Edulcorantes no nutritivos para la diabetes mellitus
Referencias
Referencias de los estudios incluidos en esta revisión
Referencias de los estudios excluidos de esta revisión
Referencias adicionales
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Ir a:
| Study characteristics | ||
| Methods | Study design: parallel randomised controlled trial | |
| Participants | Inclusion criteria For group 1:
For group 2:
For group 3:
Exclusion criteria
Diagnostic criteria: — Setting: outpatients Age group: adults and elderly people Sex: females and males Country where trial was performed: Paraguay | |
| Interventions | Intervention(s): steviol glycoside capsules (250 mg 3 times a day; purity of steviol glycosides was 92%) Comparator(s): matching placebo Duration of intervention: 3 months Duration of follow‐up: 3 months Run‐in period: none Number of study centres: not reported (presumably 1) | |
| Outcomes | Reported outcomes in full text of publication: HbA1c, body weight (kg), adverse events, anthropometric measures other than body weight (kg), lipid profile (total‐C, HDL, LDL, TG), glucose levels (fasting), serum insulin | |
| Identification | Trial identifier: — Trial terminated early: no | |
| Publication details | Language of publication: English Funding: commercial funding: Steviafarma Industrial S.A., Maringa, Brazil and non‐commercial funding: Ministry of Agriculture of Paraguay and the Banco Interamericano de Desarrollo (Interamerican Development Bank) Publication status: peer‐reviewed journal and full article | |
| Stated aim for study | Quote from publication: "The aim of this study was to investigate the effect of steviol glycosides consumption in humans (both diabetics ‐ Type 1 and Type 2 ‐ and non‐diabetics with normal/low‐normal blood pressure) in order to comply with the first part (the pharmacological effects of steviol glycosides in humans) of the Annex 2 of the 63rd meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA)" | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote from publication: "Volunteers were randomly assigned to receive either steviol glycoside capsules 250 mg t.d.i. or matching placebo" Comment: no information about the sequence generation process |
| Allocation concealment (selection bias) | Unclear risk | Quote from publication: "Volunteers were randomly assigned to receive either steviol glycoside capsules 250 mg t.d.i. or matching placebo" Comment: no information about allocation concealment |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "matching placebo" was used Comment: self‐reported outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "matching placebo" was used Comment: investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "matching placebo" was used Comment: investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "matching placebo" was used Comment: investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "matching placebo" was used Comment: investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "matching placebo" was used Comment: investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "matching placebo" was used Comment: investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: participants (i.e. outcome assessors) were blinded; self‐reported outcome |
| Blinding of outcome assessment (detection bias) | Unclear risk | Comment: no information about the blinding of outcome assessors |
| Blinding of outcome assessment (detection bias) | Unclear risk | Comment: no information about the blinding of outcome assessors |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: no information about the blinding of outcome assessors; the outcome measurement is unlikely to have been influenced by potential lack of blinding |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: no information about the blinding of outcome assessors; the outcome measurement is unlikely to have been influenced by potential lack of blinding |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: no information about the blinding of outcome assessors; the outcome measurement is unlikely to have been influenced by potential lack of blinding |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: no information about the blinding of outcome assessors; the outcome measurement is unlikely to have been influenced by potential lack of blinding |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "No drop‐outs were due to side effects" Comment: no missing data for adverse events |
| Incomplete outcome data (attrition bias) | High risk | Quote from publication: "Eighty‐six volunteers (45 women, 41 men) were enrolled in the study and 76 completed it." "The study group consisted of 76 subjects (30 with Type 2 diabetes, 16 with Type 1 diabetes and 30 without diabetes" (Group 1: type 1 diabetes, Group 2: type 2 diabetes). "Ten volunteers (4 in Group 1, 3 in Group 2 and 3 in Group 3) decided to discontinue the study for no specific reason, but no due to side effects" Comment: in total 20 participants with type 1 diabetes were randomised and 16 were analysed; in total 33 participants with type 2 diabetes were randomised and 30 analysed; reasons for attrition and balance of missing data across groups were not reported |
| Incomplete outcome data (attrition bias) | High risk | Quote from publication: "Eighty‐six volunteers (45 women, 41 men) were enrolled in the study and 76 completed it." "The study group consisted of 76 subjects (30 with Type 2 diabetes, 16 with Type 1 diabetes and 30 without diabetes" (Group 1: type 1 diabetes, Group 2: type 2 diabetes). "Ten volunteers (4 in Group 1, 3 in Group 2 and 3 in Group 3) decided to discontinue the study for no specific reason, but no due to side effects" Comment: in total 20 participants with type 1 diabetes were randomised and 16 were analysed; in total 33 participants with type 2 diabetes were randomised and 30 analysed; reasons for attrition and balance of missing data across groups were not reported |
| Incomplete outcome data (attrition bias) | High risk | Quote from publication: "Eighty‐six volunteers (45 women, 41 men) were enrolled in the study and 76 completed it." "The study group consisted of 76 subjects (30 with Type 2 diabetes, 16 with Type 1 diabetes and 30 without diabetes" (Group 1: type 1 diabetes, Group 2: type 2 diabetes). "Ten volunteers (4 in Group 1, 3 in Group 2 and 3 in Group 3) decided to discontinue the study for no specific reason, but no due to side effects" Comment: in total 20 participants with type 1 diabetes were randomised and 16 were analysed; in total 33 participants with type 2 diabetes were randomised and 30 analysed; reasons for attrition and balance of missing data across groups were not reported |
| Incomplete outcome data (attrition bias) | High risk | Quote from publication: "Eighty‐six volunteers (45 women, 41 men) were enrolled in the study and 76 completed it." "The study group consisted of 76 subjects (30 with Type 2 diabetes, 16 with Type 1 diabetes and 30 without diabetes" (Group 1: type 1 diabetes, Group 2: type 2 diabetes). "Ten volunteers (4 in Group 1, 3 in Group 2 and 3 in Group 3) decided to discontinue the study for no specific reason, but no due to side effects" Comment: in total 20 participants with type 1 diabetes were randomised and 16 were analysed; in total 33 participants with type 2 diabetes were randomised and 30 analysed; reasons for attrition and balance of missing data across groups were not reported |
| Incomplete outcome data (attrition bias) | High risk | Quote from publication: "Eighty‐six volunteers (45 women, 41 men) were enrolled in the study and 76 completed it." "The study group consisted of 76 subjects (30 with Type 2 diabetes, 16 with Type 1 diabetes and 30 without diabetes" (Group 1: type 1 diabetes, Group 2: type 2 diabetes). "Ten volunteers (4 in Group 1, 3 in Group 2 and 3 in Group 3) decided to discontinue the study for no specific reason, but no due to side effects" Comment: in total 20 participants with type 1 diabetes were randomised and 16 were analysed; in total 33 participants with type 2 diabetes were randomised and 30 analysed; reasons for attrition and balance of missing data across groups were not reported |
| Incomplete outcome data (attrition bias) | High risk | Quote from publication: "Eighty‐six volunteers (45 women, 41 men) were enrolled in the study and 76 completed it." "The study group consisted of 76 subjects (30 with Type 2 diabetes, 16 with Type 1 diabetes and 30 without diabetes" (Group 1: type 1 diabetes, Group 2: type 2 diabetes). "Ten volunteers (4 in Group 1, 3 in Group 2 and 3 in Group 3) decided to discontinue the study for no specific reason, but no due to side effects" Comment: in total 20 participants with type 1 diabetes were randomised and 16 were analysed; in total 33 participants with type 2 diabetes were randomised and 30 analysed; reasons for attrition and balance of missing data across groups were not reported |
| Selective reporting (reporting bias) | High risk | Comment: described in the methods that weight and waist circumference were measured, but values were not reported |
