Long term treatment with metformin in patients with type 2diabetes and risk of vitamin B-12 deficiency: randomisedplacebo controlled trial Jolien de Jager, resident,1,2 Adriaan Kooy, internist,2,3 Philippe Lehert, professor of statistics,4 Michiel GWulffele´, general practitioner,2,3 Jan van der Kolk, biochemical engineer,5 Danie¨l Bets, program manager,6 JoopVerburg, chief laboratory attendant,5 Ab J M Donker, professor of internal medicine,7 Coen D A Stehouwer,professor and chair8 vitamin B-12) for patients with a normal vitamin B-12 Objectives To study the effects of metformin on the incidence of vitamin B-12 deficiency (<150 pmol/l), low Conclusions Long term treatment with metformin concentrations of vitamin B-12 (150-220 pmol/l), and increases the risk of vitamin B-12 deficiency, which Centre, Bethesda GeneralHospital, Hoogeveen, Netherlands folate and homocysteine concentrations in patients with results in raised homocysteine concentrations. Vitamin type 2 diabetes receiving treatment with insulin.
B-12 deficiency is preventable; therefore, our findings Design Multicentre randomised placebo controlled trial.
suggest that regular measurement of vitamin B-12 Setting Outpatient clinics of three non-academic concentrations during long term metformin treatment Participants 390 patients with type 2 diabetes receiving Trial registration NCT00375388.
Intervention 850 mg metformin or placebo three times a Metformin is considered a cornerstone in the treat- Main outcome measures Percentage change in vitamin B- ment of diabetes and is the most frequently prescribed 12, folate, and homocysteine concentrations from first line therapy for individuals with type 2 diabetes.1 Development, Merck Netherlands,Amsterdam, Netherlands baseline at4, 17, 30, 43, and 52 months.
In addition, it is one of a few antihyperglycaemic Results Compared with placebo, metformin treatment agents associated with improvements in cardio- was associated with a mean decrease in vitamin B-12 vascular morbidity and mortality,2 3 which is a major −19% (95% confidence interval −24% to cause of death in patients with type 2 diabetes.4 −14%; P<0.001) and in folate concentration of −5% (95% There are few disadvantages to the use of metformin.
CI −10% to −0.4%; P=0.033), and an increase in Metformin does, however, induce vitamin B-12 malab- homocysteine concentration of 5% (95% CI −1% to 11%; sorption, which may increase the risk of developing P=0.091). After adjustment for body mass index and vitamin B-12 deficiency5-7—a clinically important and smoking, no significant effect of metformin on folate treatable condition. In addition, metformin treatment concentrations was found. The absolute risk of vitamin has been reported to be associated with decreased B-12 deficiency (<150 pmol/l) at study end was 7.2 folate concentration, although the mechanism of this percentage points higher in the metformin group than in effect has not been elucidated.8 Finally, decreases in the placebo group (95% CI 2.3 to 12.1; P=0.004), with a both folate and vitamin B-12 concentrations might, in number needed to harm of 13.8 per 4.3 years (95% CI turn, result in an increase in homocysteine concentra- 43.5 to 8.3). The absolute risk of low vitamin B-12 tions (web figure A), an independent risk factor for concentration (150-220 pmol/l) at study end was 11.2 cardiovascular disease, especially among individuals percentage points higher in the metformin group (95% CI 4.6 to 17.9; P=0.001), with a number needed to harm of All current evidence on vitamin B-12 deficiency in 8.9 per 4.3 years (95% CI 21.7 to 5.6). Patients with metformin treatment comes from short term vitamin B-12 deficiency at study end had a mean studies.5-712-14 No long term, placebo controlled data homocysteine level of 23.7 µmol/l (95% CI 18.8 to 30.0 on the effects of metformin on concentrations of vita- µmol/l), compared with a mean homocysteine level of min B-12 in patients with type 2 diabetes have been 18.1 µmol/l (95% CI 16.7 to 19.6 µmol/l; P=0.003) for reported. In addition, placebo controlled data on the patients with a low vitamin B-12 concentration and 14.9 effects of metformin on homocysteine concentrations µmol/l (95% CI 14.3 to 15.5 µmol/l; P<0.001 compared in type 2 diabetes are sparse,12 15 and again no long term with vitamin B-12 deficiency; P=0.005 compared with low Blood samples for this study were drawn at baseline and after 4, 17, 30, 43, and 52 months, and stored at −80°C until analysis. Concentrations of vitamin B-12, folate, and homocysteine were measured in serum.
