Nutritional supplementation on wound healing in diabetic foot: What is known and what is new?

Table 1 Strengths and Limitations of the main randomised controlled trial that evaluated the effects of specific nutritional supplement on wound healing in patients with diabetic foot ulcers

Ref.	Study design and Number ofparticipants	Nutrient(s) or Supplement Studied	Aim of study	Main results	Limitations
Eneroth et al[17], 2004	Double-blind RCT, 53 patients	20 g protein per 200 mL bottle, 1 kcal/mL	To determine the effects of supplementation on wound healing at 6 mo in subjects with DFU	10/27 (37%) participants in the oral nutritional supplement group healed at 6 mo compared with 12/26 (46%) in placebo group	The sample size was small; certainty of the evidence is very low
Armstrong[18], 2014	Double-blind RCT, 270 patients	Arginine,glutamine and β-hydroxy-β-methylbutyrate	To determine the effects of supplementation on proportion of ulcers healed at 16 wk	65/129 (50%) participants in the arginine, glutamine and β-hydroxy-β-methylbutyrate supplement group healed, compared with 65/141 (46%) in the placebo group	Certainty of the evidence is very low; no difference in quality of life, new ulcers, amputation
Wong et al[19], 2014	RCT, 27 patients	Amino acid mixture containing (beta)-hydroxy (beta)-methylbutyrate (HMB), arginine and glutamine	Compare pressure ulcer healing rates	Wound area did not decrease significantly in the short term for both groups. The proportion of viable tissues increased within 2 wk on HMB, arginine and glutamine supplementation; pressure Ulcer Scale for Healing scores showed significant improvement within 1 wk of supplementation for the experimental group	The sample size was small. Observation time was short. Amino acid does not appear to reduce wound size but to improve healing process
Basiri et al[20], 2022	RCT, 29 patients	Nutritional supplementation (total energy of 500 calories, 28 g of protein, and essential vitamins and minerals) and education	Effects of nutrition supplementation and education on inflammatory biomarkers	The mean plasma concentration of IL-6 significantly decreased in the treatment group	The sample size was small
Basiri et al[20], 2022	RCT, 29 patients	Nutritional supplementation (total energy of 500 calories, 28 g of protein, and essential vitamins and minerals) and education	Nutrient-dense formula combined with nutrition education on wound healing	Treatment group experienced a faster wound healing rate (6.43 mm2/wk more reduction in the wound area) than the control group. The mean reduction in the wound area during the first four weeks of the study was almost 13-fold greater in the treatment group compared to the control group	The sample size was small
Sipahi et al[22], 2013	Retrospective analysis, 11 patients	Beta-hydroxy-beta- methylbutyrate, arginine and glutamine	Wound healing in diabetic dialysis patients	Healing was observed on the wound depth score of 7 (63.6%) patients and on wound appearance score of 8 (72.7%) patients out of 11	Not RCT; the sample size was small
Soleimani et al[31], 2017	Double-blind RCT, 60 patients	Omega-3 PUFA	To determine the effects of flaxseed oil omega-3 fattyacids supplementation on wound healing and metabolic profiles insubjects with DFU	Significant decrease in ulcer length, width, and depth	The sample size was small. The authors did not report data on ulcer healing (percentage of ulcers healed), cost of surgery, quality of life, adverse events, development of any new foot ulcers, amputation rate, incidence osteomyelitis from surgery
Mohseni et al[37], 2017	Double-blind RCT, 60 patients	Probiotics (Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, and Bifidobacterium bifidum)	To determine the effects of oral probiotic therapy on wound healing andmetabolic status in adult patients with diabetes	Significant improvement in length, width, and depth of ulcers in treatment vs placebo groups	The sample size was small. The authors did not report data on ulcer healing (percentage of ulcers healed), quality of life, adverse events, development of any new foot ulcers, amputation rate
Gunton et al[39], 2021	Double-blind RCT, 19 patients	Vitamin C 500 mg daily in a slow-release capsule	To determine the effects of oral vitamin C supplement on wound healing	Healing at 8 wk was significantly better in the vitamin C group (median 100 v. -14 %, P = 0.041); healing without amputation occurred in all patients in the vitamin C group	The sample size was extremely small
Yarahmadi et al[40], 2021	Double-blind RCT, 25 patients	Oral vitamin E and C or placebo	To determine the effects of oral vitamin C and E supplement on wound healing	Significantly higher wound size reduction in intervention (P = 0.019); significant decrease in prooxidant-antioxidant balance and hs-CRP in the intervention group (P < 0.05)	The sample size was small. All patients were treated even with platelet-rich plasma-fibrin glue dressing and vitamin E
Razzaghi et al[46], 2018	Double-blind RCT, 60 patients	50000 IU vitamin D supplements every 2 wk	To determine the effects of oral vitamin D supplement on wound healing an on markers of Inflammation and Insulin resistance	After 12 wk vitamin D treatment resulted in treatment Greater Reduction in ulcer length, width, depth, and erythema rate vs placebo	The sample size was small
Afzali et al[47], 2019	Double-blind RCT, 70 patients	250 mg magnesium oxide	To determine the effects of oral magnesium oxide + vitamin E supplement on wound healing	Beneficial effects on ulcer size after 12 wk of treatment	The sample size was small
Razzaghi et al[46], 2018	Double-blind RCT, 57 patients	250 mg magnesium oxide plus 400 IU vitamin E	To determine the effects of oral magnesium oxide supplement on wound healing	Magnesium plus vitamin E supplements for 12 wk reduced ulcer length and depth vs placebo	The sample size was small
Momen-Heravi et al[48], 2017	Double-blind RCT, 60 patients	220 mg zinc sulfate supplements	To determine the effects of oral zinc supplement on wound healing	Zinc supplementation for 12 wk was associated with significant reductions in ulcer length and width	The sample size was small

RCT: Randomised controlled trial; DFU: Diabetic foot ulcers; PUFA: Polyunsaturated fatty acids.