Acetyl-L-Carnitine for Diabetic Acetyl-L-Carnitine for Diabetic NeuropathyNeuropathy

Shaun Cole, MD , MPH

Patrick Smithedajkul, MD

CDMJC

February 18, 2011

Department of Internal Medicine

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”

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

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

LaboratoryLaboratory

139

4.3

x

x

17

0.8

14.5

41.8

282 7.8

HbA1c – 6.9%

Glucose (fasting) - 118

TC 158, Triglycerides 85, HDL 65, LDL 76

Background- CarnitineBackground- Carnitine

• Highest concentrations found in red meat and dairy• Derived from lysine and methionine• Transports long-chain fatty acids into mitochondria

Popular UsesPopular Uses

• Heart conditions• Diabetics• Kidney Disease• Male infertility• Weight loss supplement• Neuropathy

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!

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

SearchSearch

Mesh: Acetylcarnitine AND Diabetic neuropathy

Limits: Humans, Meta-Analysis, RCT, English

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.”

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)

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

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

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)

EndpointsEndpoints• Primary

– Pain• As assessed by a 10 cm-long visual analogue scale• Performed on 342 patients (26.7%)

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

EBM Pearl EBM 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

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”

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)

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

ResultsResults

How large was the treatment effect?Not enough data to calculate number needed to treat

ResultsResults

Effect size of ALC treatment on pain as a function of DM duration. The data represent the pooled cohort.

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

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

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

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?

CostCostDose 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

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

QuestionQuestionDo 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!

PlanPlan

• Allow the patient to try ALC – Cost advantage

• Diabetes Educators as needed• Continue tight glycemic control

Questions?Questions?