Sulodexide for diabetic-induced disabilities: a systematic review and meta-analysis

Authors: Bignamini AA, Chebil A, Gambaro G, Matuška J.

Geographical coverage: Europe, Asia, North and South America and Africa

Sector: Biomedical

Sub-sector: Treatment

Equity focus: Not reported

Study population: Patients with diabetes

Review type: Effectiveness review

Quantitative synthesis method: Meta-analysis

Qualitative synthesis method: Narrative synthesis

Background: Diabetes mellitus (DM) is a leading cause of morbidities, including micro- and macro-vascular complications. These morbidities can lead to severe disabilities, as well as increase mortality rates among diabetic patients. The new antidiabetic agents (such as, glucagon-like peptide 1 receptor agonists (GLP1-RAs) and sodium-glucose cotransporter 2 (SGLT2)) are used increasingly in the treatment of diabetes and prevention of diabetic complications. However, there is still a need for more effective drugs, and sulodexide could be the one to fill this gap.

Objectives: To gather and summarise the available information on the effect of sulodexide on preventing and/or managing diabetic disabilities (for example, renal, ocular and peripheral vascular complications).

Main findings: The search identified 213 articles; 45 were included in this review, of which 26 were included in quantitative synthesis. Of the 45 included studies, four reported ocular complications, seven were on PAD or diabetes-associated trophic ulcers, and 34 were on diabetic nephropathy (DN). All patients were exposed to sulodexide, and 85% were having type 2 diabetes (T2D). Overall, 36% of studies were of high risk of bias, 24% were of low risk of bias and 40% were of medium risk of bias. The results of meta-analysis showed that sulodexide reduced the impact of diabetic retinopathy over 4-12 months, with treated patients experiencing a significant improvement compared with controls (odds ratio, [OR] 2.79, 95% confidence interval [CI] 1.16-6.74, p = 0.023). In addition, sulodexide increased the pain-free walking distance (+52 m, 95% CI 49-55, p<0.01), and maximal walking distance in peripheral arterial disease (+131 m, 95% CI 127-135, p<0.00) compared with controls. An accelerated healing of diabetes-associated trophic ulcers (average 27 days earlier, 95% CI 23-31, p<0.01); and decreased rate of albumin excretion (-1.07, -1.30 to -0.85) were also noted in subjects with nephropathy.

The review concluded that sulodexide is a useful and effective treatment for patients with type 1 (T1D) and T2D. The authors recommended further research to identify more effective treatments to prevent and manage complications of diabetes under real-life conditions.

Methodology: Searches were conducted in Medline, EMBASE, the Cochrane Central Register of Controlled Trials, and the World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal to identify all comparative and non-comparative trials assessing the efficacy of sulodexide in patients aged 13 years and over with T1D or T2D, in relation to the relevant complications affecting the eye, the peripheral circulation and the kidney. The search timeframe was restricted to include papers published up to 31 December 2019. The authors did not apply any language or publication date limits. Reference lists of identified studies were manually reviewed to identify any additional studies.

The title and abstract and full-text screening were conducted by two reviewers independently. The data was extracted by one reviewer and was checked by another reviewer for accuracy. The quality appraisal of the included studies was conducted by two reviewers independently. Risk of bias of included studies was assessed using the risk of bias tool. The included studies were assigned a low, medium and high risk-of-bias category. The data was synthesised using the random-effects model meta-analysis. Heterogeneity was assessed using Q, tau and I² statistics.

Applicability/external validity: The review authors reported that the wide geographical distribution of the studies across countries and health care systems favours the general applicability of the evidence.

Geographic focus:

The applicability of these findings to low and middle income countries may be limited by several factors, such as: availability and affordability of sulodexide, the generalisability and transferability of the evidence from included studies which were mostly conducted in high income countries or upper middle income countries with different health care settings and patient characteristics.

Summary of quality assessment: Overall, there is high confidence in the conclusions about the effects of this study, as it used a rigorous approach to conduct the review.