12

Update On Clinical Applications

Abstract

Vitamin B12 is an essential co-factor for methionine synthase and L-methyl-malonyl-CoA mutase, which are required in DNA synthesis and vital in hematopoietic pathways. There are several risk factors for B12 deficiency and associated anemia, including vegetarian or vegan diets and increasing age. Supplemental vitamin B12 is overwhelmingly safe and although there is insufficient evidence to establish the best long term route of administration for B12, the evidence suggests that oral, intramuscular, and parenteral administration are equally effective. Homocysteine and vitamin B12 levels should be routinely checked in individuals with cognitive decline and Alzheimer’s disease, as vitamin B12 is a viable treatment option. The totality of evidence is unclear as to the independent impact of vitamin B12 in relation to cardiovascular risk, but key studies will be discussed. Vitamin B12 is effective at ameliorating the symptoms of depression, as shown by improvements in various validated questionnaires. This article reviews the trials conducted using supplemental vitamin B12 in the treatment of these various health conditions and provides a clinical update. 

Introduction

Vitamin B12, also known as cobalamin, can come in many forms including cyano-, methyl-, and hydroxy-cobalamin, among others (O’Leary 2010). It is involved in many physiological pathways in the body and a deficiency causes megaloblastic anemia, as well as a potential host of other damaging consequences. Serum B12 is currently the principle means of assessing B12 status (Carmel 2009), and as discussed below this test alone is insufficient for accurately establishing all stages of B12 deficiency. The addition of holotranscobalamin, methylmelonic acid, and homocysteine to the standard serum B12 measurement provides a more accurate assessment of functional B12 status (Herrmann 2003). Utilizing this expanded four test profile to assess B12 status can help to identify earlier stages of deficiency and initiate appropriate treatment before the manifestation of clinically evident deficiency symptoms (Herrmann 2003). Supplemental vitamin B12 is overwhelmingly safe and no toxic effects have been encountered from administration, indicating that B12 is essentially nontoxic (Food and Nutrition Board 1998). This is applicable when administering amounts at or below the recommended dietary allowance. However, there is limited data for high-dose B12 and there have been some reports of mild side effects such as rash, pruritus, and diarrhea. There is also not enough data to make any conclusions about the safety of large doses of vitamin B12 in pregnancy and breast feeding. In addition to anemia, vitamin B12 has been used as a treatment for numerous health issues, including for cardiovascular health, in depression, and for cognitive health. This article will review the evidence available in each of these areas and update practitioners on the clinical applications of vitamin B12.

Anemia Recent estimates suggest up to 14% of anemias may be associated with folate or vitamin B12 deficiency (Pang 2012). Vitamin B12 is an essential co-factor for methionine synthase and L-methyl-malonyl-CoA mutase, which are required in DNA synthesis and thus vital in hematopoietic pathways (O’Leary 2010). There are several risk factors for B12 deficiency and associated anemia, including vegetarian and vegan diets (Pawlak 2013), and increasing age (Chatthanawaree 2013, Park 2006). An important and often overlooked risk of vitamin B12 deficiency is depletion from drug interactions including proton pump inhibitors, metformin, anti-seizure medications, and nitric oxide (Mazokopakis 2008). Also of interest is a recent study indentifying an increased risk of vitamin B12 (as well as folate and iron) deficiency in patients following gastric bypass, with over 60% developing anemia within three years (Vargas-Ruiz 2008).

The most common anemia associated with vitamin B12 is pernicious anemia (PA), a macrocytic anemia caused by atrophic gastritis and an associated loss of intrinsic factor (IF), which is required to cleave vitamin B12 from protein sources thereby facilitating absorption (Stabler 2013). PA is most common in the seventh or eighth decade of life, with milder atrophic gastritis affecting an estimated 20% of older individuals (Stabler 2013). Long term risk factors of neurologic complications including peripheral neuropathy, and lateral spinal cord and cerebrum lesions, can be prevented or reversed if PA is recognized early in disease progression and supplemental vitamin B12 is provided (Annibale 2011). Since oral supplements provide vitamin B12 unbound to protein even in the absence of IF, absorption can still occur. PA has an insidious onset with non-descript signs and symptoms including fatigue, weakness, headaches, lack of concentration, paresthesias, and digestive disturbance, making it challenging, but important to diagnose early (O’Leary 2010). Patients with PA should be given supplemental doses of at least 500-1000mcg (O’Leary 2010).

Several studies investigating the merits of intramuscular, parenteral, and oral administration routes of vitamin B12 have concluded that in the short term, oral supplementation is equally as effective as other routes in cases of pernicious anemia and malabsoprtion (Seal 2002). Complicating the implications of study results is the common use of the cyanocobalamin form of vitamin B12 (hydroxy, and methyl are available commercially and used clinically), variety in dosing regimens, and unclear long-term comparisons of administration routes. Although cost of oral supplementation is significantly less than IM or parenteral, both IM and parenteral may be more effective in cases where compliance is an issue (Drug and Therapeutics Bulletin 2009).