Vitamin B-12 and folate concentrations were deter- mined by an electrochemiluminescence immunoassay(ECLIA) using the competition principle. The meanintra-assay coefficients of variation for vitamin B-12 and folate were 2.3% and 3.5%, respectively. Themean inter-assay coefficients were 2.9% and 4.7%, We studied the effects of metformin treatment on serum concentrations of vitamin B-12, folate, and Total homocysteine concentration was measured homocysteine in patients with type 2 diabetes in a using a kit from Chromsystems (Martinsried, Ger- many). The results were corrected against two typesof “consensus plasma samples” (SKML, Nijmegen, the Netherlands) that had concentrations of 13 µmol/ l and 55 µmol/l. The correction factor found was 0.90.
This study was part of the Hyperinsulinaemia: the Out- The intra-assay coefficients of variation were 2.2% and come of its Metabolic Effects (HOME) randomised 1.8% at 12.8 µmol/l and 72.2 µmol/l, respectively. The trial investigating the effects of metformin on meta- inter-assay coefficients of variation were 6.1% and bolism and on microvascular and macrovascular dis- 5.2% at 9.8 µmol/l and 21.1 µmol/l, respectively.
ease in type 2 diabetes. The trial included 390 patients In the HOME trial, vitamin B-12, folate, and homo- aged 30-80 years with type 2 diabetes who were receiv- cysteine concentrations had been measured previously ing treatment with insulin, as previously described.3 16 in samples obtained at baseline and after 16 weeks oftreatment.12 To investigate the stability of the assay procedures, we compared the previously obtainedvalues with values obtained for the present investiga- The HOME trial was conducted in the outpatient tion. The correlation between old and new measure- clinics of three non-academic hospitals in the Nether- ments of vitamin B-12 was 0.58 for baseline lands: Bethesda General Hospital, Hoogeveen; measurements and 0.91 for measurements taken after Diaconessen Hospital, Meppel; and Aleida Kramer 16 weeks; for folate these values were 0.90 and 0.83, respectively, and for homocysteine 0.99 and 0.99, assigned by a computer program to receive either respectively. The relatively low correlation for vitamin 850 mg of metformin three times a day or 850 mg of B-12 values obtained at baseline was caused by five placebo thrice daily, which were provided in identical cases for which a large discrepancy existed between old and new values; these cases were subsequently The trial consisted of three phases: the 12 week excluded from analyses involving vitamin B-12.
pre-randomisation phase, in which patients were trea-ted with insulin only and concomitant medication was discontinued; the 16 week short term treatment phase, Sample size calculations were based on expected dif- at the beginning of which patients were randomised to ferences in the occurrence of disease related end receive either metformin or placebo in addition to points, as described previously.3 With the sample size insulin therapy; and the four year (48 month) long obtained, however, a decrease in vitamin B-12 concen- term treatment phase (fig 1). An interim analysis was tration of 5% in the metformin group compared with conducted at the end of the short term treatment phase, the placebo group according ANCOVA tests should during which the treatment codes were not disclosed to be detectable at a two sided 95% confidence level,with a power of 0.82.
We log transformed data on vitamin B-12, folate, and homocysteine concentrations before analysis because their distribution was skewed. Data are given Patients visited the clinics at the start of the pre-rando- as geometric means with 95% confidence intervals.
misation phase (three months before randomisation), at Given that log values are not directly interpretable, baseline (for randomisation to metformin or placebo), the antilogs are reported instead. These values are the and one month after baseline (to check the tolerance of geometric mean percentage change from baseline.
the drug titration), then subsequently every three The end point of interest was the percentage change months until the end of the trial. During these visits, a of each variable from baseline at 4, 17, 30, 43, and physical examination was carried out, a medical history 52 months, which was calculated from baseline values was taken, and laboratory investigations were per- and the summary mean. The differences between the formed. At baseline, and after 10 and 52 months, dietary metformin and the placebo group were tested by a cen- counselling was given to all patients.
tral t test on log transformed values. We also calculated more extensively elsewhere.3 Only two participants were lost to follow-up (at 33 and 26 months, respec-tively), both of whom were in the metformin group.