| Other bias | Unclear risk | Comment: steviol glycoside capsules were supplied by the industry |
| Study characteristics | ||
| Methods | Study design: cross‐over randomised controlled trial | |
| Participants | Inclusion criteria:
Exclusion criteria: — Diagnostic criteria: — Setting: outpatients Age group: adults Sex: females and males Country where trial was performed: Germany | |
| Interventions | Intervention(s): sodium‐cyclamate 348 ± 270 mg/day Comparator(s): sucrose 24 ± 13 g/day Duration of intervention: 4 weeks Duration of follow‐up: 4 weeks Run‐in period: 4 weeks Number of study centres: 1 | |
| Outcomes | Reported outcomes in full text of publication: HbA1c, body weight, lipid profile (total‐C, HDL, TG), glucose levels (postprandial) | |
| Identification | Trial identifier: — Trial terminated early: no | |
| Publication details | Language of publication: English Funding: — Publication status: peer‐reviewed journal and full article | |
| Stated aim for study | Quote from publication: "we have studied the metabolic effects of sucrose included in the diet of Type 1 diabetic outpatients treated with continuous subcutaneous insulin infusion" | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote from publication: "patients were assigned to use either sucrose or sodium‐cyclamate as sweetener in random order" Comment: based on information from the authors random sequence was generated by tossing a coin |
| Allocation concealment (selection bias) | High risk | Quote from publication: "They were then asked to change over to sodium‐cyclamate or sucrose, respectively, for another 4‐week period." Comment: based on information from the authors allocation to treatment groups was done "openly" |
| Blinding of participants and personnel (performance bias) | High risk | Quote from publication: "During the sucrose‐period, sucrose and sucrose‐sweetened foods were allowed ad libidum." "During the cyclamate period, sodium cyclamate was allowed ad libidum within the limitations set up by the World Health Organisation." Comment: participants were not blinded; investigator‐assessed outcome measure |
| Blinding of participants and personnel (performance bias) | High risk | Quote from publication: "During the sucrose‐period, sucrose and sucrose‐sweetened foods were allowed ad libidum." "During the cyclamate period, sodium cyclamate was allowed ad libidum within the limitations set up by the World Health Organisation." Comment: participants were not blinded; postprandial plasma glucose; investigator‐assessed outcome measure |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "During the sucrose‐period, sucrose and sucrose‐sweetened foods were allowed ad libidum." "During the cyclamate period, sodium cyclamate was allowed ad libidum within the limitations set up by the World Health Organisation." Comment: participants were not blinded; investigator‐assessed outcome measure; outcome unlikely to have been influenced by lack of blinding |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "During the sucrose‐period, sucrose and sucrose‐sweetened foods were allowed ad libidum." "During the cyclamate period, sodium cyclamate was allowed ad libidum within the limitations set up by the World Health Organisation." Comment: participants were not blinded; total cholesterol, HDL‐cholesterol, triglycerides were assessed by the investigators; outcome unlikely to have been influenced by lack of blinding |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the publication does not address blinding of outcome assessors; based on information from the authors, body weight was measured independently by personnel unrelated to the study; exact equipment used for measurement; investigator‐assessed outcome measure |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome measure |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome measure |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome measure |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "Ten Type 1 diabetic subjects, eight women and two men (...) volunteered to participate in the study" Comment: data available for all included participants |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "Ten Type 1 diabetic subjects, eight women and two men (...) volunteered to participate in the study" Comment: data available for all included participants |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "Ten Type 1 diabetic subjects, eight women and two men (...) volunteered to participate in the study" Comment: data available for all included participants |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "Ten Type 1 diabetic subjects, eight women and two men (...) volunteered to participate in the study" Comment: data available for all included participants |
| Selective reporting (reporting bias) | Low risk | Comment: low risk of bias according to ORBIT |
| Other bias | Unclear risk | Comment: cross‐over design without washout period between interventions |
| Study characteristics | ||
| Methods | Study design: cross‐over randomised controlled trial | |
| Participants | Inclusion criteria:
Exclusion criteria: — Diagnostic criteria: criteria for type 2 diabetes mellitus: based on the National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance Setting: outpatients Age group: adults and elderly people (median: 66 ± 5 years) Sex: females and males Country where trial was performed: Australia | |
| Interventions | Intervention(s): aspartame 162 mg daily, added to the usual diet Comparator(s): sucrose 45 g daily, added to the usual diet Duration of intervention: 6 weeks Duration of follow‐up: 6 weeks for both interventions Run‐in period: not reported Number of study centres: 1 | |
| Outcomes | Reported outcomes in full text of publication: HbA1c, body weight (kg), lipid profile (total‐C, HDL, TG), glucose levels (fasting) | |
| Identification | Trial identifier: — Trial terminated early: no | |
| Publication details | Language of publication: English Funding: commercial funding; aspartame (Equal) was supplied by Searle Laboratories, Division of Searle Australia Propriety Limited, Crows Nest, New South Wales, Australia Publication status: peer‐reviewed journal and full article | |
| Stated aim for study | Quote from publication: "The aim of this study was to compare the metabolic effects of the daily addition of sucrose or an equivalent sweetening amount of aspartame to the usual diet of subjects with well‐controlled NIDDM. The purpose was twofold: to further examine the issue of a possible deleterious effect of sucrose in the diabetic diet and to ascertain whether an alternative sweetener has any particular advantage" | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote from publication: "Subjects were randomly allocated to one of two groups" Comment: unclear how sequence was determined |
| Allocation concealment (selection bias) | Unclear risk | Quote from publication: "Subjects were randomly allocated to one of two groups" Comment: insufficient information to judge allocation concealment |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The sucrose and aspartame were packed in plain sachets labelled A or B according to a code. Each sachet contained 5 g sucrose or 18 mg aspartame (...) bulked to 0.5 g with lactose." Comment: appropriate packing of sweeteners to ensure blinding; investigator‐assessed outcome measure |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The sucrose and aspartame were packed in plain sachets labelled A or B according to a code. Each sachet contained 5 g sucrose or 18 mg aspartame (...) bulked to 0.5 g with lactose." Comment: appropriate packing of sweeteners to ensure blinding; fasting glucose; investigator‐assessed |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The sucrose and aspartame were packed in plain sachets labelled A or B according to a code. Each sachet contained 5 g sucrose or 18 mg aspartame (...) bulked to 0.5 g with lactose." Comment: appropriate packing of sweeteners to ensure blinding; investigator‐assessed outcome measure |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The sucrose and aspartame were packed in plain sachets labelled A or B according to a code. Each sachet contained 5 g sucrose or 18 mg aspartame (...) bulked to 0.5 g with lactose." Comment: appropriate packing of sweeteners to ensure blinding; investigator‐assessed outcome measure |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The sucrose and aspartame were packed in plain sachets labelled A or B according to a code. Each sachet contained 5 g sucrose or 18 mg aspartame (...) bulked to 0.5 g with lactose." Comment: appropriate packing of sweeteners to ensure blinding; investigator‐assessed outcome measure |