Establishing parameters to measure B12 deficiency is not straightforward. Traditionally the lower limit of reference ranges for serum B12 reflected the level at which megaloblastic anemia normally presented (O’Leary 2010). While serum testing of total vitamin B12 is available and regularly used, it may misrepresent vitamin B12 status as it includes B12 in the form of hepatocorrin, which is biologically unavailable (Green 2011). More recently holotranscobolamin II, the available form of vitamin B12, has been recognized as a useful measure of B12 status (Green 2011). Measurements of other metabolic markers of vitamin B12 status are helpful in determining not only vitamin B12 status, but also differentiating vitamin B12 and folate deficiencies. Elevated levels of both homocysteine and methylmalonic acid are regularly noted in B12 deficiency, while homocysteine elevation with normal methylmalonic acid levels are more common in folate deficiency, although both markers may be elevated with normal B12 and folate status (Green 2011). Vitamin B12 deficiency is a risk factor for anemia and routine screening of haematological markers along with serum vitamin B12, homocysteine, and methylmalonic acid should be evaluated in individuals at risk of B12 deficiency, specifically elderly and vegetarian populations. Additionally, appropriate identification of PA is crucial in preventing serious long-term consequences. There is insufficient evidence to establish the best long term route of administration for B12, although oral, intramuscular, and parenteral administration appear to be equivocal in the short-term.

Cardiovascular Health Many prospective intervention studies have examined the role of vitamin B12 in cardiovascular disease. Unfortunately, there have been a number of limitations to these trials, including inadequate treatment with vitamin B12 and confounding effects from other simultaneous treatments (Righetti 2009). One recent systematic review of cohort studies included seven studies with varying populations, length of follow-up, study outcomes, and data analysis (Rafnsson 2011). Only one high-quality study reported that low B12 increased the risk of incident cerebral ischaemia. After controlling for homocysteine, the association persisted although weakened, suggesting that the effects of low B12 were only partly mediated by homocysteine. In two studies, higher B12 levels were associated with a greater risk of total mortality and combined fatal and non-fatal coronary events (Rafnsson 2011).

In examining other trials that were excluded from the aforementioned systematic review, there are two that stand out. The first is the Vitamin Intervention for Stroke Prevention Trial (Spence 2007). In the original interpretation of the trial, it was shown that vitamin therapy (B12, B6, folate) had no benefit for homocysteine lowering. However, there were problems with the trial, including the lack of a placebo control, the use of a multiple vitamin with low doses of vitamins, patients in both arms of the trial received injections of B12, and folate fortification of grain products in North America coincided with the initiation of the trial. Upon further interpretation of a subgroup from which patients who could not have responded to the study treatment were excluded, there was a significant reduction of stroke, coronary events, and death. When stratified by median entry level of B12, serum B12 status was the key determinant of response, with those with high serum B12 at entry who received high-dose vitamin (0.4mg cyano-cobalamin was considered the high-dose) had a 33% reduction of events compared to those with low B12 who received low-dose vitamins (Spence 2007). The second trial of interest is the Heart Outcomes Prevention Evaluation 2 Trial (Lonn 2006). In this trial, they evaluated whether long-term therapy with folic acid 2.5mg and vitamins B6 50mg and B12 1mg reduced the risk of major cardiovascular events in a high-risk population. The results showed a 25% significant reduction of stroke with vitamin therapy (p = 0.03), but the authors considered this a chance finding (Lonn 2006). Overall, the totality of evidence is unclear as to the independent impact of vitamin B12 in relation to cardiovascular risk. It is also difficult to make large generalizations based on studies with a range of doses, with limited experimental evidence available for supplemental doses above 1mg of B12.

Depression Low levels of vitamin B12 have been measured in patients with depressive disorders and in some studies, women with metabolically significant deficiencies have been found to have a two-fold higher risk of depression (Penninx 2000). Although many studies examine both folate and vitamin B12, one study has suggested B12 deficiency is independently related to depressive disorders (Tiemeier 2002). A separate study conducted with outpatients diagnosed with major depressive disorder looked at vitamin B12 levels and the consequent six-month treatment outcomes (Hintikka 2003). The authors examined haematological indices, including erythrocyte folate and serum vitamin B12 levels. The study included 115 outpatients with DSM-III-R major depressive disorder at baseline. The 17-item Hamilton Depression Rating Scale was compiled. The results showed that higher vitamin B12 levels were significantly associated with a better outcome at six-months (Hintikka 2003). More recently, a Finnish population-based study examined the association between vitamin B12 levels and melancholic depressive symptoms (Seppala 2013). Subjects were randomly selected from the National Population Register as part of the Finnish diabetes prevention program and the study consisted of 2806 participants. Health examinations were carried out and depressive symptoms were based on the Beck Depression Inventory. Groups were further divided by melancholic or non-melancholic subgroups based on the DSM-IV. The results showed that the mean vitamin B12 level was associated with melancholic depressive symptoms (Seppala 2013).

