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Shaun Cole Mayo Journal Club
- 1. Acetyl-L-Carnitine for DiabeticAcetyl-L-Carnitine for Diabetic NeuropathyNeuropathy Shaun Cole, MD , MPH Patrick Smithedajkul, MD CDMJC February 18, 2011 Department of Internal Medicine
- 2. HistoryHistory • PMH – DM2 w/o retinopathy – HTN – CAD – Hyperlipidemia • NKDA • Social History – Former smoker – No alcohol • ROS – Burning sensation of feet 80 yo gentleman with a history of DMT2 “My nephew says I can take this supplement for my foot pain”
- 3. HistoryHistory • Medications – Lisinopril 2.5 mg daily – Bisoprolol/HCTZ 10/6.25 PO daily – Zocor 40 mg PO daily – Fish oil [Sea Omega 50] 1 capsule daily – Aspirin 81 mg PO QHS – Metformin 500 mg daily – Vitamin C 500 mg daily – Toprol XL 100 mg daily – Norvasc 5 mg daily
- 4. Physical ExamPhysical Exam • Vitals – 83.0 kg, T = 36.7 C – BP 114/78, HR 74 – BMI = 26 • General – NAD • HEENT – PERRLA, MMM • Lungs – CTA • CV – RRR. S1, S2. No S3, S4. – 2/6 SEM, No bruits • Abd – +BS. Soft / NT / ND • Neuro – CN II-XII intact – Diminished LE reflexes – Decreased distal LE vibratory sensation, R = L • Extremities – Nonerythematous with mild edema
- 5. LaboratoryLaboratory 139 4.3 x x 17 0.8 14.5 41.8 2827.8 HbA1c – 6.9% Glucose (fasting) - 118 TC 158, Triglycerides 85, HDL 65, LDL 76
- 6. Background- CarnitineBackground- Carnitine • Highest concentrations found in red meat and dairy • Derived from lysine and methionine • Transports long-chain fatty acids into mitochondria
- 7. Popular UsesPopular Uses • Heart conditions • Diabetics • Kidney Disease • Male infertility • Weight loss supplement • Neuropathy
- 8. QuestionQuestion Do you take a lesson from the nephew and recommend ALC? 1. Start Neurontin alone 2. Start Neurontin and recommend ALC 3. Try ALC alone and hold off on the Neurontin 4. I have no idea, UptoDate time!
- 9. Clinical QuestionClinical Question • P: Patients with relatively well controlled Type 2 diabetes mellitus and mild diabetic neuropathy • I: Acetyl-L-Carnitine • C: Placebo • O: Symptomatic relief • T: Therapy • T: Randomized control trial
- 10. SearchSearch Mesh: Acetylcarnitine AND Diabetic neuropathy Limits: Humans, Meta-Analysis, RCT, English
- 11. ObjectiveObjective “We evaluated frozen databases from two 52- week randomized placebo-controlled clinical diabetic neuropathy trials testing two doses of Acetyl-L-Carnitine (ALC): 500 and 1,000 mg/day t.i.d.”
- 12. Study DesignStudy Design • 2 multicenter randomized, double-blind, placebo-controlled studies • Evaluated separately and combined • 1,257 participants analyzed • 28 US and Canadian centers (UCS) • 24 US, Canadian and European centers (UCES) • Sponsored by Sigma Tau Research – Manufacturer of Carnitor (levocarnitine)
- 13. Study DesignStudy Design • Inclusion Criteria – DPN – Men and nonpregnant women – Ages 18-70 y/o – DMT1 and DMT2 • Greater than 1 year • HbA1c >5.9% – Detectable sural nerve amplitudes • Exclusion Criteria – Other causes of PN – Significant neurological d/o – Alcohol abuse – Significant hepatic d/o – HIV – Malignant disease – Women of childbearing age without effective contraception
- 14. Similarity of Patient Prognosis? • Were the patients randomized? – Yes • Was the randomization concealed? – Not specified • Were patients similar with respect to prognostic factors? – Not specified, though the two study populations had baseline differences
- 15. DemographicsDemographics – No tables provided • Assuming similarity between control and experimental arms – UCS • Weight and BMI significantly greater (p<0.0001, 0.0004) – UCES • Duration of DM longer (P<0.0004) • More Type 1 DM (P<0.02)
- 16. EndpointsEndpoints • Primary – Pain • As assessed by a 10 cm-long visual analogue scale • Performed on 342 patients (26.7%)
- 17. EndpointsEndpoints • Secondary – Sural nerve morphometric studies • myelinated fiber number, mean fiber size, axon to myelin ratio, fiber density • density of regenerating clusters – Electrophysiological parameters • b/l sural nerve NCV and amplitude, peroneal NCV and amplitude – Vibratory threshold examinations
- 18. EBM PearlEBM Pearl ANOVAANOVA – Classic scenario • Two variables: 1 Categorical and 1 Quantitative • Main Question: Do the means of the quant. variable depend on which group (i.e. categorical variable) the individual is in? – From USMLE Prep • What classic test would we use if we only have 2 groups (categorical variables)? – 2 sample t-test – Now what if we want to assess 3 or more groups? • This is where we can use ANOVA
- 19. What does ANOVA do?What does ANOVA do? – In the most basic use ANOVA tests the following hypotheses: – H0 : The means of all the groups are equal – HA: Not all the means are equal • Does not say how or which ones differ • Can be followed up with “multiple comparisons”
- 20. ResultsResults • Nerve Biopsy Data – 500 mg ALC arm showed a significant increase in fiber numbers (P = 0.049) – Also a significant increase in regenerating clusters (P = 0.033) – 1,000 mg ALC arm numerically superior to placebo but not statistically different • Electrophysiological data – None of the NCV or amplitude measures showed significant changes in the 500 or 1,000 mg ALC groups • (combined cohort and individual study groups)
- 21. ResultsResults • Vibration perception threshold (UCS) – VP improved significantly in the fingers in both the 500 mg (P = 0.04) and 1,000 mg (P = 0.010) groups – VP improved in the toes in pts treated with 1,000 mg (P = 0.047) • Stratified Analysis – Greater reductions in VP threshold seen in the following subpopulations (UCS group only) • Age <55 years, BMI <30, T2DM and HbA1c <8.5
- 22. ResultsResults How large was the treatment effect? Not enough data to calculate number needed to treat
- 23. ResultsResults Effect size of ALC treatment on pain as a function of DM duration. The data represent the pooled cohort.
