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

33. Questions?Questions?