Many case studies have reported that supplemental vitamin B12 and folic acid can improve the symptoms of depression (Mitchell 2007). In this study, a sample of 12 outpatients with dysthymic disorder was supplemented with 800mcg of folic acid and 1000mcg of vitamin B12 for six weeks. Two instruments were used to measure depressive symptoms: the Beck Depression Inventory- II and the Symptom Checklist-90-Revised. At the end of the six weeks, the raw and t-scores of each of the participants indicated a reduction in the reported levels of symptoms of depression (Mitchell 2007). One large study examined the effects of dietary intake of vitamin B6, folate, and vitamin B12 on depressive symptoms (Skarupski 2010). The study sample consisted of 3503 adults aged over 65 years from the Chicago Health and Aging project. Dietary assessment was made by food-frequency questionnaire and incident depression was measured by the presence of at least four depressive symptoms from the 10-item version of the Center for Epidemiologic Studies Depression scale. The results showed that the higher total intakes of vitamin B6 and B12 were associated with a decreased likelihood of depression for up to 12 years of follow-up, after adjustments were made, including for antidepressant medication use. Each 10 additional milligrams of vitamin B6 and 10 additional micrograms of vitamin B12 were associated with 2% lower odds of depressive symptoms per year (Skarupski 2010). Finally, the B-VITAGE trial is a double-blind, placebo-controlled, randomized trial of homocysteine lowering treatment of depression in later life that is currently in progress (Ford 2010). Participants will receive daily citalopram (20-40mg), plus vitamin B12 (0.4mg), B6 (25mg), and folic acid (2mg) compared to citalopram plus placebo. Over the course of 52 weeks, depressive symptoms will be measured using validated questionnaires. This trial will clarify whether the systematic use of B-vitamins improve the response of older adults to standard antidepressant treatment. Although teasing out the specific effects of vitamin B12 is difficult, the evidence that is available suggests it is both a safe and effective option in the treatment of depressive symptoms.

Cognitive Decline and Alzheimer Disease Vitamin B12 deficiency and elevations in associated biomarkers of low vitamin B12 status, are associated with cognitive decline (CD) (Riggs 1996), including Alzheimer Disease (AD) (Wang 2001). The mechanism implicated in the relationship between Vitamin B12 status and CD is the homocysteine lowering effect of B12 (Werder 2010). Studies have shown that in individuals with elevated homocysteine levels and CD, reducing homocysteine through therapies including combinations of folate, vitamin B12, and vitamin B6, has a favourable benefit on cognitive function (Nilsson 2001).

Results of RCTs evaluating vitamin B12 supplementation as a treatment for CD and AD are mixed (Malouf 2003). Although a number of RCTs are available, due to small sample size and poor study design, a large number do not provide significant power with which to draw conclusions (Malouf 2003). Factors including dose and duration of treatment, extent and duration of cognitive decline, homocysteine levels, vitamin B12 status (and laboratory techniques used for evaluation), all confound results. A 2003 Cochrane review included only two RCTs evaluating vitamin B12 supplementation in the treatment of CD and AD, and concluded insufficient evidence of efficacy, primarily due to small trial size (Malouf 2003). Several newer studies demonstrate positive outcomes with supplemental B12 (0.5mg) in CD, with the largest effect in individuals with elevated homocysteine levels and with the shortest duration of cognitive decline (De Jager 2013). Additionally, studies have demonstrated a decrease in accelerated brain atrophy in both AD (Douaud 2013) and mild CD with homocysteine-lowering therapy by vitamin B12, folate and vitamin B6 (Smith 2010).

Supplemental B12 in combination with folate also shows benefit in as a preventative therapy in decreasing cognitive decline in older individuals with depressive disorders. A 2012 RCT showed significant improvement in cognitive measures after 24 months of supplementation of Vitamin B12 (100mcg) and folate in individuals over 60 (Walker 2012). Of note, in combination therapy with folate, one RCT showed no statistically significant improvement in CD with supplementation, which was likely due to the inclusion of individuals with low or normal homocysteine levels, suggesting lowering homocysteine below normal levels is of no benefit in CD (Pratico 2009). Although there is conflicting evidence represented in research regarding vitamin B12 supplementation in the treatment of CD and AD, there is significant evidence that supplementation in individuals with elevated homocysteine levels early in CD is effective (Walker 2012). Based on the relative safety of vitamin B12 administration and possible degree of benefit, homocysteine and vitamin B12 levels should be routinely checked in individuals with cognitive decline and vitamin B12 (along with folate and vitamin B6) considered as a viable treatment option to lower homocysteine and improve markers of mild CD and AD.

Conclusion

Supplemental vitamin B12 is overwhelmingly safe and no toxic effects have been encountered, especially at doses at or below 1000mcg. Regarding optimal route of administration, there is insufficient evidence to establish the best long term option, but oral, intramuscular, and parenteral administration are all adequate in the short-term. It is imperative to detect vitamin B12 deficiency in those at risk, especially the elderly. Vitamin B12 is an effective treatment for anemia in these cases. Despite some promising results, the totality of evidence is unclear as to the independent impact of vitamin B12 in relation to cardiovascular risk. Vitamin B12 is effective in treating the symptoms of depression, as shown by improvements in various validated questionnaires. Additional well-designed trials are currently in progress. Finally, earlier studies on CD and AD had small sample sizes and poor designs, but newer trials have shown that B12 supplementation in individuals with elevated homocysteine levels early in CD is effective, even in small doses.

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Diabetes Medications

Reduced risk of disease-related complications?