Excluded (n=355)Did not give informed consent The actual mean dose in the metformin group was 2050 mg a day. At the final visit, laboratory samples were available for 256 patients (127 metformin, 129placebo). The main outcomes of this trial have beenreported previously.3 Table 1 shows baseline characteristics of all patients analysed. Five randomised patients were excluded from the analysis because of poor correlations between old and newly measured vitamin B-12 values (see Methods). Patients randomised to metformin were older than those randomised to placebo (64±10 years v 59±11 years), and were more likely to have a history of cardiovascular disease and less likely to be a smoker(30 (19%) v 59 (30%)). The other characteristics were comparable between the two treatment groups.
Vitamin B-12, folate, and homocysteine concentrationsDuring the 52 months of placebo treatment, vitamin B-12 concentration increased from baseline by 0.2 pmol/ the hazard ratio for developing vitamin B-12 defi- l (0% change, 95% confidence interval −3% to 4%), ciency, which was defined as a vitamin B-12 concentra- folate increased by 1.01 nmol/l (8%, 95% CI 4% to tion below the value of 150 pmol/l, and of having low 12%), and homocysteine increased by 1.60 μmol/l vitamin B-12 levels, which was defined as a vitamin B- (20%, 95% CI 16% to 25%; fig 3). During metformin 12 concentration below 220 pmol/l but above 150 treatment, vitamin B-12 decreased by 89.8 pmol/l pmol/l.17 All analyses were by intention to treat and (−19%, 95% CI −22% to −15%) from baseline, whereas used the last observation carried forward. To test folate concentration increased by 0.21 nmol/l (3%, whether results obtained were robust, we also used 95% CI −1% to 6%) and homocysteine concentration mixed models analysis to impute missing data. Patients increased by 3.26 μmol/l (26%, 95% CI 21% to 31%).
with vitamin B-12 concentrations below 150 pmol/l at Compared with placebo, metformin treatment was baseline, at the interim analysis, or at both time points associated with a 19% decrease in vitamin B-12 con- were supplemented at 16 weeks (n=8) and, therefore, centration (95% CI −24% to −14%; P<0.001) and a5% decrease in folate concentration (95% CI −10% to excluded from analyses after 16 weeks.
−0.4%; P=0.033), and a 5% increase in homocysteine We used linear mixed models to explore the effects concentrations (95% CI −1% to 11%; P=0.091). The of metformin on concentrations of vitamin B-12, folate, effects of metformin on concentrations of vitamin B- and homocysteine. We also investigated whether met- 12, folate, and homocysteine were re-analysed follow- formin associated changes in homocysteine concentra- ing adjustment for age, previous metformin treatment, tions, if any, could be explained by changes in the duration of diabetes, gender, insulin dose, and smok- concentrations of folate, vitamin B-12, or both, and, if ing habits. None of these variables materially changed so, whether the changes were independent of age, gen- the results for vitamin B-12 and homocysteine (data der, duration of diabetes, smoking, body mass index, not shown), but they did have an effect on the results insulin dose, serum creatinine, high density lipopro- for folate. After adjustment for body mass index and tein cholesterol, or glycated haemoglobin. The good- smoking, no significant effect of metformin on folate ness of fit between alternative models was compared concentration was found (change in concentration using the maximum likelihood technique.
compared with placebo −0.1%; P=0.57).
At baseline, three patients (1.6%) in the metformin group and four (2.2%) in the placebo group had vita- min B-12 deficiency (vitamin B-12 concentration We screened the medical files of all three participating <150 pmol/l), whereas 14 patients (7.3%) and 14 outpatient clinics and identified 745 eligible patients.
patients (7.5%), respectively, had a low vitamin B-12 All were approached to enrol into the trial and 390 concentration (150-220 pmol/l). At the end of the individuals gave written informed consent. A total of study period, 19 patients (9.9%) in the metformin 196 patients were randomised to receive metformin group and five (2.7%) in the placebo group had vita- and 194 to receive placebo. Out of the 390 included min B-12 deficiency, whereas 35 patients (18.2%) and patients, 277 individuals (72%) were still receiving met- 13 patients (7.0%), respectively, had a low vitamin formin or placebo at the end of the trial (fig 2). A total of 46 patients (30 metformin, 16 placebo) discontinued The risk for vitamin B-12 deficiency at study end was because of adverse effects, which have been described 7.2 percentage points higher in the metformin group Table 1 | Baseline characteristics of all patients analysed The interaction between treatment and time was a sig- nificant determinant of vitamin B-12 concentration (P=0.023)—that is, the lowering effect of metformin on vitamin B-12 concentrations increased with time.
