Recipient Organization
UNIV OF CONNECTICUT
438 WHITNEY RD EXTENSION UNIT 1133
STORRS,CT 06269
Performing Department
Kinesiology
Non Technical Summary
Hydroxy-methyl-glutaryl Coenzyme A reductase inhibitors (statins) are among the most effective drugs for reducing low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) morbidity and mortality. Despite their potency and cost-effectiveness, statins are underutilized, with 50% of high-risk statin-eligible patients currently untreated and adherence rates as low as 30-40% after the first year of treatment. Seventy five percent of statin users with poor statin adherence and discontinuation report the reason for their intolerance as statin-associated muscle symptoms (SAMS) which encompass a range of symptoms including muscle aching, pain and stiffness. Pharmacological treatments for SAMS are very limited, with data from randomized clinical trials inconclusive as to the effectiveness of any treatment. Curcumin is a natural dietary polyphenol with a range of pharmacological properties that produce antioxidant, anti-inflammatory and analgesic effects. Curcumin supplementation reduces muscle damage, atrophy and pain associated with osteoarthritis, rheumatoid arthritis, acute injury, and fibromyalgia. Notably, it is also a cost-effective, over-the-counter supplement that can improve the blood lipid profile by lowering LDL-C and raising high-density lipoprotein cholesterol (HDL-C). This project addresses CAHNR/ NIFA priorities for augmenting Food Safety, Nutrition and Health in several ways. First, the antioxidant, anti-proliferative, anti-inflammatory, neuroprotective, anti-cancer and anti-diabetic properties of curcumin have supported its therapeutic potential for the treatment of multiple chronic diseases. These potential health benefits make it particularly efficacious for improving statin adherence in patients most likely to experience SAMS, who are those patients with CV risk factors or established disease. Second, curcumin is a safe and efficacious nutraceutical that could prove a more economically, agriculturally, and environmentally sustainable alternative to standard pharmaceutical treatments for certain diseases and health conditions. Indeed, turmeric can be grown in a variety of agricultural settings, indoors and outdoors, with no major known disease or pest issues and a growing season of 120-360 days, and curcumin when ingested as turmeric is equally efficacious for nutritional bioactivity. Third, the burden of poor statin adherence increases per-patient medical expenditures by an estimated $1000-$3000/year, a cost that is born by public and private insurers and employers. At the average cost of 25 cents/pill or $150 for a yearly supply, curcumin is a cost-effective solution that can be produced by CT-based agriculture and thus is worthy of exploring.
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Goals / Objectives
In this study we seek to test the effectiveness of curcumin for treating SAMS by recruiting 40 patients with SAMS to randomize to treatment with 1g curcumin/day or placebo (with statin) for 8 weeks as a first step in establishing efficacy of curcumin for SAMS. We will test:a) As a primary hypothesis: Curcumin treatment will reduce SAMS (measured by symptom presence and severity) relative to placebo treatment.b) As a secondary hypothesis: Patients treated with combined curcumin and statin therapy will also exhibit lower LDL-C relative to those treated with placebo and statin.c) As a secondary hypothesis: Curcumin will improve muscle oxygenation during handgrip exercise (an index of mitochondrial function that we have demonstrated is blunted in patients with SAMS) relative to placebo treatment in patients with SAMS. We hypothesize that curcumin will reduce SAMS, as measured by symptom severity and muscle oxygenation, and that patients using statins and curcumin will also demonstrate an improved blood lipid profile relative to the placebo group. Should our hypotheses be supported, this common nutraceutical may hold promise for improving statin adherence and ultimately reducing the burden of preventable CVD events.
