Oral nutritional supplement with 20 g protein per 200 mL bottle, 1 kcal/mL, nutritional supplement with added vitamins, minerals and trace elements versus placebo for treating foot ulcers in people with diabetes

Patient or population: people with diabetes and foot ulcers
Settings: diabetic foot care clinic at the department of internal medicine
Intervention: oral nutritional supplement with 20 g protein per 200 mL bottle, 1 kcal/mL, nutritional supplement with added vitamins, minerals and trace elements

Comparison: placebo

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time)

Ulcer healing (proportion of ulcers healed)

RR 0.80
(0.42 to 1.53)

53 participants
(1 study)

⊕⊝⊝⊝
Very low^a

10/27 (37%) participants in the oral nutritional supplement with 20 g protein per 200 mL bottle, 1 kcal/mL, nutritional supplement with added vitamins, minerals and trace elements group healed at 6 months compared with 12/26 (46%) participants in the placebo group. It is uncertain whether oral nutritional supplement increases the proportion of ulcers healed at 6 months more than placebo, because the certainty of the evidence is very low.

Quality of life

Adverse events (death)

RR 0.96

(0.06 to 14.60)

53 participants (1 study)

⊕⊝⊝⊝
Very low^b

1/27 (3%) participants in the oral nutritional supplement with 20 g protein per 200 mL bottle, 1 kcal/mL, nutritional supplement with added vitamins, minerals and trace elements group died within the 6 months' follow‐up, and 1/26 (3%) participants in the placebo group died. It is uncertain whether oral nutritional supplement reduces the number of adverse events (deaths) more than placebo, because the certainty of the evidence is very low.

Development of any new foot ulcers

Amputation rate

RR 4.82
(0.24 to 95.88)

53 participants
(1 study)

⊕⊝⊝⊝
Very low^c

2/27 (7%) participants in the oral nutritional supplement with 20 g protein per 200 mL bottle, 1 kcal/mL, nutritional supplement with added vitamins, minerals and trace elements group had an amputation within the 6 months' follow‐up, compared with none (0/26; 0%) of the participants in the placebo group. It is uncertain whether oral nutritional supplement reduces the number of amputations more than placebo, because the certainty of the evidence is very low.

*The basis for the assumed risk is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the mean risk in the intervention group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Arginine, glutamine and β‐hydroxy‐β‐methylbutyrate supplement versus placebo for treating foot ulcers in people with diabetes

Patient or population: people with diabetes and foot ulcers
Settings: individuals from 38 hospital and wound care centres
Intervention: arginine, glutamine and β‐hydroxy‐β‐methylbutyrate supplement

Comparison: placebo

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time)

Ulcer healing

(proportion of ulcers healed)

RR 1.09

(0.85 to 1.40)

270 participants
(1 study)

⊕⊝⊝⊝
Very low^a

65/129 (50%) participants in the arginine, glutamine and β‐hydroxy‐β‐methylbutyrate supplement group healed, compared with 65/141 (46%) participants in the placebo group. It is uncertain whether arginine, glutamine and β‐hydroxy‐β‐methylbutyrate supplement increases the proportion of ulcers healed at 16 weeks compared with placebo, because the certainty of the evidence is very low.

Quality of life

MD −0.03 (−0.09 to 0.03)

270 participants (1 study)

⊕⊝⊝⊝
Very low^b

DFS‐SF scale 0‐100: higher scores = better health‐related quality of life

In the arginine, glutamine and β‐hydroxy‐β‐methylbutyrate supplement group the mean score was 0.73 ± 0.20, the mean score in the placebo group was 0.76 ± 0.23. It is uncertain whether arginine, glutamine and β‐hydroxy‐β‐methylbutyrate supplement increases quality of life compared with placebo, because the certainty of the evidence is very low.