| Blinding of outcome assessment (detection bias) | Unclear risk | Comment: no information about the blinding of outcome assessors; investigator‐assessed outcome measure |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome measure |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome measure |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome measure |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome measure |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote from publication: "Nine subjects (eight males, one female) who satisfied the criteria for NIDDM were studied." Comment: the number of participants randomised is not clearly described |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote from publication: "Nine subjects (eight males, one female) who satisfied the criteria for NIDDM were studied." Comment: the number of participants randomised is not clearly described |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote from publication: "Nine subjects (eight males, one female) who satisfied the criteria for NIDDM were studied." Comment: the number of participants randomised is not clearly described |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote from publication: "Nine subjects (eight males, one female) who satisfied the criteria for NIDDM were studied." Comment: the number of participants randomised is not clearly described |
| Selective reporting (reporting bias) | Low risk | Comment: the study protocol is unavailable, but it seems that the published report includes all expected outcomes (ORBIT classification) |
| Other bias | Unclear risk | Comment: cross‐over design without washout period; aspartame was supplied by the industry |
| Study characteristics | ||
| Methods | Study design: cross‐over randomised controlled trial | |
| Participants | Inclusion criteria: type 2 diabetes mellitus outpatients Exclusion criteria:
Diagnostic criteria: — Setting: outpatients Age group: adults and elderly people Sex: females and males Country where trial was performed: Australia | |
| Interventions | Intervention(s): saccharin and starch 30 g daily Comparator(s): sucrose 28 g daily Duration of intervention: 6 weeks Duration of follow‐up: 6 weeks each dietary sequence Run‐in period: none Number of study centres: 1 | |
| Outcomes | Reported outcomes in full text of publication: HbA1c, body weight (kg), lipid profile (total‐C, HDL, LDL, TG), glucose levels (fasting), serum insulin | |
| Identification | Trial identifier: — Trial terminated early: no | |
| Publication details | Language of publication: English Funding: commercial funding: grant from the Australian Sugar Industry in co‐operation with CSR and Millaquin Sugar Publication status: peer‐reviewed journal and full article | |
| Stated aim for study | Quote from publication: "The aim of this study was to compare both the short‐ and medium‐term metabolic effects of sucrose supplementation with those of saccharin and starch supplementation in non‐insulin‐dependent diabetic outpatients" | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote from publication: "patients were randomly allocated to each 6‐week dietary sequence (11 sucrose diet first and 6 saccharin diet first)" Comment: insufficient information about the sequence generation process |
| Allocation concealment (selection bias) | Unclear risk | Quote from publication: "patients were randomly allocated to each 6‐week dietary sequence" Comment: insufficient information about the allocation concealment |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The usual diet of each patient was supplemented daily with either 28 g sucrose (sucrose diet) or saccharin and starch (saccharin diet). The saccharin and starch supplements were equivalent to about 28 g sucrose in sweetness and energy, respectively." Comment: placebos were described to be similar in taste (sweetness); investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The usual diet of each patient was supplemented daily with either 28 g sucrose (sucrose diet) or saccharin and starch (saccharin diet). The saccharin and starch supplements were equivalent to about 28 g sucrose in sweetness and energy, respectively." Comment: placebos were described to be similar in taste (sweetness); fasting glucose; investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The usual diet of each patient was supplemented daily with either 28 g sucrose (sucrose diet) or saccharin and starch (saccharin diet). The saccharin and starch supplements were equivalent to about 28 g sucrose in sweetness and energy, respectively." Comment: placebos were described to be similar in taste (sweetness); investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The usual diet of each patient was supplemented daily with either 28 g sucrose (sucrose diet) or saccharin and starch (saccharin diet). The saccharin and starch supplements were equivalent to about 28 g sucrose in sweetness and energy, respectively." Comment: placebos were described to be similar in taste (sweetness); investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The usual diet of each patient was supplemented daily with either 28 g sucrose (sucrose diet) or saccharin and starch (saccharin diet). The saccharin and starch supplements were equivalent to about 28 g sucrose in sweetness and energy, respectively." Comment: placebos were described to be similar in taste (sweetness); investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Unclear risk | Comment: the blinding of outcome assessors was not addressed; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "patients were randomly allocated to each 6‐week dietary sequence (11 sucrose diet first and 6 saccharin diet first)" Comment: no missing outcome data; results for all 17 randomised participants were reported |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "patients were randomly allocated to each 6‐week dietary sequence (11 sucrose diet first and 6 saccharin diet first)" Comment: no missing outcome data; results for all 17 randomised participants were reported |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "patients were randomly allocated to each 6‐week dietary sequence (11 sucrose diet first and 6 saccharin diet first)" Comment: no missing outcome data; results for all 17 randomised participants were reported |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "patients were randomly allocated to each 6‐week dietary sequence (11 sucrose diet first and 6 saccharin diet first)" Comment: no missing outcome data; results for all 17 randomised participants were reported |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "patients were randomly allocated to each 6‐week dietary sequence (11 sucrose diet first and 6 saccharin diet first)" Comment: no missing outcome data; results for all 17 randomised participants were reported |
| Selective reporting (reporting bias) | Low risk | Comment: the study protocol is unavailable, but the publication seems to include all expected outcomes (ORBIT classification) |
| Other bias | Unclear risk | Comment: cross‐over without washout period; industry funding |
| Study characteristics | ||
| Methods | Study design: parallel randomised controlled trial | |
| Participants | Inclusion criteria:
Exclusion criteria:
Diagnostic criteria: "according to WHO criteria" Setting: outpatients Age group: adults Sex: females and males Country where trial was performed: India, USA | |
| Interventions | Intervention(s): Splenda 1.5 g, 3 times a day, dissolved in 125 to 250 mL of water Comparator(s): tagatose 15 g, 3 times a day, dissolved in 125 to 250 mL of water Duration of intervention: 10 months Duration of follow‐up: 10 months Run‐in period: 8 weeks Number of study centres: multicentre study (number of centres not provided) | |
| Outcomes | Reported outcomes in full text of publication: HbA1c, lipid profile (total‐C, HDL, TG), glucose levels (fasting) | |
| Identification | Trial identifier:NCT00955747; CTRI/2009/091/000536 Trial terminated early: no | |
| Publication details | Language of publication: English Funding: commercial funding: Biospherics subsidiary of Spherix Inc; non‐commercial funding: grant from the National Center for Research Resources and the National Center for Advancing Translational Sciences, US National Institutes of Health Publication status: peer‐reviewed journal and full article | |
| Stated aim for study | Quote: "The primary objective of this Phase 3 clinical trial was to evaluate the placebo‐controlled effect of D‐tagatose on glycemic control and safety in subjects with type 2 diabetes over the course of a 10‐month treatment. The secondary objectives of this clinical trial were to evaluate the placebo‐controlled effects of D‐tagatose on fasting blood glucose, insulin, lipid profiles, and changes in BMI." | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote from publication: "A total of 494 subjects were randomized into the study" "There were 494 subjects randomized, 185 subjects in the US and 309 subjects in India", "Randomization was stratified according to screening HbA1c values (<7.5% and ≥7.5%) to achieve a balanced distribution of subjects across two arms (treatment and placebo)" Comment: insufficient information about the sequence generation process |