Project Methods
The below methods outlines the full 3 year project that is detailed in the attached proposal. However, this project initiation is being submitted for year one of the project. During the first year of this project a graduate research assistant will be recruited and being training, the IRB will be developed and submitted for review and approval and the study procedures will be developed as described. Study Participants: We will recruit equal numbers of men and women ≥40 yrs of age, since older age is a risk factor for SAMSand 25% of U.S. adults ≥40 yrs report statin use.We will not exclude individuals with diagnosed coronary artery disease, peripheral vascular disease, or an elevated CK off treatment<10 upper normal limit (UNL) because spontaneous elevations in CK levels are normal in the general population. Participants will not be asked to discontinue other non-statin lipid lowering drugs, but we will exclude patients who: are treated with other medications known to alter statin metabolism or muscle performance; have diagnosed hypo- or hyperthyroidism, hepatic or renal dysfunction; have physical disabilities prohibiting the handgrip protocol; or are pregnant or trying to become pregnant.Study Visits: At the beginning of the study, while participants are on statin only, participants will undergo a visit consisting of a comprehensive health and medical history, administration of the Brief Pain Inventory questionnaire and a physical activity questionnaire (since change in physical activity can impact muscle symptoms), handgrip strength testing, muscle oxygenation testing, and a blood draw. This visit will take approximately one hour. The participant will be fasted for 8-12 hours prior to this visit. This visit will be repeated after the participant has been treated with curcumin or placebo for two months. Participants will be reimbursed $50 for their time at the end of the study. Participants who drop out will be reimbursed $25 for the visit they have completed.Blinding Procedures: Dr. White will generate the study randomization code. Approximately 40 patients with prior reported SAMS will be randomized to curcumin vs. placebo in alternating, balanced order. Dr. White will generate a study log-in sheet where recruited patients will be enrolled, logged in, and their study number assigned. This number will correspond to study drug prescription dispensed by Dr. White or his pharmacy fellow. After each vial is dispensed to the patient, the date of drug release will be recorded. Dr. White will maintain dual copies of the randomization code and will be available via cellphone 24 hours seven days a week. Patients will be unblinded if their physician or study physician deems it necessary. The entire study will be unblinded once the last participant has completed the protocol.Drug and Placebo Formulation: OmnibActive Health Technologies (Morristown, NJ) has agreed to provide identical curcumin (CurcuWIN) and placebo at no cost for the current project. We chose the CurcuWIN formulation because in a comprehensive pharmacokinetic assessment, it provided superior achievement of maximum blood curcumin and total curcuminoid concentrations as well as total systemic exposure to curcumin and total curcuminoids over time.Compared to the standard curcumin extract, the CurcuWIN formulation had 136.3 times the curcumin bioavailability and 45.9 times total curcuminoid bioavailability. While the Phytosome formulation of curcumin at 5g/day was specifically studied in DOMS,the CurcuWIN formulation has 10.7 times the curcumin bioavailability and 5.8 times the total curcuminoid bioavailability, leading us to use a dose of 1g/day (irrespective of body weight) which is equivalent to higher doses used in previous studies(and thus more cost-effective).Medication Compliance Assessment: We will use similar methodology as our previous studies.Patients will be instructed to take two study pills (and statin) every day and to take the pills the next day before noon if they miss a day. On the weekly phone calls, participants will be asked about any medication changes or problems and the approximate number of pills they have missed over the prior week. In addition, they will be asked to return their unused medication after the study and pills will be counted to calculate compliance (%).Muscle Oxygenation to Handgrip Exercise: Skeletal muscle tissue oxygenation will be measuredwith a near-infrared spectroscopy (NIRS) system (PortaMon MKII, Artinis Medical Systems, PW Elst, The Netherlands). This system is based on an infrared light absorption method, where the infrared light is emitted at different wavelengths. The probe will be positioned longitudinally on the forearm and secured with velcro straps around the dominant upper arm. Measurements will be made of probe placement relative to the humerus, elbow, radius and ulna and recorded to ensure uniform probe placement in each participant throughout the study. Preceding each NIRS test, the maximal voluntary contraction (MVC) will be determined in the dominant arm using a digital handgrip dynamometer (Zonaplus, Boise, ID). After the placement of the NIRS probe on the muscles, a pneumatic cuff (Hokanson Medical Electronics; Bellevue, WA) will be placed around the ipsilateral upper arm. The participant will perform the complete exercise protocol in supine position. The protocol begins with a forearm arterial occlusion by inflating the cuff to 260 mmHg until a steady state in deoxy[Hb+Mb] is reached. After the occlusion, there is a minimum 5 min rest period before baseline conditions are reached again and then the incremental handgrip task is initiated. This task consists of 2 min periods during which incremental cyclic contractions are performed at the rate of ½ Hz (1 s contraction, 1 s relaxation) at increasing percent of MVC with contraction periods separated by a 60 s rest period. The work intensity is initiated at 20% MVC and increased by 10% MVC at each step. This protocol continues until exhaustion is reached (typically < 5 steps) and force cannot be maintained. To determine the mean values within the protocol, a smoothing procedure will be performed in which the 10s mean values are determined by means of a moving average. Since NIRS is a relative measure that depends on the individual characteristics of the skeletal muscle and vasculature, the amplitude of the deoxy[Hb+Mb] response during arterial occlusion is used as an index for each patient's maximal O2 extraction and is set at 100%. The changes in deoxy[Hb+Mb] during each work step are expressed relative to this amplitude.Muscle Pain: The Brief Pain Inventory (Short Form) (BPI-SF) will be used to measure the location(s) and intensity of participants' muscle pain, as well as the extent to which the muscle pain interferes with daily functioning. Pain severity and pain interference scores will be calculated as in our previous studies.Serologic Markers: Blood samples will be obtained using standard venipuncture techniques at each visit. Whole blood will be centrifuged, serum separated, and samples will be stored at -80°C until analyzed. Serum samples will be analyzed at the end of the study in order to maintain blinding of treatments and to minimize variability. Serum CK as well as total, HDL-C, LDL-C and triglycerides will be measured by standard assay at Quest Diagnostics at Hartford Hospital.