Adverse events

Development of any new foot ulcers

RR 1.04 (0.71 to 1.51

270 participants
(1 study)

⊕⊝⊝⊝
Very low^c

38/129 (29.5%) participants in the arginine, glutamine and β‐hydroxy‐β‐methylbutyrate supplement group developed a new ulcer compared with 40/141 (28.4%) in the placebo group. It is uncertain whether arginine, glutamine and β‐hydroxy‐β‐methylbutyrate supplement reduces the number of new ulcers that develop compared with placebo, because the certainty of the evidence is very low.

Amputation rate

RR 0.66 (0.16 to 2.69)

270 participants (1 study)

⊕⊝⊝⊝
Very low^d

3/129 (2.3%) participants in the arginine, glutamine and β‐hydroxy‐β‐methylbutyrate supplement group underwent an amputation, compared with 5/141 (3.5%) in the placebo group. It is uncertain whether arginine, glutamine and β‐hydroxy‐β‐methylbutyrate supplement decreases the number of amputations compared with placebo, because the certainty of the evidence is very low.

*The basis for the assumed risk is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the mean risk in the intervention group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; DFS‐SF: Diabetic Foot Ulcer Scale ‐ Short Form; MD: mean difference; RR: risk ratio

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

220 mg zinc sulphate supplements containing 50 mg elemental zinc versus placebo for treating foot ulcers in people with diabetes

Patient or population: people with diabetes and foot ulcers
Settings: hospital clinic
Intervention: 220 mg zinc sulphate supplement containing 50 mg elemental zinc

Comparison: placebo

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time: mean (SD) cm wound length reduction)

MD −0.60 (−1.10 to −0.10)

60
(1 study)

⊕⊝⊝⊝
Very low^a

Mean wound length reduced by −1.5 ± 0.7 in the 220 mg zinc sulphate supplement containing 50 mg elemental zinc group, and −0.9 ± 1.2 in the placebo group (MD −0.60, 95% CI −1.10 to −0.10). It is uncertain whether 220 mg zinc sulphate supplement containing 50 mg elemental zinc increases the percentage change in wound length over time, because the certainty of the evidence is very low.

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time: mean (SD) cm wound depth reduction)

MD −0.50 (−0.92 to −0.08)

60
(1 study)

⊕⊝⊝⊝
Very low^b

Mean wound depth reduced by −0.8 ± 0.6 in the 220 mg zinc sulphate supplement containing 50 mg elemental zinc group, and −0.3 ± 1.0 in the placebo group (MD −0.50, 95% CI −0.92 to −0.08). It is uncertain whether 220 mg zinc sulphate supplement containing 50 mg elemental zinc increases the percentage change in wound depth over time, because the certainty of the evidence is very low.

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time: mean (SD) cm wound width reduction)

MD −0.60 (−1.06 to −0.14)

60
(1 study)

⊕⊝⊝⊝
Very low^c

Mean wound width reduced by −1.4 ± 0.8 in the 220 mg zinc sulphate supplement containing 50 mg elemental zinc group, and −0.8 ± 1.0 in the placebo group (MD −0.60, 95% CI −1.06 to −0.14). It is uncertain whether 220 mg zinc sulphate supplement containing 50 mg elemental zinc increases the percentage change in wound width over time, because the certainty of the evidence is very low.

Ulcer healing

(proportion of ulcers healed)

Quality of life

Adverse events

Development of any new foot ulcers

Amputation rate

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

250 mg magnesium oxide supplement versus placebo for treating foot ulcers in people with diabetes

Patient or population: people with diabetes and foot ulcers
Settings: hospital clinic
Intervention: 250 mg magnesium oxide supplement

Comparison: placebo

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time: mean (SD) cm wound length reduction)

MD −0.90 (−1.66 to −0.14)

70
(1 study)

⊕⊝⊝⊝
Very low^a

Mean wound length reduced by −1.8 ± 2.0 in the 250 mg magnesium oxide supplement group, and −0.9 ± 1.1 in the placebo group (MD −0.90, 95% CI −1.66 to −0.14). It is uncertain whether 250 mg magnesium oxide supplement increases the percentage change in wound length over time, because the certainty of the evidence is very low.