Abstract 

It is not debatable that the elevated blood glucose levels associated with diabetes represent a serious risk marker for macrovascular and microvascular adverse developments and events, and that the risk increases with the average of the daily fluctuations. This provides the principal rationale for maintaining both fasting blood glucose and the indicator of the long- term average, glycated hemoglobin, at levels close to normal. More than a dozen prescription drugs are currently used individually or in combination to treat type 2 diabetes. They act by decreasing liver glucose production, increasing insulin secretion, increasing insulin sensitivity, inhibiting glucagon release and slowing the absorption of carbohydrates. These drugs decrease serum glucose and glycated hemoglobin with the goal of glucose reduction to targets approaching normal, a result that is generally believed will significantly decrease the incidence of the complication associated with the disease. Failure to achieve blood glucose control generally results in additional drugs and even insulin, and is frequently termed intensive treatment. As will be discussed, there are not only new studies but recent meta-analyses that have examined the impact of intensive blood glucose lowering on complications in type 2 diabetes. Evidence will be presented that in fact glucose lowering, either intensive or not, is a failed therapy if judged by the impact on clinical complications, a failure termed by some medical scientists the Diabetes Paradox.

Introduction 

Even before the beginning of the 20^th century, carbohydrate restriction was the established medical response to diabetes and obesity. This changed dramatically in the early 1960s when the hypothesis that fat and in particular saturated fat increased the risk of both heart disease and cancer was accepted as true without adequate evidence and profoundly altered diets. The macronutrients that were most effective in driving up blood sugar, elevating insulin, and viewed as causing insulin resistance, beta cell dysfunction and diabetes became the main components of the so-called healthy, low fat diet in the developed world. These were mostly carbohydrates and as the trend accelerated, these were more refined and had higher glycemic activity. Then drugs became available which would lower blood sugar and its daily average and offered a logical solution. The number of anti-hyperglycaemic agents increased rapidly. If used intensively, the drugs were able to bring glucose levels down to somewhat above normal and this was viewed as a success. Thus the blood glucose elevations associated with diets rich in carbohydrates were counteracted, once diabetes had developed, by daily dosing with antihyperglycemic drugs. The impact on complications, the principal reason for glucose control, is however a developing story and the subject of this article. In what follows, the evidence will be presented that once one has diabetes, controlling both the daily fluctuations and lowering the long-term average of blood glucose with pharmaceutical intervention in fact has almost no impact on the incidence of complications. This is not good news for patients with diabetes who obviously have reason to be seriously concerned about the need to prevent complications.

Standard vs. Intensive glucose control 

There has been great interest in intensive blood glucose control and the natural (or perhaps simplistic) assumption has been that lowering levels to the pre-diabetic range with multiple drugs, insulin and dose escalation would be beneficial. The wake-up call came in 2008. Two papers simultaneously published in the New England Journal of Medicine reported on studies designed to address this issue with large cohorts. The ACCORD study randomized 10,251 patients with type 2 diabetes to receive intensive therapy targeted with polypharmacy, increased doses and insulin if necessary, all directed at getting HbA1c down from a median level of 8.1% to below 6.0%, generally considered high-normal or pre-diabetic. The controls received standard drug therapy targeting a level of 7.0% to 7.9%. As compared with standard therapy, the use of intensive therapy for 3.5 years increased mortality resulting in early trial termination and did not significantly reduce major cardiovascular events (Gerstein 2008).

The ADVANCE study randomized 11,140 patients with type 2 diabetes to either standard glucose control using mostly oral glycemic drugs or an intensive intervention group mainly using the modified release sulfonylurea Gliclazide, plus other drugs including insulin if needed to achieve a HbA1c of 6.5%. For over a median five- year follow-up, there was a small (1.9%) absolute decrease in risk associated with the primary endpoint, combined micro- and macrovascular events, in the intensive treatment group. But this was due to new or worsening nephropathy. Among 14 secondary endpoints, only new-onset miroablinuria showed a decreased absolute risk of 2%. Thus there was no impact on the remaining common complications of type 2 diabetes including all cause mortality, major or all coronary events, all cerebrovascular events, peripheral vascular events, visual deteriation or new or worsening neuropathy (Patel 2008).

A smaller trial, the Veterans Affairs Diabetes Trial (VADT) that reported in 2009, involved a comparison between intensive and standard glucose control in patients with type II diabetes with suboptimal response to therapy. In this study 1791 men, mean age 60, were randomized to two groups with a median follow-up of 5.6 years. Median HbA1c dropped from 8.4% in the standard therapy group to 6.9% in the intensive group. The primary endpoint was the time from randomization to first occurrence of a major cardiovascular event, which was a composite of MI, stroke, deaths from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease and amputation for gangrene. The comparison was with standard drug therapy. It was found that intensive glucose control had no significant impact on the endpoints of major cardiovascular events, death or microvascular complications with the exception of evidence of the progression to kidney disease. Statistically significant increased incidence of nephropathy was seen in subgroup analysis when micro- and macroalbuminuria were combined (Duckworth 2009).

In 2011 a systematic review and meta-analysis of randomized trials concerning intensive glycemic control appeared in BMJ (Hemmingsen 2011). No impact on all cause mortality was found. With regard to other endpoints, the authors found that data available remained insufficient to prove or refute a relative risk reduction of CVD mortality, non-fatal MI, composite microvascular complications, or retinopathy at a relative risk reduction threshold they considered clinically significant, but identified a 30% increase in severe hypoglycemia.

Prompted by the ADVANCE and VADT results and earlier studies related to kidney complications, a study involving meta-analysis reporting in 2012 investigated if intensive vs. standard glucose control decreased significant renal clinical outcomes such as doubling of serum creatinine levels, end-stage renal disease or death from renal disease during the years of follow-up. No evidence was found when seven trials with follow-up from two to 15 years were evaluated (Coca 2012).