Body mass index and smoking were strong inverse determinants of folate concentration (P=0.003 and P<0.0001, respectively). There was no relation between time and folate concentration. After adjust- ment for body mass index and smoking, treatment with metformin was not a significant determinant of folate concentration, nor was the interaction between treatment and time (P=0.57 and P=0.23, respectively).
Vitamin B-12 and folate levels were strong determi- nants of homocysteine concentration (P<0.0001).
Homocysteine concentration increased with age at baseline (P<0.0001). There was no significant inter- action between treatment and time for homocysteine Per protocol analysis using only available data for those patients who remained in the trial until the final visit Low density lipoprotein cholesterol (mmol/l) (n=256) yielded similar results to our original intention to treat analysis (data not shown). General mixed High density lipoprotein cholesterol (mmol/l) model analysis yielded similar results to analysis using last observation carried forward (data not shown).
Our study on the long term effects of metformin treat- ment on serum concentrations of vitamin B-12, folate, and homocysteine in patients with type 2 diabetes trea- ted with insulin had three main findings. Firstly, met- formin significantly reduced concentrations of vitamin Values are mean (standard deviation) unless otherwise stated.
B-12, in accordance with findings from previousstudies.131819 Importantly, our study shows that thisdecrease is not a transitory phenomenon, but persists than in the placebo group (95% CI 2.3 to 12.1; and grows over time. Secondly, a small, significant P=0.004), with a number needed to harm of 13.8 per 4.
decrease in folate concentrations was found in the met- 3 years (95% CI 43.5 to 8.3). The risk difference at formin group compared with the placebo group; how- study end for a low vitamin B-12 concentration was ever, this reduction was not statistically significant after 11.2 percentage points higher in the metformin group adjustments for body mass index and smoking.
(95% CI 4.6 to 17.9; P=0.001), with a number needed Thirdly, the decrease in vitamin B-12 concentrations to harm of 8.9 per 4.3 years (95% CI 21.7 to 5.6). The was associated with an increase in homocysteine levels, hazard ratio for developing vitamin B-12 deficiency which was not statistically significant. Further analyses, when treated with metformin was 5.5 (95% CI 1.6 to however, showed that homocysteine concentrations 19.1; P=0.01), and the hazard ratio for a low vitamin B- did increase in individuals in whom vitamin B-12 levels 12 concentration was 3.0 (95% CI 1.3 to 6.6; P=0.007).
decreased below the concentration generally consid- Patients with a vitamin B-12 deficiency at the end of ered to indicate clinical deficiency—that is, 150 pmol/l.
the study had a mean homocysteine level at study end The finding of decreases in vitamin B-12 concentra- of 23.7 µmol/l (95% CI 18.8 to 30.0 µmol/l), compared tion during metformin treatment is not novel and has with 18.1 µmol/l (95% CI 16.7 to 19.6 µmol/l; been reported before. A novel finding here, however, P=0.003) for patients with a low vitamin B-12 concen- is that the decrease in vitamin B-12 levels is progres- tration and 14.9 µmol/l (95% CI 14.3 to 15.5 µmol/l; sive. Furthermore, concentrations in some patients P<0.001 compared with vitamin B-12 deficiency; drop to the level at which most authorities agree vita- P=0.005 compared with low vitamin B-12) for patients min substitution is required. This is also a novel find- with a normal vitamin B-12 level (>220 pmol/l; fig 4).
ing, because although earlier trials in well fed, middle Homocysteine concentrations did not differ signifi- aged patients showed that metformin decreases vita- cantly between treatment groups when stratified for min B-12 concentrations, levels recorded remained end of treatment vitamin B-12 concentration.