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time: mean (SD) cm wound depth reduction)

MD −0.50 (−0.81 to −0.19)

70
(1 study)

⊕⊝⊝⊝
Very low^b

Mean wound depth reduced by −0.8 ± 0.8 in the 250 mg magnesium oxide supplement group, and −0.3 ± 0.5 in the placebo group (MD −0.50, 95% CI −0.81 to −0.19). It is uncertain whether 250 mg magnesium oxide supplement increases the percentage change in wound depth over time, because the certainty of the evidence is very low.

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time: mean (SD) cm wound width reduction)

MD −0.80 (−1.53 to −0.07)

70
(1 study)

⊕⊝⊝⊝
Very low^c

Mean wound width reduced by −1.6 ± 2.0 in the 250 mg magnesium oxide supplement group, and −0.8 ± 0.9 in the placebo group (MD −0.80, 95% CI −1.53 to −0.07). It is uncertain whether 250 mg magnesium oxide supplement increases the percentage change in wound width over time, because the certainty of the evidence is very low.

Ulcer healing

(proportion of ulcers healed)

Quality of life

Adverse events

Development of any new foot ulcers

Amputation rate

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

1000 mg/day omega‐3 fatty acid from flaxseed oil supplement versus placebo for treating foot ulcers in people with diabetes

Patient or population: people with diabetes and foot ulcers
Settings: hospital clinic
Intervention: 1000 mg/day omega‐3 fatty acid from flaxseed oil supplements

Comparison: placebo

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time: mean (SD) cm wound length reduction)

MD −1.00 (−1.91 to −0.09)

60
(1 study)

⊕⊝⊝⊝
Very low^a

Mean wound length reduced by −2.1 ± 2.3 in the 1000 mg/day omega‐3 fatty acid from flaxseed oil supplement group, and −1.0 ± 1.1 in the placebo group (MD −1.00, 95% CI −1.91 to −0.09). It is uncertain whether 1000 mg/day omega‐3 fatty acid from flaxseed oil supplement increases the percentage change in wound length over time, because the certainty of the evidence is very low.

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time: mean (SD) cm wound depth reduction)

MD −0.30 (−0.58 to −0.02)

60
(1 study)

⊕⊝⊝⊝
Very low^b

Mean wound depth reduced by −0.80 ± 0.60 in the 1000 mg/day omega‐3 fatty acid from flaxseed oil supplement group, and −0.50 ± 0.50 in the placebo group (MD −0.30, 95% CI −0.58 to −0.02). It is uncertain whether 1000 mg/day omega‐3 fatty acid from flaxseed oil supplement increases the percentage change in wound depth over time, because the certainty of the evidence is very low.

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time: mean (SD) cm wound width reduction)

MD −0.80 (−1.51 to −0.09)

60
(1 study)

⊕⊝⊝⊝
Very low^c

Mean wound width reduced by −1.8 ± 1.7 in the 1000 mg/day omega‐3 fatty acid from flaxseed oil supplement group, and −1.0 ± 1.0 in the placebo group (MD −0.80, 95% CI −1.51 to −0.09). It is uncertain whether 1000 mg/day omega‐3 fatty acid from flaxseed oil supplement increases the percentage change in wound width over time, because the certainty of the evidence is very low.

Ulcer healing

(proportion of ulcers healed)

Quality of life

Adverse events

Development of any new foot ulcers

Amputation rate

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

150,000 IU of vitamin D versus 300,000 IU of vitamin D for treating foot ulcers in people with diabetes

Patient or population: people with diabetes and foot ulcers
Settings: hospital clinic
Intervention: 150,000 IU of vitamin D

Comparison: 300,000 IU of vitamin D

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time: mean (SD) cm wound area)

MD: 0.61 (−0.04 to 1.26)

47
(1 study)

⊕⊝⊝⊝
Very low^a

Mean wound area was 5.23 ± 1.29 in the 300,000 IU of vitamin D group and 5.84 ± 0.97 in the 150,000 IU of vitamin D group (MD 0.61, 95% CI −0.04 to 1.26). It is uncertain whether 150,000 IU of vitamin D when compared with 300,000 IU of vitamin D increases the percentage change in mean wound area over time, because the certainty of the evidence is very low.