Metformin monotherapy 

The standard care almost always involves either metformin alone or metformin plus another drug. Since the American Diabetes Association (ADA) recommends metformin as the first-line of standard care after diagnosis of type 2 diabetes (ADA 2012), to what extent does it reduce the macro- and microvascular complications of diabetes when compared with a placebo or non-drug treatment such as diet? This may seem like an odd issue bring up. Metformin has been used for decades. Metformin is also the most common standard against which other drugs are judged in clinical trials.

In 2012 a meta-analysis was published where the efficacy of metformin was examined. The trials were either metformin vs. diet or non-drug care or a placebo, metformin plus a sulphonylurea vs. the sulphonylurea alone, or metformin plus insulin vs. insulin plus a placebo or metformin vs. total withdrawal from the drug. For the above comparisons, no significant benefit was found for all-cause mortality, cardiovascular mortality, all MI, all strokes, congestive heart failure, peripheral vascular events, amputation, or microvascular events (Boussageon 2012).

It is also important to look at just the studies in the above meta-analysis where metformin alone was compared with a placebo, diet or usual non-drug care and there were more than a few events. There are only two studies with longer than 12 months follow-up (Rachmani, 2002, UKPDS-34 1998), and only the endpoints of all cause mortality, cardiovascular mortality and all MI (heart attacks) were common to these studies. A third study lasting only 12 months was not judged relevant but was in fact negative (Cryer 2005). If the results from the two eligible studies are pooled and given equal weight (in the above meta-analysis they were given approximately equal weight), then as shown in the table below, for the three endpoints there was no statistically significant benefit found (95% confidence interval contains 1.0) These two studies together involved 537 subjects in the treated group and 609 in the control group.

Pooled analysis of two trials of metformin vs. diet (UKPDS-34 1998) or metformin withdrawal (Rachmani 2002).

The withdrawal study obtained only non-significant results indicating no benefit. The UKPDS-34 study is generally the only trial cited to justify the use of metformin because it claimed to have obtained evidence of benefit (UKPDS-34 1998). This study actually started in 1983 and reported finally in 1998. Over this period, the primary and main endpoints were changed a number of times and the announced termination date repeatedly extended. Furthermore, the study was not blinded for the investigators and the results of interim analysis were available. This study protocol is obviously open to bias. To quote one citric, “It seems that the authors continued the study until they obtained a result that was significant without adjusting for repeatedly looking at the data” (Ewart 2001). An investigator involved in the trial commented in 2008 that “UKPDS-34 broke almost all the rules of trial design. We are taught to believe that a study protocol should be predetermined and set in stone, but this study went to the other extreme, elevating the ad hoc into an art form” (Gale 2008). Thus the key study appears flawed.

In 2009 it was pointed out (Reaven 2009), based on the six-year report from UKPDS (UKPDS-16 1995), that following enrolment there was a progressive deteriation of glycemic control in all groups including those assigned to intensive control. In addition, beta cell function was estimated by HOMA-β and the investigators concluded that increasing hyperglycemia and decreasing beta cell function were significant features irrespective of the drug protocol used. Reaven also points out that the loss of secretory function does not appear to be inexorable and cites two studies where weight loss improved glycemic control. This view is supported by a study discussed below (Lim 2011).

The 2012 American Diabetes Association (ADA) Standards of Medical Care in Diabetes clearly indicates that metformin should be initiated as therapy for type 2 diabetes at the time of diagnosis. If the patient has markedly elevated blood glucose or HbA1c, then the advice is to consider insulin with or without oral agents. If metformin alone does not achieve or maintain satisfactory HbA1c levels over three to six months at maximal tolerated doses, the recommendation is to add a second oral agent (ADA 2012). This more intensive treatment is of course the subject of the several major studies discussed above which in general found no benefit. Furthermore, in the intensive vs. standard glucose lowering studies, metformin, the common reference treatment, itself does not appear to be effective. It is in fact quite remarkable that UKPDS-34 is the study used to justify metformin as the primary treatment and the drug used as a principal standard against which other drugs are tested.

Discussion and conclusions 

There appears to be only very weak if any evidence regarding the ability of current drug treatments to significantly reduce the incidence of the many complications of type 2 diabetes, independent of the HbA1c level achieved. Among some diabetes researchers this is acknowledged and is termed the Diabetes Paradox, i.e. hyperglycemia is necessary for the development of late diabetic complications but average blood glucose (HbA1c) explains only a small percentage of complications (Bierhause 2011). Concerned researchers are now looking into the complex details of type 2 diabetes such as for example the potential for reactive glucose metabolites and their intermediates to act as active agents in the disease etiology and progression (Fleming 2012). There is obviously an urgent need for a new treatment paradigm rather than to merely reduce markers such as HbA1c.

In the past few years there have been calls (from the wilderness) for a return to the traditional approach used for decades for treating type 2 diabetes, the adoption of carbohydrate restriction in the context of both prevention and therapy (Accurso 2008, Leite 2009, Volek 2005a, Volek 2005b, Volek 2008, Volek 2009). However, such proposals face strong opposition from those who fear the substitution of fat for carbohydrates, even though there is compelling literature indicating that such fears are groundless (Ware 2012). The success achieved by Richard K. Bernstein using carbohydrate restriction and carefully selected carbohydrates matched to the individual’s metabolism is now documented in several editions of his book Dr. Bernstein’s Diabetes Solution (Bernstein 2011). The HbA1c levels he achieves are significantly better than anything conventional medicine appears able to accomplish, and this is generally only with diet. In fact, a recent study found complete reversal of type 2 diabetes achieved over a short period by a starvation diet, and

the benefits appear durable after return to higher calorie intake, strongly suggesting beta-cell regeneration and a permanent increase in insulin sensitivity (Lim 2011).

