Efficacy of glucosamine plus diacerein versus monotherapy of glucosamine: a double-blind, parallel randomized clinical trial

The study did not provide any strong evidence that coadministration of diacerein with patented crystalline glucosamine sulfate (pCGS) improves pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score compared with pCGS monotherapy in patients with mild to moderate osteoarthritis (OA) of the knee.

Osteoarthritis is one of the most common disease affecting joints. The incidence of OA in developed countries is expected to increase at much faster rate in upcoming years due to a significant increase in obesity and longevity these days. According to the latest research, more than 40% of the individuals above 65 years of age are known have knee or hip OA. There is currently no known cure for OA and apart from joint replacement surgery, there is no known treatment that can suspend the development of the disease. The first line therapy for OA includes non-steroidal anti-inflammatory drugs (NSAIDs). These are widely prescribed, but its benefits come along with some adverse effects like an increased risk of cardiovascular events. This is the reason that we require therapeutic agents which offer better safety profile and also delays the further progression of the disease. Patented crystalline glucosamine sulfate and diacerein are usually used for the treatment of symptomatic mild to moderate knee OA to relieve joint pain and delay joint destruction and cartilage loss. Earlier, pCGS was prescribed for OA in Europe and Asia, but has now been sold as over the counter product in the U.S. and Australia. The efficacy of pCGS and diacerein have been previously investigated and results of these investigations had suggested that diacerein is a better option than glucosamine for reducing pain, but both hold almost similar efficacy in improving the joint function. It is expected that the combination of pCGS and diacerein will produce synergistic effects, but till date, none of the trials has directly compared the effect of combination of these drugs.

Rationale behind research:

• pCGS and diacerein monotherapy have been recommended for treatment of mild to moderate OA, but evidences of efficacy for combined treatments are lacking
• The present study was conducted to compare clinical outcomes (i.e., pain and WOMAC score) at 6 months as well as the safety profile of treatment with combined pCGS and diacerein versus pCGS alone

Objective:

The aim of this randomized clinical trial was to compare the clinical outcomes (i.e., pain and OA score) at 6 months as well as the safety profiles of treatment with combined pCGS and diacerein versus pCGS alone.

Study outcomes:

Primary outcomes: Primary outcomes were the pain score measured at 24 weeks using a VAS (ranging from 0 to 10, where higher score indicates greater pain) and the OA score measured at 24 weeks using the Thai version of the WOMAC. The WOMAC consists of 3 domains and 22 items comprising pain (5 items), function (15 items), and stiffness (2 items). Each item was graded from 0 to 10, with higher scores indicating more severe symptoms. Total and subdomain scores were calculated by summation of scores for relevant items. The total scores range from 0 to 220, where higher scores indicate more severe OA.

Secondary outcomes: Secondary outcomes were the WOMAC subscores for pain, function, stiffness, and joint space width (JSW), which is defined as the distance from the distal femoral condyle to the proximal tibia. It was measured by one orthopedist (JK) at 12 and 24 weeks after treatment. It was assessed using weight-bearing metatarsophalangeal radiography at baseline, 12 weeks, and 24 weeks, and determined by computer-generated measurements taken from digitized images. The WOMAC scores were measured by a well-trained research assistant using WOMAC questionnaires at baseline and weeks 4, 8, 12, 16, 20, and 24 after treatment.

Time points:

Primary outcomes: Baseline and 24 weeks

Secondary outcomes: Baseline, 12 and 24 weeks

Outcomes

Baseline: There was not much differences in the baseline chracterstics between the two groups.

Primary Outcomes:

VAS pain score: VAS scores at 24 weeks were 2.97 and 2.88 in the pCGS plus diacerein and glucosamine plus placebo groups. This indicated no significant difference between the two groups, with an estimated mean difference of 0.09. Post hoc analysis was performed in a subgroup of patients whose VAS pain scores at baseline were 5 or higher. The overall mean VAS scores were 6.72±1.69 and 6.92±1.56 in the combined treatment and monotherapy groups, respectively, but there was no statistically significant difference (P=0.607).

WOMAC total score: WOMAC total scores at 24 weeks were 48.59 and 48.69 in the pCGS plus diacerein and glucosamine plus placebo groups. This indicated no significant difference between the two groups, with an estimated mean difference of −0.1.

Secondary Outcomes:

WOMAC Pain Score: WOMAC pain scores at 24 weeks were 12.02 and 11.76 in the pCGS plus diacerein and glucosamine plus placebo groups. This indicated no significant difference between the two groups, with an estimated mean difference of 0.26.

WOMAC stiffness score: WOMAC stiffness scores at 24 weeks were 3.85 and 4.16 in the pCGS plus diacerein and glucosamine plus placebo groups. This indicated no significant difference between the two groups, with an estimated mean difference of −0.32 .

WOMAC function score: WOMAC function scores at 24 weeks wer 32.74 and 32.74 in the pCGS plus diacerein and glucosamine plus placebo groups. This indicated no significant difference between the two groups, with an estimated mean difference of 0.01.

Minimal joint space width: JSWs at 24 weeks was 2.63 mm and 2.59 mm in the pCGS plus diacerein and glucosamine plus placebo groups. This indicated no significant difference between the two groups, with an estimated mean difference of 0.04 mm.

The study failed to demonstrate that the coadministration of diacerein with pCGS improves pain and WOMAC scores compared with pCGS monotherapy in patients with mild to moderate OA with Kellgren-Lawrence grade 2–3. The findings suggests that this combination treatment does not reduce VAS pain score, WOMAC total score, or WOMAC subscores as compared with pCGS monotherapy in patients with mild to moderate knee OA. Although the efficacy in both treatment groups did not differ, clinical signs and symptoms were improved in both the treatment groups at 12–24 weeks, and this was particularly evident in the pCGS plus placebo group.

In a recent animal study, researchers found chondroprotective effects of diacerein and pCGS, but a better range of motion of the knee joint was found in response to diacerein than to pCGS. With the different mechanisms of action of pCGS and diacerein, it could be expected that combined treatments should result in synergetic effects. The findings of the current study are similar to those of a previous study in which researchers compared combined pCGS plus chondroitin sulfate with pCGS or chondroitin sulfate alone in patients with OA of the knee whose KellgrenLawrence grade was 2–3. That study was later combined in a network meta-analysis, which showed similar results. Although the potential synergistic effects derived from a pharmacologic study of pCGS and diacerein looked promising, the findings of current study indicate that combination treatments did not provide any benefit over monotherapy.