- 24. Adverse EventsAdverse Events • Adverse Effects – Most common • pain and paresthesia – Other events included cardiovascular and GI symptoms • details not provided – No patients had to withdraw from the study due to adverse events • No data to calculate a number needed to harm value
- 25. Further Validity AnalysisFurther Validity Analysis • Were all patients who entered the trial properly accounted for and attributed at its conclusion? – No • Were patients analyzed in the groups to which they were randomized? – ITT, yes?? 1,257 or 93% of enrolled patients • Were patients, health workers, and study personnel blinded? – Yes • Were there clearly identified comparison groups that were similar with respect to important determinants of outcome? – No statistics listed – Weight and BMI significantly different between two studies -When analyzed by region, Europeans had lower BMI, longer duration of diabetes, higher proportion of T1DM and included a higher proportion of Caucasians
- 26. Are the Results Valid?Are the Results Valid? • Were the outcomes and exposures measured in the same way in the groups being compared? – Yes • Was follow-up sufficiently long and complete? – Yes/No. 12 months limited time for outcome measures in nerve regrowth • Nerve growth notoriously slow • Is the temporal relationship correct? – Yes • Is there a dose response gradient? – Yes, except for the nerve biopsy data * MayoAccess v1.34
- 27. Back to the Patient…Back to the Patient… • Are the results applicable to my patient? – Somewhat… • Patient met most inclusion criteria for study – He was older than the upper limits of the study participants • Caucasian • Hb A1c greater than 5.9% • Were all clinically important outcomes considered? – Yes. • Are the likely treatment benefits worth potential harms / costs?
- 28. CostCost Dose Monthly Cost Acetyl-L-Carnitine 1000 mg TID $29 Neurontin 300 mg TID $207 3600 mg TID $2484 Carnitor 330 mg TID $255 990 mg TID $765
- 29. Study WeaknessesStudy Weaknesses • Did not grade the severity of DPN • No accounting for other DPN medications • Paper did not specify how pts were randomized, followed up or if concealment took place • Short trial period • Subgroups not predefined • Only 26% of pop for pain • Funded by Sigma-Tau
- 31. QuestionQuestion Do you take a lesson from the nephew and recommend ALC? 1. Start Neurontin alone 2. Start Neurontin and recommend ALC 3. Try ALC alone and hold off on the Neurontin 4. I still have no idea, UptoDate time!
- 32. PlanPlan • Allow the patient to try ALC – Cost advantage • Diabetes Educators as needed • Continue tight glycemic control
Editor's Notes
- Carnitine transports long-chain acyl groups from fatty acids into the mitochondrial matrix, so they can be broken down through β-oxidation to acetyl-CoA to obtain usable energy via the citric acid cycle.
- Unfortunately there was no algorithmic breakdown of the study populations regarding randomization, pts lost to follow up, etc
- Run in period for compliance?
- Differences became even more apparent when segregated by regions. Europeans were signifcantly lighter, longer duration of DM, higher proportion of DMT1 Differences between experimental and placebo arms not significant in both studies
- 26.7 percent reported pain as their most bothersome symptom To account for heterogeneity in the response data for pain VAS, a further analysis was performed with an approach using a mixture of linear models to account for such heterogeneities.
- Used O’brien rank sum testing and ANOVA
- O’Brien’s Test A nonparametric test procedure for assessing whether multiple outcomes in one group have consistently larger values than outcomes in a second treatment group. based on the rank of each individual variable among the combined observations from two samples Under the null hypothesis, the two MV samples have the same distribution.
- O’Brien’s Test A nonparametric test procedure for assessing whether multiple outcomes in one group have consistently larger values than outcomes in a second treatment group. based on the rank of each individual variable among the combined observations from two samples Under the null hypothesis, the two MV samples have the same distribution.
- Morphometric evaluations of sural nerve bxs revealed a significant increase in the Obrien rank score for all biopsy parameters in the 500 mg ALC arm N=245
- In the UCES group, no subpopulation showed significant reductions in vibration perception threshold. For stratified analysis, unclear whether this was predefined
- 27 percent of patients reported pain as the most bothersome symptom at baseline demographics and baseline characteristics of these pts did not differ from those of the entire population (data not shown). In subgroup analysis, the pts who showed the greatest benefit in pain reduction with 1 g after 52 weeks were those with type 2 DM (P= 0.55), adequate drug compliance ( P=0.01) and HbA1c &gt;8.5% (P=0.009) mixture of linear models approach yielded the same significant results.
- In the pooled studies, the responsiveness of pain to ALC treatment was inversely related to duration of diabetes
- short period- not allowing regenerating clusters to develop into mature myelinated fibers How could Mayo improve this study?