Are type 2 diabetes patients being given a false sense of security? They are told they need to get their blood glucose under control and many attempt to accomplish this in the belief that this reduces the risk of complications, which does not seem to be the case. The net result is a missed opportunity to restrict carbohydrates and calories and thus address the role of insulin in both insulin resistance, fat storage, and leptin resistance, deal with obesity and the metabolic syndrome, and also build muscle with resistance exercise to help increase insulin sensitivity. Another missed opportunity involves alternative medicines such as curcumin, which has produced better glucose control than prescription drugs and even appears to have reversed type 2 diabetes (Chuengsamarn 2012, Na 2012). Those who argue, probably with some justification, that severe carbohydrate restriction is not practical and adherence nearly impossible are also admitting that progress in reducing the complications of diabetes is at present nearly hopeless.

Reference List 

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ADA. Standards of medical care in diabetes–2012. Diabetes Care 2012; 35 Suppl 1: S11-S63. 

Bernstein,R.K., 2011. Dr. Bernstein’s Diabetes Solution. The complete guide to acheiving normal blood sugars. Little, Brown and Company, New York. 

Bierhause,A., 2011. Failure of glucose lowering in clinical trials: The way to novel biochemical concedpts explaining diabetic late complications.The 26th Camillo Golgi Lecture, European Association for the Study of Diabetes. Annual meeting, Lisbon, September 2012. 

Boussageon,R., Supper,I., Bejan-Angoulvant,T., Kellou,N., Cucherat,M., Boissel,J.P., Kassai,B., Moreau,A., Gueyffier,F. and Cornu,C. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med 2012; 9(4): e1001204. 

Chuengsamarn,S., Rattanamongkolgul,S., Luechapudiporn,R., Phisalaphong,C. and Jirawatnotai,S.

Curcumin extract for prevention of type 2 diabetes. Diabetes Care 2012; 35(11): 2121-2127.

Coca,S.G., Ismail-Beigi,F., Haq,N., Krumholz,H.M. and Parikh,C.R. Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes. Arch Intern Med 2012; 172(10): 761-769.

Cryer,D.R., Nicholas,S.P., Henry,D.H., Mills,D.J. and Stadel,B.V. Comparative outcomes study of metformin intervention versus conventional approach the COSMIC Approach Study. Diabetes Care 2005; 28(3): 539-543.

Duckworth,W., Abraira,C., Moritz,T., Reda,D., Emanuele,N., Reaven,P.D., Zieve,F.J., Marks,J., Davis,S.N., Hayward,R., Warren,S.R., Goldman,S., McCarren,M., Vitek,M.E., Henderson,W.G. and Huang,G.D. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360(2): 129-139.

Ewart,R.M. The case against aggressive treatment of type 2 diabetes: critique of the UK prospective diabetes study. BMJ 2001; 323(7317): 854-858.

Fleming,T., Cuny,J., Nawroth,G., Djuric,Z., Humpert,P.M., Zeier,M., Bierhaus,A. and Nawroth,P.P. Is diabetes an acquired disorder of reactive glucose metabolites and their intermediates? Diabetologia 2012; 55(4): 1151-1155.

Gale,E.A. Glucose control in the UKPDS: what did we learn? Diabet. Med 2008; 25 Suppl 2: 9-12.

Gerstein,H.C., Miller,M.E., Byington,R.P., Goff,D.C., Jr., Bigger,J.T., Buse,J.B., Cushman,W.C., Genuth,S., Ismail-Beigi,F., Grimm,R.H., Jr., Probstfield,J.L., Simons-Morton,D.G. and Friedewald,W.T. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358(24): 2545-2559.

Hemmingsen,B., Lund,S.S., Gluud,C., Vaag,A., Almdal,T., Hemmingsen,C. and Wetterslev,J. Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ 2011; 343: d6898.

Leite,J.O., DeOgburn,R., Ratliff,J.C., Su,R., Volek,J.S., McGrane,M.M., Dardik,A. and Fernandez,M.L. Low-carbohydrate diet disrupts the association between insulin resistance and weight gain. Metabolism 2009; 58(8): 1116-1122.

Lim,E.L., Hollingsworth,K.G., Aribisala,B.S., Chen,M.J., Mathers,J.C. and Taylor,R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011; 54(10): 2506-2514.

Na,L.X., Li,Y., Pan,H.Z., Zhou,X.L., Sun,D.J., Meng,M., Li,X.X. and Sun,C.H. Curcuminoids exert glucose-lowering effect in type 2 diabetes by decreasing serum free fatty acids: a double-blind, placebo-controlled trial. Mol Nutr Food Res 2012.

Patel,A., MacMahon,S., Chalmers,J., Neal,B., Billot,L., Woodward,M., Marre,M., Cooper,M., Glasziou,P., Grobbee,D., Hamet,P., Harrap,S., Heller,S., Liu,L., Mancia,G., Mogensen,C.E., Pan,C., Poulter,N., Rodgers,A., Williams,B., Bompoint,S., de Galan,B.E., Joshi,R. and Travert,F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358(24): 2560-2572.