| Allocation concealment (selection bias) | Unclear risk | Quote from publication: "This was a Phase 3, multicenter, randomized, double‐blind, placebo‐controlled, parallel group study" Comment: not clear whether allocation sequence was concealed |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The placebo amounts were chosen to match sweetness for blinding. The powder packets were the same size and bore the same labeling with the exception of the designation 'Substance A' or 'Substance B'" Comment: placebos were described to be similar in sweetness and packaging; investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The placebo amounts were chosen to match sweetness for blinding. The powder packets were the same size and bore the same labeling with the exception of the designation 'Substance A' or 'Substance B'" Comment: placebos were described to be similar in sweetness and packaging; investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The placebo amounts were chosen to match sweetness for blinding. The powder packets were the same size and bore the same labeling with the exception of the designation 'Substance A' or 'Substance B'" Comment: placebos were described to be similar in sweetness and packaging; fasting glucose; investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The placebo amounts were chosen to match sweetness for blinding. The powder packets were the same size and bore the same labeling with the exception of the designation 'Substance A' or 'Substance B'" Comment: placebos were described to be similar in sweetness and packaging; investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The placebo amounts were chosen to match sweetness for blinding. The powder packets were the same size and bore the same labeling with the exception of the designation 'Substance A' or 'Substance B'" Comment: placebos were described to be similar in sweetness and packaging; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Unclear risk | Comment: the blinding of outcome assessors was not addressed; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Unclear risk | Comment: the blinding of outcome assessors was not addressed; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Incomplete outcome data (attrition bias) | High risk | Quote from publication: "A total of 494 subjects were randomized into the study (...) Of these, 480 were treated, 248 with placebo and 232 with D‐tagatose" "The ITT population was approximately evenly divided between males and females (...) with approximately equivalent distributions in the D‐tagatose and placebo groups." "Three analysis populations were evaluated: (1) The Intent‐to‐Treat (ITT) population, (2) the Per Protocol (PP) population, and (3) the Safety population." Comment: in total 494 participants were randomised, out of these 356 (72.1%) were analysed in the ITT population, 204 (41.3%) in the PP population, and 392 (79.4%) in the safety population; reasons for attrition were not reported |
| Incomplete outcome data (attrition bias) | High risk | Quote from publication: "A total of 494 subjects were randomized into the study (...) Of these, 480 were treated, 248 with placebo and 232 with D‐tagatose" "The ITT population was approximately evenly divided between males and females (...) with approximately equivalent distributions in the D‐tagatose and placebo groups." "Three analysis populations were evaluated: (1) The Intent‐to‐Treat (ITT) population, (2) the Per Protocol (PP) population, and (3) the Safety population." Comment: data for body weight (kg) not provided |
| Incomplete outcome data (attrition bias) | High risk | Quote from publication: "A total of 494 subjects were randomized into the study (...) Of these, 480 were treated, 248 with placebo and 232 with D‐tagatose" "The ITT population was approximately evenly divided between males and females (...) with approximately equivalent distributions in the D‐tagatose and placebo groups." "Three analysis populations were evaluated: (1) The Intent‐to‐Treat (ITT) population, (2) the Per Protocol (PP) population, and (3) the Safety population." Comment: in total 494 participants were randomised, out of these 356 (72.1%) were analysed in the ITT population, 204 (41.3%) in the PP population, and 392 (79.4%) in the safety population; reasons for attrition were not reported |
| Incomplete outcome data (attrition bias) | High risk | Quote from publication: "A total of 494 subjects were randomized into the study (...) Of these, 480 were treated, 248 with placebo and 232 with D‐tagatose" "The ITT population was approximately evenly divided between males and females (...) with approximately equivalent distributions in the D‐tagatose and placebo groups." "Three analysis populations were evaluated: (1) The Intent‐to‐Treat (ITT) population, (2) the Per Protocol (PP) population, and (3) the Safety population." Comment: in total 494 participants were randomised, out of these 356 (72.1%) were analysed in the ITT population, 204 (41.3%) in the PP population, and 392 (79.4%) in the safety population; reasons for attrition were not reported |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote from publication: "A total of 494 subjects were randomized into the study (...) Of these, 480 were treated, 248 with placebo and 232 with D‐tagatose" "The ITT population was approximately evenly divided between males and females (...) with approximately equivalent distributions in the D‐tagatose and placebo groups." "Three analysis populations were evaluated: (1) The Intent‐to‐Treat (ITT) population, (2) the Per Protocol (PP) population, and (3) the Safety population." Comment: in total 494 participants were randomised, out of these 356 (72.1%) were analysed in the ITT population, 204 (41.3%) in the PP population, and 392 (79.4%) in the safety population; reasons for attrition were not reported |
| Selective reporting (reporting bias) | High risk | Comment: body weight and BMI were both measured, but it is only reported that no significant differences were observed between intervention and control groups. For serum insulin concentration, it is only stated that "there was no detectable consistent change in serum insulin concentrations in this trial". |
| Other bias | Unclear risk | Comment: the study was supported in part by a commercial grant |
| Study characteristics | ||
| Methods | Study design: parallel randomised controlled trial | |
| Participants | Inclusion criteria:
Exclusion criteria: — Diagnostic criteria: — Setting: outpatients Age group: adults Sex: females and males Country where trial was performed: USA | |
| Interventions | Intervention(s): sucralose, 667 mg daily in capsules Comparator(s): placebo (cellulose) capsules Duration of intervention: 13 weeks Duration of follow‐up: 17 weeks (13 weeks intervention and 4 weeks follow‐up) Run‐in period: 4 weeks; all participants received placebo capsules 2 times a day Number of study centres: 5 | |
| Outcomes | Reported outcomes in full text of publication: HbA1c, glucose levels (fasting), adverse events | |
| Identification | Trial identifier: — Trial terminated early: no | |
| Publication details | Language of publication: English Funding: commercial funding: McNeil Specialty Products Company and Tate Lyle Speciality Sweeteners Publication status: peer‐reviewed journal and full article | |
| Stated aim for study | Quote from publication: "To investigate the effect of 3‐months’ daily administration of high doses of sucralose, a non‐nutritive sweetener, on glycemic control in subjects with type 2 diabetes." | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote from publication: "The study had a double‐blind, randomized, parallel‐group design" Comment: no information about the sequence generation process |