Ulcer healing

(proportion of ulcers healed)

Quality of life

Adverse events

Development of any new foot ulcers

Amputation rate

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Magnesium and vitamin E co‐supplementation versus placebo for treating foot ulcers in people with diabetes

Patient or population: people with diabetes and foot ulcers
Settings: hospital clinic
Intervention: magnesium and vitamin E co‐supplementation

Comparison: placebo

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time: mean (SD) cm wound length)

MD −0.70
(−1.33 to −0.07)

57
(1 study)

⊕⊝⊝⊝
Very low^a

Mean wound length was 1.6 ± 1.10 in the magnesium and vitamin E co‐supplementation group and 2.3 ± 1.3 in the placebo group (MD −0.70, 95% CI −1.33 to −0.07). It is uncertain whether magnesium and vitamin E co‐supplementation increases the percentage change in mean wound length over time, because the certainty of the evidence is very low.

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time: mean (SD) cm wound depth)

MD −0.50

(−0.71 to −0.29 )

57
(1 study)

⊕⊝⊝⊝
Very low^b

Mean wound depth was 0.40 ± 0.30 in the magnesium and vitamin E co‐supplementation group and 0.90 ± 0.50 in the placebo group (MD −0.50, 95% CI −0.71 to −0.29). It is uncertain whether magnesium and vitamin E co‐supplementation increases the percentage change in mean wound depth over time, because the certainty of the evidence is very low.

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time: mean (SD) cm wound width)

MD −0.60

(−1.09 to −0.11)

57
(1 study)

⊕⊝⊝⊝
Very low^c

Mean wound width was 1.2 ± 0.90 in the magnesium and vitamin E co‐supplementation group and 1.8 ± 1.0 in the placebo group (MD −0.60, 95% CI −1.09 to −0.11). It is uncertain whether magnesium and vitamin E co‐supplementation increases the percentage change in mean wound width over time, because the certainty of the evidence is very low.

Ulcer healing

(proportion of ulcers healed)

Quality of life

Adverse events

Development of any new foot ulcers

Amputation rate

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Vitamin D versus placebo for treating foot ulcers in people with diabetes

Patient or population: people with diabetes and foot ulcers
Settings: hospital clinic
Intervention: vitamin D

Comparison: placebo

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time:

mean (SD) cm wound length reduction

MD −1.00
(−1.10 to −0.90)

60
(1 study)

⊕⊝⊝⊝
Very low^a

Mean wound length reduced by −2.1 ± 0.20 in the vitamin D group, and −1.1 ± 0.20 in the placebo group (MD −1.00, 95% CI −1.10 to −0.90). It is uncertain whether vitamin D increases the percentage change in wound length over time, because the certainty of the evidence is very low.

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time:

mean (SD) cm wound depth reduction

MD −0.50
(−0.55 to −0.45)

60
(1 study)

⊕⊝⊝⊝
Very low^b

Mean wound depth reduced by −1.0 ± 0.10 in the vitamin D group, and −0.50 ± 0.1 in the placebo group (MD −0.5, 95% CI −0.55 to −0.45). It is uncertain whether vitamin D increases the percentage change in wound depth over time, because the certainty of the evidence is very low.

Ulcer healing

(absolute change in individual parameters of ulcer dimensions over time:

mean (SD) cm wound width reduction

MD −0.80
(−0.90 to −0.70)

60
(1 study)

⊕⊝⊝⊝
Very low^c

Mean wound width reduced by −1.9 ± 0.20 in the vitamin D group, and −1.1 ± 0.20 in the placebo group (MD −0.80, 95% CI −0.90 to −0.70). It is uncertain whether vitamin D increases the percentage change in wound width over time, because the certainty of the evidence is very low.

Ulcer healing

(proportion of ulcers healed)

Quality of life

Adverse events

Development of any new foot ulcers

Amputation rate

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.