Rachmani,R., Slavachevski,I., Levi,Z., Zadok,B., Kedar,Y. and Ravid,M. Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med 2002; 13(7): 428.

Reaven,G.M. HOMA-beta in the UKPDS and ADOPT. Is the natural history of type 2 diabetes characterised by a progressive and inexorable loss of insulin secretory function? Maybe? Maybe not? Diab. Vasc Dis Res 2009; 6(2): 133-138.

UKPDS-16 U.K. prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes 1995; 44(11): 1249-1258.

UKPDS-34. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352(9131): 854-865.

Volek,J.S. and Feinman,R.D. Carbohydrate restriction improves the features of Metabolic Syndrome. Metabolic Syndrome may be defined by the response to carbohydrate restriction. Nutr Metab (Lond) 2005a; 2: 31.

Volek,J.S., Fernandez,M.L., Feinman,R.D. and Phinney,S.D. Dietary carbohydrate restriction induces a unique metabolic state positively affecting atherogenic dyslipidemia, fatty acid partitioning, and metabolic syndrome. Prog. Lipid Res 2008; 47(5): 307-318.

Volek,J.S. and Forsythe,C.E. The case for not restricting saturated fat on a low carbohydrate diet. Nutr Metab (Lond) 2005b; 2: 21.

Volek,J.S., Phinney,S.D., Forsythe,C.E., Quann,E.E., Wood,R.J., Puglisi,M.J., Kraemer,W.J., Bibus,D.M., Fernandez,M.L. and Feinman,R.D. Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet. Lipids 2009; 44(4): 297-309.

Ware,W.R. Saturated fat. Friend, foe or simply neutral. Integrated Healthcare Practitioners 2012; 5(2): 68.

Chemotherapy-Related Cognitive Impairment

Strategies for intervention

Abstract

Chemotherapy-related cognitive impairment (CRCI) is characterized by memory loss, lack of concentration and attention, difficulty multitasking, organizing, planning, and thinking. CRCI can have a significant impact on quality of life but treatment options with strong supporting evidence of efficacy are scarce. This review highlights the current state of evidence regarding CRCI and therapies that may help improve cognitive function in this patient population.

Introduction

Chemobrain, also referred to as chemofog, or chemotherapy-related cognitive impairment, is a phenomenon that has been reported by patients receiving various forms of chemotherapy for the past three decades. Estimates of chemotherapy-related cognitive decline (CRCI) in breast cancer survivors are as high as 75% (Ahles 2002, Brezden 2000, Schagen 1999, Tchen 2003, Van Dam 1998). The cognitive impairment is typically characterized by memory loss, lack of concentration and attention, difficulty thinking, organizing, planning, and multi-tasking (Matsuda 2005, Reid-Arndt 2009).

While it was generally accepted by the 1990s that chemotherapeutic agents could be acutely neurotoxic when delivered directly to the nervous system, CRCI was still regarded as psychogenic (Hede 2008, Myers 2009). Given the inability of many chemotherapeutic agents to cross the blood-brain-barrier, it was believed that chemotherapy was an unlikely cause of neurotoxicity when administered systemically (O’Farrell 2013). Many confounding factors such as psychological distress associated with having cancer, fatigue, anxiety, depression, and effects of medication prescribed in conjunction with chemotherapeutic intervention, all can alter cognitive function as well.

Due to advancements in cancer treatment, there is also increased survival. As a result, there are a rising number of patients who are living with long-term side effects of these anti-cancer agents, which canhave significant negativeimpactson quality of life.

Impact on Quality of Life

In a 2010 survey conducted by the Canadian Breast Cancer Network, women who had received chemotherapy had the greatest reduction in house-hold income, took more time off work, were more likely to have had to quit their jobs, and had a greater perception that the financial burden imposed by their illness would impact their long-term health (Dunbrack 2010). In a study by Reid-Arndt et al., women with stages I-III breast cancer were evaluated one month after completing adjuvant chemotherapy. Data was collected regarding cognitive, emotional, social, and vocational functioning and an association between executive functioning deficits and decreased productivity, community involvement, and social role functioning was found (2009).

Advancements in Research

Studies on CRCI in the recent past reported poor, if any, correlation between subjective reports of cognitive decline and objective measures of cognitive performance (Biglia 2012, Hutchinson 2012, Jansen 2011). In order to establish appropriate guidelines for study design and methodology when performing research in this field, the International Cognition and Cancer Task Force (ICCTF) was created in 2006. This aided tremendously in promoting comparable findings among studies and reducing the number of confounding variables in the research (Wefel 2008).

Dr. Patricia Ganz conducted one of the first studies demonstrating that cognitive complaints after breast cancer treatment are associated with neuropsychological test performance. Her team enrolled 189 breast cancer patients one month post surgery, with or without radiation and/or chemotherapy, and prior to commencing hormone therapy—a common confounding factor. The control group consisted of a sample of age-matched healthy women and found that 23.3% of the breast cancer patients reported higher memory complaints and 19% had higher executive function complaints post-treatment; >1 SD above the mean for healthy control sample (Ganz 2013).