| Allocation concealment (selection bias) | Unclear risk | Quote from publication: "The study had a double‐blind, randomized, parallel‐group design" Comment: insufficient information to judge whether intervention allocation could have been foreseen in advance |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "subjects were randomized to treatment groups, the identity of which was unknown to either the study subjects or the investigators" Comment: it is stated that blinding of participants and key personnel was ensured; self‐reported outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "subjects were randomized to treatment groups, the identity of which was unknown to either the study subjects or the investigators" Comment: it is stated that blinding of participants and key personnel was ensured; fasting glucose; investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "subjects were randomized to treatment groups, the identity of which was unknown to either the study subjects or the investigators" Comment: it is stated that blinding of participants and key personnel was ensured; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Quote from publication: "subjects were randomized to treatment groups, the identity of which was unknown to either the study subjects or the investigators" Comment: it is stated that blinding of participants (i.e. assessors of adverse events) was ensured; self‐reported outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome measurement is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome measurement is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "There were no significant differences between the treatment groups in the type, number, or severity of adverse events reported. No subjects discontinued from the study because of an adverse event, and no adverse events were documented as being probably or definitely related to treatment" Comment: adverse events are not listed in the manuscript, but they were described to be balanced in numbers across intervention groups |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote from publication: "A total of 136 subjects entered the test phase of the study. Of theses, 67 were randomized to receive sucralose and 69 to receive placebo. Eight subjects (4 each in the sucralose and placebo groups) discontinued after randomization to the test phase, none as a consequence of an adverse event. Therefore, 128 subjects completed the study" and were analysed Comment: missing outcome data are balanced in numbers across intervention groups; dropout rates are low (6.0% in the sucralose and 5.8% in the placebo group); reason for attrition is not provided |
| Incomplete outcome data (attrition bias) | Unclear risk | Comment: missing outcome data are balanced in numbers across intervention groups; dropout rates are low (6.0% in the sucralose and 5.8% in the placebo group); reason for attrition is not provided |
| Selective reporting (reporting bias) | High risk | Comment: there are outcomes of interest (HbA1c, fasting glucose, adverse events) which were reported incompletely (ORBIT classification) |
| Other bias | Unclear risk | Comment: commercial funding |
| Study characteristics | ||
| Methods | Study design: parallel randomised controlled trial | |
| Participants | Inclusion criteria:
Exclusion criteria:
Diagnostic criteria: — Setting: outpatients Age group: adults Sex: females and males Country where trial was performed: USA | |
| Interventions | Intervention(s): rebaudioside A 1000 mg daily in capsules (4 x 250 mg capsules; 97% purity) Comparator(s): placebo capsules (microcrystalline cellulose) Duration of intervention: 16 weeks Duration of follow‐up: 16 weeks Run‐in period: 2 weeks Number of study centres: 6 | |
| Outcomes | Reported outcomes in full text of publication: HbA1c, body weight (kg), adverse events, lipid profile (total‐C, HDL, LDL, TG), glucose levels (fasting), serum insulin | |
| Identification | Trial identifier: — Trial terminated early: no | |
| Publication details | Language of publication: English Funding: commercial funding: from Cargill Inc, Food Ingredients and Systems North America to the last author for consulting services Publication status: peer‐reviewed journal and full article | |
| Stated aim for study | Quote from publication: "The present study was designed to provide data on the effects, if any, of steviol glycosides on glucose homeostasis in individuals with type 2 diabetes." | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote from publication: "Subjects were randomly assigned to receive placebo or rebaudioside A" Comment: the method used to generate the allocation sequence was not described |
| Allocation concealment (selection bias) | Unclear risk | Quote from publication: "Subjects were randomly assigned to receive placebo or rebaudioside A" Comment: no information about the allocation concealment provided |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "This was a randomized, double‐blind, placebo‐controlled clinical trial" Comment: double‐blind procedure |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "This was a randomized, double‐blind, placebo‐controlled clinical trial" Comment: double‐blind procedure |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "This was a randomized, double‐blind, placebo‐controlled clinical trial" Comment: double‐blind procedure |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "This was a randomized, double‐blind, placebo‐controlled clinical trial" Comment: double‐blind procedure |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "This was a randomized, double‐blind, placebo‐controlled clinical trial" Comment: double‐blind procedure |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "This was a randomized, double‐blind, placebo‐controlled clinical trial" Comment: double‐blind procedure |
| Blinding of outcome assessment (detection bias) | Low risk | Quote from publication: "This was a randomized, double‐blind, placebo‐controlled clinical trial" Comment: participants (i.e. outcome assessors) were blinded; self‐reported outcome |
| Blinding of outcome assessment (detection bias) | Unclear risk | Comment: the outcome measurement is unlikely to have been influenced by lack of blinding; method of assessment not reported |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome measurement is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome measurement is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome measurement is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome measurement is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "122 persons with previously diagnosed type 2 diabetes mellitus were randomly assigned to receive either rebaudioside A 1000 mg/d (N = 60) or placebo (N = 62) for 16 weeks", "The reasons for discontinuation included (...) adverse events [rebaudioside A, N = 2 (gastrointestinal haemorrhage and hyperglycemia) and placebo, N = 1 (bronchitis)", "A total of 50 subjects reported at least one adverse event during the study..." Comment: both discontinuation of the study due to an adverse event and adverse events not leading to discontinuation were properly described |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "122 persons with previously diagnosed type 2 diabetes mellitus were randomly assigned to receive either rebaudioside A 1000 mg/d (N = 60) or placebo (N = 62) for 16 weeks" Comment: body weight was described for all the 122 participants randomised |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "122 persons with previously diagnosed type 2 diabetes mellitus were randomly assigned to receive either rebaudioside A 1000 mg/d (N = 60) or placebo (N = 62) for 16 weeks" Comment: fasting glucose levels were described for all the 122 participants randomised |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "122 persons with previously diagnosed type 2 diabetes mellitus were randomly assigned to receive either rebaudioside A 1000 mg/d (N = 60) or placebo (N = 62) for 16 weeks" "Glycosylated hemoglobin data were imputed by last‐observation carried forward for four subjects in the rebaudioside A group and two in the placebo group). The results did not differ materially when the data were analyzed with and without the imputed data points (data not shown)." Comment: imputed data balanced in numbers across intervention groups; imputed data not presented; missing data: 3.3% |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "122 persons with previously diagnosed type 2 diabetes mellitus were randomly assigned to receive either rebaudioside A 1000 mg/d (N = 60) or placebo (N = 62) for 16 weeks" Comment: serum insulin levels were described for all the 122 participants randomised |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "122 persons with previously diagnosed type 2 diabetes mellitus were randomly assigned to receive either rebaudioside A 1000 mg/d (N = 60) or placebo (N = 62) for 16 weeks" Comment: total‐C, HDL, LDL, and TG levels were described for all the 122 participants randomised |
| Selective reporting (reporting bias) | Low risk | Comment: the study protocol is unavailable, but based on ORBIT classification all expected outcomes seem to have been included in the publication |
| Other bias | Unclear risk | Comment: the last author received commercial funding |
| Study characteristics | ||
| Methods | Study design: parallel randomised controlled trial | |
| Participants | Inclusion criteria:
Exclusion criteria: — Diagnostic criteria: diagnosis of diabetes had been established by a fasting plasma glucose > 140 mg/dL, an abnormal oral glucose tolerance test as interpreted by the US Public Health Service criteria, or an unequivocal history of diabetes; insulin‐dependent diabetes mellitus: participants who, by history, developed ketosis or ketoacidosis when adequate exogenous insulin was not provided; non‐insulin‐dependent diabetes mellitus: individuals who are not on insulin and are not ketotic or who, if on insulin, have no history of ketoacidosis Setting: presumably outpatients Age group: adults Sex: not reported, but probably females and males Country where trial was performed: USA | |
| Interventions | Intervention(s): aspartame 2.7 g daily, in capsules Comparator(s): placebo capsules containing cornstarch, 1.8 g daily Duration of intervention: 18 weeks Duration of follow‐up: 18 weeks Run‐in period: 1 week Number of study centres: 1 | |