Metformin is thought to induce malabsorption of vitamin B-12 and intrinsic factor in the ileum, an effect that can be reversed by increasing calcium intake.618 The consequences of clinically important decreases invitamin B-12 concentrations—such as macrocytic anaemia, neuropathy, and mental changes—can be profound. We note that there is no consensus on the issue of whether “asymptomatic” vitamin B-12 defi-ciency should be treated.20 However, studies show that some symptoms of vitamin B-12 deficiency are dif- ficult to diagnose and can be irreversible, and treatment of vitamin B-12 deficiency is relatively easy, cheap, safe, and effective,21-24 in effect arguing in favour of treatment. In addition, although the necessity of treat- ing “spontaneous” vitamin B-12 deficiency may be debated, one should be more easily inclined to treatdrug induced vitamin B-12 deficiency, as a key princi- ple of drug prescription is to do no harm. On the otherhand, our study shows that it is reasonable to assume harm will eventually occur in some patients with met- formin induced low concentrations of vitamin B-12.
Folate concentration increased in both the metfor- min group and the placebo group, possibly as a result of dietary counselling received by all patients through-out the trial. Our short term interim analysis showed a significantly larger increase in folate concentration in the placebo group,12 a finding that was initially repli- cated in the current analysis but that disappeared after adjustment for body mass index and smoking.
Previous studies have shown either no or small effects of metformin treatment on concentrations of homocysteine.13 14 25 26 We clearly show that homocys- teine concentrations do increase with decreasing levels of vitamin B-12 (fig 4). The finding that metformintreatment significantly lowered concentrations of vita- min B-12 but did not significantly alter levels of homo- cysteine probably reflects the relatively low incidence of vitamin B-12 deficiency in the entire study popula- tion. As treatment with metformin continues, however, we expect that vitamin B-12 levels will continue to decrease, making increases in homocysteine concen-trations inevitable in time.
Strengths of our study include the randomised, pla- Number of available samplesMetformin group cebo controlled, double blind design and its relatively long follow-up of 4.3 years, as well as frequent serum collection. Furthermore, the study was conducted in a non-academic setting and, therefore, the findings have Fig 3 | Concentrations of vitamin B-12, folate, and homocysteine with 95% confidence intervals. Solid lines Another strength is that we used last observation car- represent the metformin group, dotted lines the placebo ried forward in this analysis because this method is con- group. Number of available samples for the metformin and sidered more conservative than general mixed model placebo group is indicated. Five patients were excluded from analysis, “freezing” any observed divergence between the analysis because of poor correlations between old and two groups by retaining the last observation made. In a newly measured vitamin B-12 values (see Methods). In mixed model analysis with missing data, estimations of addition, some patients had vitamin B-12 levels below 150pmol/l at baseline, at interim analysis, or at both stages, and future observations are made on the basis of observa- were supplemented; these individuals were also excluded.
tions made earlier in the trial, thereby reflecting adivergence more accurately but less conservatively.
Limitations of our study include the fact that we mea- sured only total vitamin B-12 levels and not levels of treated with metformin had a seven percentage pointgreater absolute risk of vitamin B-12 deficiency than those treated with placebo during 4.3 years of follow- up. In addition, the reduction in vitamin B-12 concen- tration associated with metformin increased with time.
Current guidelines indicate that metformin is a cor- nerstone in the treatment of type 2 diabetes, but make no recommendations on the detection and preventionof vitamin B-12 deficiency during treatment. Our data provide a strong case for routine assessment of vitaminB-12 levels during long term treatment with metformin.
Contributors: AK, AJMD, and CDAS are responsible for the study concept and design. JdJ, AK, MGW, and DB collected the data, and statisticalanalysis was conducted by PL and JdJ. JdJ, AK, PL, and CDAS undertook Fig 4 | Homocysteine concentrations with 95% confidence analysis and interpretation of the data. JdJ, AK, and CDAS drafted the intervals for patients with a normal vitamin B-12 manuscript, and AK, AJMD, and CDAS undertook critical revisions of themanuscript for important intellectual content. Administrative, technical or concentration (>220 pmol/l), a low vitamin B-12 concentration material support was provided by JvdK, DB, JV, MGW, JdJ, and AK. JdJ, AK, (150-220 pmol/l), and vitamin B-12 deficiency (<150 pmol/l) and PL had full access to all of the data in the study and take responsibility after 4.3 years. The number of patients in each treatment for the integrity of the data and the accuracy of the data analysis. JdJ, AK, and CDAS accept full responsibility for the work and the conduct of thestudy, had access to the data, and controlled the decision to publish, and holotranscobalamin II or methylmalonic acid, which as such act as guarantors for the study.