McDonald et al. performed the first controlled prospective MRI study in the field of neuroimaging whereby significant decreases in gray matter density were found in bilateral, frontal, temporal, and cerebellar regions as well as the right thalamus in breast cancer patients shortly following chemotherapy treatment. These changes were not evident in either a disease or healthy control group.

The cognitive changes could also not be accounted for by postsurgical effects, disease stage, psychiatric symptoms, psychotropic medication, or hormonal treatment status, suggesting the changes were due to chemotherapy treatment (2010). No other study had prospectively examined gray matter changes in patients both receiving and not receiving chemotherapy with a pre-treatment baseline with which to compare post-treatment changes. This groundbreaking study was the first to show decline in brain gray matter density shortly after chemotherapy and degree of long-term recovery via a prospective longitudinal approach.

Evidence-Based Interventions 

Modafinil

Sixty-eight participants with memory problems persisting two years post-chemotherapy treatment for breast cancer were given 200mg daily of Modafinil (a psychostimulant used in the treatment of patients with narcolepsy) for four weeks, finding modest but statistically significant improvement in speed of memory and episodic memory, but not in working memory, compared with controls (Kohli 2009, Von 2011). Other groups have tried a one-time dose of 200mg, finding improvement in attention and psychomotor speed but not in working memory (Lundorff 2009). 

In another study by Blackhall et al., initial doses of 100mg Modafinil for two weeks, increasing to 200mg daily in 27 patients with cancer of all stages, did not show improvement in cognitive functioning. Due to the mixed results and small sample sizes, effectiveness of this medication for the treatment of CRCI has not been established (2009).

Exercise 

Korstjens evaluated the effects of a 12-week rehabilitation program combining exercise with a psychoeducational program on various aspects of quality of life, including cognition. Physical exercise sessions overseen by a physiotherapist occurred twice a week for two hours and included aqua aerobics, group sports, or individual endurance and strength training. The psychoeducational program consisted of seven two-hour sessions focused on coping with cancer. Improvements in global cognitive function were reported based on two items on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (2006). Although some improvements were reported in cognitive function in this and other studies (Schwartz 2002), it is difficult to determine the effect of an exercise intervention on cognitive impairment because of the difference in definition and delivery of the exercise intervention programs, small sample sizes, and study designs (combined multiple interventions). Further research is required.

Natural Environment Intervention 

Attention-restoring theory identifies that the environment may influence one’s ability to concentrate and capacity to direct attention (Cimprich 2003); thus, natural restorative environmental interventions may replenish psychological reserves and improve cognitive functioning. Two studies were found that evaluated the impact of natural restorative environmental intervention on cognitive function in patients with cancer (Cimprich 1993, Cimprich 2003).

Cimprich examined the impact of a natural restorative environmental intervention (walking in nature or gardening for 20-30 minutes three times a week) in 32 patients with breast cancer and assessed their level of attention at three, 18, 60, and 90 days after surgery. Significant and sustained improvement in attentional fatigue scores were noted across all four time periods (1993). Similarly, in a follow-up randomized, controlled trial of 157 patients with breast cancer, Cimprich and Ronis demonstrated that those who were exposed to the natural environment for 120 minutes per week had improved capacity to direct attention from pretreatment as compared with the nonintervention group, even after controlling for age, education, attention scores prior to surgery, other health problems, distress, and extent of the surgery (2003). Additional longitudinal research is needed to understand its sustainability throughout the course of cancer treatment, as well as to test outcomes in other cancer populations.

Acetyl-L-Carnitine 

Though not yet clinically tested for cognitive impairments due to chemotherapy, ALC improved memory, visuo-spatial capacity, and vocabulary recall when given at two grams per day over a test period of three months in cognitively impaired ex-alcoholics aged 30-60 years (Tempesta 1990).

In controlled trials, ALC improved depression as well as cooperation, sociability, and attention to personal appearance, though it did not consistently improve anxiety (Bonavita 1986). Dosage ranges from 1,500-3000mg per day with most trials using two grams or more (Kidd 1999).

Given that acetyl-L-carnitine aids in the treatment/prevention of chemotherapy-induced peripheral neuropathy (CIPN) and that CIPN can be caused by chemotherapeutic agents such as Paclitaxel and Cisplatin— known to also cause chemotherapy-related cognitive impairment—the use of ALC may help to target more than one of these side effects which may impact quality of life significantly (Pisano 2003).

Phosphatidylserine (PS) 

PS is present in all cells of the human body and particularly in the membrane systems of nerve cells. While also not clinical studied for CRCI, phosphatidylserine consistently benefits memory, learning, concentration, word choice, mood, and relieves anxiety and depression, and the capacity to cope with stress (Crook 1992, Kidd 1998, Maggioni 1990). Effective intakes of PS range from 100mg per day (for smaller children and for maintenance in healthy adults) to 300mg/day for memory loss and up to 600mg/day for mood enhancement (Kidd 1998).

Conclusion 

For the past several decades research on CRCI has focused on proving whether this side effect is psychogenic or neurological in nature. With studies now using advanced neuroimaging techniques, new research may attempt to elucidate mechanisms by which various chemotherapeutic agents may be causing cognitive decline in patients with other forms of cancer, not limited to breast cancer. Insight into mechanisms of action will in turn allow for more research regarding treatment and prevention of CRCI. Sample sizes of the majority of the present studies are too small to make appropriate inferences about any conclusions made. Patient populations in these studies are typically females with breast cancer and not representative of all other types of cancer.

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