| Outcomes | Reported outcomes in full text of publication: HbA1c, adverse events, glucose levels (fasting and postprandial) | |
| Identification | Trial identifier: — Trial terminated early: no | |
| Publication details | Language of publication: English Funding: commercial funding: GD Searle & Co., Skokie, Illinois, and non‐commercial funding: University of Illinois Publication status: peer‐reviewed journal and full article | |
| Stated aim for study | Quote from publication: "... subjects having either insulin‐dependent or non‐insulin‐dependent diabetes completed a randomised, double‐blind study comparing effects of aspartame or a placebo on blood glucose control" | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote from publication: "Capsules were provided in coded bottles, which contained either aspartame or placebo according to a randomization table, and were assigned to subjects in sequential order" Comment: random number tables are an adequate method to generate the allocation sequence |
| Allocation concealment (selection bias) | Low risk | Quote from publication: "Capsules were provided in coded bottles, which contained either aspartame or placebo according to a randomization table, and were assigned to subjects in sequential order" Comment: the method used ensured that intervention allocation could not have been foreseen in advance or changed after assignment |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "identical appearing placebo capsules" were used Comment: self‐reported outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "identical appearing placebo capsules" were used Comment: fasting and postprandial glucose levels; investigator‐assessed outcome |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "identical appearing placebo capsules" were used Comment: investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Quote from publication: "identical appearing placebo capsules" were used Comment: outcome assessors (i.e. participants) were blinded; self‐reported outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome measurement is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: the outcome measurement is unlikely to have been influenced by lack of blinding; investigator‐assessed outcome |
| Incomplete outcome data (attrition bias) | Low risk | Quote from publication: "Of the 63 subjects, 62 completed the study." Comment: the only dropout was because of an adverse event (gastrointestinal symptoms). Types and numbers of adverse reactions are also clearly stated for participants who completed the study. |
| Incomplete outcome data (attrition bias) | Unclear risk | Comment: only 1 participant dropped out during the study from the aspartame group; dropout rate: 1.6%; the table containing fasting plasma glucose results does not report on sample sizes, i.e. it is unclear whether the data shown are for the 62 participants who completed the study |
| Incomplete outcome data (attrition bias) | Unclear risk | Comment: only 1 participant dropped out during the study from the aspartame group; dropout rate: 1.6%; the table containing HbA1c results does not report on sample sizes, i.e. it is unclear whether the data shown are for the 62 participants who completed the study |
| Selective reporting (reporting bias) | Low risk | Comment: the study protocol is unavailable, but based on ORBIT classification all expected outcomes seem to have been included in the publication |
| Other bias | Unclear risk | Comment: the study was supported in part by a commercial grant |
| Study characteristics | ||
| Methods | Study design: parallel randomised controlled trial | |
| Participants | Inclusion criteria:
Exclusion criteria: — Diagnostic criteria: — Setting: outpatients Age group: adults Sex: females and males Country where trial was performed: USA | |
| Interventions | Intervention(s): aspartame 1.8 g daily, in the form of 2 capsules 3 times daily added to the usual diet Comparator(s): matched placebo Duration of intervention: 13 weeks Duration of follow‐up: 13 weeks Run‐in period: 1 week Number of study centres: 2 | |
| Outcomes | Reported outcomes in full text of publication: body weight (unit unclear), adverse events, lipid profile (total‐C, TG), glucose levels (fasting) | |
| Identification | Trial identifier: — Trial terminated early: no | |
| Publication details | Language of publication: English Funding: non‐commercial funding: grant‐in‐aid from G.D. Searle & Co. (for presentation of study results at a scientific meeting) Publication status: peer‐reviewed journal and full article | |
| Stated aim for study | Quote from publication: "The present study was designed to determine whether non‐insulin‐dependent diabetic subjects could consume 1.8 g aspartame daily for 90 days (a) without signs or symptoms of intolerance occurring, (b) without fasting plasma phenylalanine levels exceeding 4 mg/100 ml, and/or (c) without deterioration in diabetic control" | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote from publication: "randomly assigned volunteers" Comment: no information on sequence generation |
| Allocation concealment (selection bias) | Unclear risk | Quote from publication: "randomly assigned volunteers" Comment: no information on allocation concealment |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The study design was double blind with the subjects randomly assigned to receive aspartame or matching placebo capsules." Comment: it is stated that placebos were similar; self‐reported outcome measure |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The study design was double blind with the subjects randomly assigned to receive aspartame or matching placebo capsules." Comment: it is stated that placebos were similar; investigator‐assessed outcome measure |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The study design was double blind with the subjects randomly assigned to receive aspartame or matching placebo capsules." Comment: it is stated that placebos were similar; fasting glucose levels; investigator‐assessed outcome measure |
| Blinding of participants and personnel (performance bias) | Low risk | Quote from publication: "The study design was double blind with the subjects randomly assigned to receive aspartame or matching placebo capsules." Comment: it is stated that placebos were similar; investigator‐assessed outcome measure |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: outcome assessors (i.e. participants) were blinded; self‐reported outcome |
| Blinding of outcome assessment (detection bias) | Unclear risk | Comment: not reported; investigator‐assessed outcome |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: this outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed |
| Blinding of outcome assessment (detection bias) | Low risk | Comment: this outcome is unlikely to have been influenced by lack of blinding; investigator‐assessed |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote from publication: "Sixty‐nine subjects completed the study." "Six other participants were lost to follow‐up or were discontinued for medical reasons not related to the study" Comment: dropout rate: 8%; reasons for attrition and whether they were balanced across groups was not described |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote from publication: "Sixty‐nine subjects completed the study." "Six other participants were lost to follow‐up or were discontinued for medical reasons not related to the study" Comment: dropout rate: 8%; reasons for attrition and whether they were balanced across groups was not described; unit for body weight is missing, therefore results are incomplete |
| Incomplete outcome data (attrition bias) | High risk | Comment: glucose levels were measured in both centres, but data are reported for only 1 study centre; missing data: 62.3% |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote from publication: "Sixty‐nine subjects completed the study." "Six other participants were lost to follow‐up or were discontinued for medical reasons not related to the study" Comment: dropout rate: 8%; reasons for attrition and whether they were balanced across groups was not described |
| Selective reporting (reporting bias) | Unclear risk | Comment: data for body weight were reported incompletely (without unit), data for glucose levels were reported only for 1 of the 2 study centres |
| Other bias | Unclear risk | Comment: funding of the study is unclear |
—: denotes not reported
BMI: body mass index; BP: blood pressure; BUN: blood urea nitrogen; HbA1c: glycosylated haemoglobin A1c; HDL: high‐density lipoprotein; HOMA: homeostatic model assessment; IA: investigator‐assessed; JECFA: Joint FAO/WHO Expert Committee on Food Additives; LDL: low‐density lipoprotein; ORBIT: Outcome Reporting Bias In Trials; SR: self‐reported; total‐C: total cholesterol; TG: triglycerides; WHO: World Health Organization.