Funding: Hyperinsulinaemia: the Outcome of its Metabolic Effects may have been more precise indicators of vitamin (HOME) trial was supported by grants from Altana, Lifescan, Merck Santé, B-12 status. Finally, it is likely that, if anything, we Merck Sharp & Dohme, and Novo Nordisk. The sponsors had no role in the underestimated the impact of metformin treatment on design and conduct of the study; in the collection, analysis, and the risk of clinically important vitamin B-12 deficiency.
interpretation of the data; or in the preparation, review, or approval of themanuscript.
We showed that metformin treatment was associated Competing interests: All authors have completed the Unified Competing not only with a raised risk of developing vitamin B-12 Interest form at (available on request concentrations below 150 pmol/l but also with an ele- from the corresponding author) and all authors want to declare: (1) vated risk of developing vitamin B-12 levels between Financial support for the submitted work from Merck Sharp & Dohme. All 150 and 220 pmol/l, which is likely to represent clini- authors also declare: (2) No financial relationships with commercialentities that might have an interest in the submitted work; (3) No cally important vitamin B-12 deficiency in at least some spouses, partners, or children with relationships with commercial entities individuals.27 A further reason that we may have some- that might have an interest in the submitted work; and (4) No non- what underestimated the adverse effects of metformin financial interests that may be relevant to the submitted work.
is that all participants in our trial received frequent diet- Ethical approval: The medical ethical committees of the threeparticipating hospitals approved the trial protocol. The trial has been ary counselling, which may have attenuated the impact conducted in accordance with the Committee for Medicinal Products for of metformin treatment on vitamin status and may not Human Use note for guidance on good clinical practice (CPMP/ICH/135/ be available in routine clinical practice.
95), dated 17 July 1996, and in accordance with the Declaration of Helsinki(revised version of Hong Kong in 1989 and Edinburgh in 2000). Allpatients gave written informed consent.
Data sharing: No additional data available.
In conclusion, we showed that in patients with type 2diabetes being treated with insulin, those additionally Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. AnnIntern Med 2002;137:25-33.
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Efficacy of metformin in patients with non-insulin-dependent Few and only short term data exist on the effect of metformin treatment on vitamin B-12, diabetes mellitus. N Engl J Med 1995;333:541-9.
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Increased intake of calcium reverses vitamin B12 malabsorptioninduced by metformin. Diabetes Care 2000;23:1227-31.
Ting RZ-W, Szeto CC, Chan MH-M, Ma KK, Chow KM. Risk factors ofvitamin B12 deficiency in patients receiving metformin. Arch Intern Long term treatment with metformin in patients with type 2 diabetes receiving insulin increases the risk of vitamin B-12 deficiency, which results in higher levels of homocysteine Carlsen SM, Folling I, Grill V, Bjerve KS, Schneede J, Refsum H.
Metformin increases total serum homocysteine levels in non- The negative effect of metformin on vitamin B-12 concentrations increases over time diabetic male patients with coronary heart disease. Scand J Clin Lab Our data provide a strong case for routine assessment of vitamin B-12 levels during long term Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 18 Adams JF, Clark JS, Ireland JT, Kesson CM, Watson WS. Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide 10 Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients 19 Tomkin GH, Hadden DR, Weaver JA, Montgomery DA. Vitamin-B12 with coronary artery disease. N Engl J Med 1997;337:230-6.
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9b infectolab co-infektionen engl 01.07.1

BCA-clinic Betriebs GmbH & Co. KG Dr. med. Armin Schwarzbach Facharzt für Labormedizin Increasing importance of co-infections for Lyme disease patients – with or instead of a Lyme disease infection An article by Armin Schwarzbach,M.D., PhD., laboratory medicine specialist In the past months presentations of scientific conferences have shown a noticeable increase of the importa


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