Characteristics of excluded studies [ordered by study ID]
Ir a:
| Study | Reason for exclusion |
| Duration of intervention < 4 weeks | |
| Not a primary study (narrative overview) | |
| Not a primary study (narrative overview) | |
| Not a primary study (narrative overview) | |
| Duration of intervention < 4 weeks | |
| Not a primary study (narrative overview) | |
| Participants were non‐diabetic | |
| Not a primary study (narrative overview) | |
| Not a primary study (narrative overview) | |
| Not a primary study (narrative overview) | |
| Duration of intervention < 4 weeks | |
| Not a primary study (narrative overview) | |
| Trial was never started (based on information from authors: "the study have never been executed"). | |
| Not a randomised controlled trial | |
| Duration of intervention < 4 weeks | |
| Participants were non‐diabetic. | |
| Duration of intervention < 4 weeks | |
| Not a primary study (narrative overview) | |
| Not a primary study (narrative overview) | |
| Not a primary study (narrative overview) | |
| Intervention unclear ("8 candies with no sugar, 6 biscuits, and 5 sugar bars, daily") | |
| Participants were non‐diabetic | |
| Participants were non‐diabetic | |
| Participants were non‐diabetic | |
| Not a primary study (narrative overview) | |
| Intervention unclear ("subjects were instructed to continue to drink DBs (250 mL) once daily after lunch (main meal) 5 times a week") | |
| Participants were non‐diabetic | |
| Duration of intervention < 4 weeks | |
| Participants were non‐diabetic | |
| Not a primary study (narrative overview) | |
| Not a randomised controlled trial | |
| Not a primary study (narrative overview) | |
| Not a primary study (narrative overview) | |
| Participants were non‐diabetic | |
| Duration of intervention < 4 weeks | |
| Participants were non‐diabetic | |
| Intervention unclear ("diet beverages after the main meal") | |
| Participants were non‐diabetic | |
| Not a randomised clinical trial | |
| Duration of intervention < 4 weeks | |
| Not a randomised controlled trial | |
| Intervention unclear ("diet beverage (DB) of choice ") | |
| Duration of intervention < 4 weeks | |
| Not a randomised clinical trial | |
| Participants were non‐diabetic | |
| Participants were non‐diabetic | |
| Participants were non‐diabetic | |
| Participants were non‐diabetic | |
| Duration of intervention < 4 weeks | |
| Duration of intervention < 4 weeks | |
| Not a primary study (narrative overview) | |
| Participants were non‐diabetic | |
| Participants were non‐diabetic | |
| Participants were non‐diabetic | |
| Concomitant interventions were not similar: one group received a diet based on the American Diabetic Association's nutrition recommendations, and the other group received a modified, low‐calorie diet containing a fat replacer (beta‐glucans derived from oats) and the sweeteners, sucralose and fructose | |
| Not a randomised controlled trial | |
| Participants were non‐diabetic | |
| Duration of intervention < 4 weeks | |
| Wrong intervention (not an NNS) | |
| Effects of an intervention with either 20 g glucose, 20 g sucrose, or 26 g honey | |
| Not a primary study (narrative overview) | |
| Not a randomised controlled trial | |
| Not a randomised controlled trial | |
| Not a randomised controlled trial | |
| Effect of consuming 200 mL Aronia melanocarpa juice (with artificial sweeteners, but also containing flavonoids, vitamins, minerals, trace elements) compared to no intervention | |
| Not a primary study (narrative overview) | |
| Not a primary study (narrative overview) | |
| Not a primary study (narrative overview) | |
| Not a primary study (narrative overview) | |
| Participants were non‐diabetic | |
| Participants were non‐diabetic | |
| Participants were non‐diabetic | |
| Not a primary study (narrative overview) | |
| Participants were non‐diabetic | |
| Not a primary study (narrative overview) | |
| Duration of intervention < 4 weeks | |
| Not a primary study (narrative overview) | |
| Not a randomised controlled trial | |
| Not a primary study (narrative overview) | |
| Not a primary study (narrative overview) | |
| Not a randomised controlled trial | |
| Not a primary study (narrative overview) | |
| Participants were non‐diabetic |
ADA: American Dietetic Association; NNS: non‐nutritive sweetener.
Data and analyses
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 HbA1c (%) Show forest plot | 3 | 72 | Mean Difference (IV, Random, 95% CI) | 0.35 [‐0.54, 1.24] |
| Analysis 1.1  Comparison 1: NNS versus sugar, Outcome 1: HbA1c (%) | ||||
| 1.2 Body weight (kg) Show forest plot | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐0.07 [‐2.72, 2.59] |
| Analysis 1.2  Comparison 1: NNS versus sugar, Outcome 2: Body weight (kg) | ||||
| 1.3 Total cholesterol (mg/dL) Show forest plot | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐0.77 [‐11.10, 9.56] |
| Analysis 1.3  Comparison 1: NNS versus sugar, Outcome 3: Total cholesterol (mg/dL) | ||||
| 1.4 HDL cholesterol (mg/dL) Show forest plot | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.09 [‐5.59, 3.42] |
| Analysis 1.4  Comparison 1: NNS versus sugar, Outcome 4: HDL cholesterol (mg/dL) | ||||
| 1.5 LDL cholesterol (mg/dL) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Analysis 1.5  Comparison 1: NNS versus sugar, Outcome 5: LDL cholesterol (mg/dL) | ||||
| 1.6 Triglycerides (mg/dL) Show forest plot | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.52 [‐14.96, 11.91] |
| Analysis 1.6  Comparison 1: NNS versus sugar, Outcome 6: Triglycerides (mg/dL) | ||||
| 1.7 Fasting blood glucose levels (mg/dL) Show forest plot | 2 | 52 | Mean Difference (IV, Random, 95% CI) | ‐5.02 [‐28.31, 18.26] |
| Analysis 1.7  Comparison 1: NNS versus sugar, Outcome 7: Fasting blood glucose levels (mg/dL) | ||||
| 1.8 Postprandial blood glucose levels (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.8  Comparison 1: NNS versus sugar, Outcome 8: Postprandial blood glucose levels (mg/dL) | ||||
| 1.9 Serum insulin (microunits/mL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.9  Comparison 1: NNS versus sugar, Outcome 9: Serum insulin (microunits/mL) | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 HbA1c (%) Show forest plot | 4 | 360 | Mean Difference (IV, Random, 95% CI) | ‐0.00 [‐0.13, 0.13] |
| Analysis 2.1  Comparison 2: NNS versus placebo, Outcome 1: HbA1c (%) | ||||
| 2.1.1 Studies with final value scores | 2 | 108 | Mean Difference (IV, Random, 95% CI) | ‐0.11 [‐0.51, 0.28] |
| 2.1.2 Studies with change‐from‐baseline scores | 2 | 252 | Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.13, 0.17] |
| 2.2 Body weight (kg) Show forest plot | 2 | 184 | Mean Difference (IV, Random, 95% CI) | ‐0.19 [‐1.01, 0.63] |
| Analysis 2.2  Comparison 2: NNS versus placebo, Outcome 2: Body weight (kg) | ||||
| 2.2.1 Studies with final value scores | 1 | 62 | Mean Difference (IV, Random, 95% CI) | 0.90 [‐6.82, 8.62] |
| 2.2.2 Studies with change‐from‐baseline scores | 1 | 122 | Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐1.02, 0.62] |
| 2.3 Adverse events (n/N) Show forest plot | 3 | 231 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.39, 1.56] |
| Analysis 2.3  Comparison 2: NNS versus placebo, Outcome 3: Adverse events (n/N) | ||||
| 2.4 BMI (kg/m²) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 2.4  Comparison 2: NNS versus placebo, Outcome 4: BMI (kg/m²) | ||||
| 2.5 Total cholesterol (mg/dL) Show forest plot | 3 | 228 | Mean Difference (IV, Random, 95% CI) | 1.99 [‐4.82, 8.80] |
| Analysis 2.5  Comparison 2: NNS versus placebo, Outcome 5: Total cholesterol (mg/dL) | ||||
| 2.5.1 Studies with final value scores | 2 | 106 | Mean Difference (IV, Random, 95% CI) | 3.75 [‐10.83, 18.32] |
| 2.5.2 Studies with change‐from‐baseline scores | 1 | 122 | Mean Difference (IV, Random, 95% CI) | 1.50 [‐6.20, 9.20] |
| 2.6 HDL cholesterol (mg/dL) Show forest plot | 2 | 168 | Mean Difference (IV, Random, 95% CI) | ‐0.39 [‐2.17, 1.39] |
| Analysis 2.6  Comparison 2: NNS versus placebo, Outcome 6: HDL cholesterol (mg/dL) | ||||
| 2.6.1 Studies with final value score | 1 | 46 | Mean Difference (IV, Random, 95% CI) | ‐0.32 [‐4.99, 4.35] |
| 2.6.2 Studies with change‐from‐baseline scores | 1 | 122 | Mean Difference (IV, Random, 95% CI) | ‐0.40 [‐2.32, 1.52] |
| 2.7 LDL cholesterol (mg/dL) Show forest plot | 2 | 168 | Mean Difference (IV, Random, 95% CI) | 3.09 [‐2.90, 9.08] |
| Analysis 2.7  Comparison 2: NNS versus placebo, Outcome 7: LDL cholesterol (mg/dL) | ||||
| 2.7.1 Studies with final values | 1 | 46 | Mean Difference (IV, Random, 95% CI) | 1.04 [‐11.45, 13.53] |
| 2.7.2 Studies with change‐from‐baseline scores | 1 | 122 | Mean Difference (IV, Random, 95% CI) | 3.70 [‐3.13, 10.53] |
| 2.8 Triglycerides (mg/dL) Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| Analysis 2.8  Comparison 2: NNS versus placebo, Outcome 8: Triglycerides (mg/dL) | ||||
| 2.8.1 Studies with final value scores | 2 | 106 | Mean Difference (IV, Random, 95% CI) | 18.47 [‐6.78, 43.72] |
| 2.9 Fasting blood glucose levels (mg/dL) Show forest plot | 5 | 384 | Mean Difference (IV, Random, 95% CI) | 2.24 [‐11.60, 16.07] |
| Analysis 2.9  Comparison 2: NNS versus placebo, Outcome 9: Fasting blood glucose levels (mg/dL) | ||||
| 2.9.1 Studies with final value scores | 4 | 251 | Mean Difference (IV, Random, 95% CI) | 1.07 [‐23.65, 25.79] |
| 2.9.2 Studies with change‐from‐baseline scores | 1 | 133 | Mean Difference (IV, Random, 95% CI) | 3.96 [‐7.30, 15.22] |
| 2.10 Postprandial blood glucose levels (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 2.10  Comparison 2: NNS versus placebo, Outcome 10: Postprandial blood glucose levels (mg/dL) | ||||
| 2.10.1 Studies with final value scores | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.11 Serum insulin (microunits/mL) Show forest plot | 2 | 152 | Mean Difference (IV, Random, 95% CI) | ‐2.51 [‐5.39, 0.37] |
| Analysis 2.11  Comparison 2: NNS versus placebo, Outcome 11: Serum insulin (microunits/mL) | ||||
| 2.11.1 Studies with final value scores | 1 | 30 | Mean Difference (IV, Random, 95% CI) | ‐3.70 [‐11.13, 3.73] |
| 2.11.2 Studies with change‐from‐baseline scores | 1 | 122 | Mean Difference (IV, Random, 95% CI) | ‐2.30 [‐5.42, 0.82] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 HbA1c (%) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 3.1  Comparison 3: NNS versus another type of sweetener, Outcome 1: HbA1c (%) | ||||
| 3.2 Total cholesterol (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 3.2  Comparison 3: NNS versus another type of sweetener, Outcome 2: Total cholesterol (mg/dL) | ||||
| 3.3 HDL cholesterol (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 3.3  Comparison 3: NNS versus another type of sweetener, Outcome 3: HDL cholesterol (mg/dL) | ||||
| 3.4 LDL cholesterol (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 3.4  Comparison 3: NNS versus another type of sweetener, Outcome 4: LDL cholesterol (mg/dL) | ||||
| 3.5 Triglycerides (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 3.5  Comparison 3: NNS versus another type of sweetener, Outcome 5: Triglycerides (mg/dL) | ||||
| 3.6 Fasting glucose (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 3.6  Comparison 3: NNS versus another type of sweetener, Outcome 6: Fasting glucose (mg/dL) | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 HbA1c (%) Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| Analysis 4.1  Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 1: HbA1c (%) | ||||
| 4.1.1 Correlation coefficient: 0 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | 0.36 [‐0.52, 1.24] |
| 4.1.2 Correlation coefficient: 0.8 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | 0.34 [‐0.57, 1.26] |
| 4.2 Body weight (kg) Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| Analysis 4.2  Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 2: Body weight (kg) | ||||
| 4.2.1 Correlation coefficient: 0 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐0.06 [‐3.81, 3.68] |
| 4.2.2 Correlation coefficient: 0.8 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐0.07 [‐1.75, 1.61] |
| 4.3 Total cholesterol (mg/dL) Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| Analysis 4.3  Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 3: Total cholesterol (mg/dL) | ||||
| 4.3.1 Correlation coefficient: 0 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐0.87 [‐15.35, 13.62] |
| 4.3.2 Correlation coefficient: 0.8 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.38 [‐10.21, 7.46] |
| 4.4 HDL cholesterol (mg/dL) Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| Analysis 4.4  Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 4: HDL cholesterol (mg/dL) | ||||
| 4.4.1 Correlation coefficient: 0 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.10 [‐7.40, 5.21] |
| 4.4.2 Correlation coefficient: 0.8 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.06 [‐3.98, 1.86] |
| 4.5 LDL cholesterol (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 4.5  Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 5: LDL cholesterol (mg/dL) | ||||
| 4.5.1 Correlation coefficient: 0 | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.5.2 Correlation coefficient: 0.8 | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.6 Triglycerides (mg/dL) Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| Analysis 4.6  Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 6: Triglycerides (mg/dL) | ||||
| 4.6.1 Correlation coefficient: 0 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.53 [‐19.91, 16.84] |
| 4.6.2 Correlation coefficient: 0.8 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.49 [‐10.75, 7.77] |
| 4.7 Fasting blood glucose levels (mg/dL) Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| Analysis 4.7  Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 7: Fasting blood glucose levels (mg/dL) | ||||
| 4.7.1 Correlation coefficient: 0 | 2 | 52 | Mean Difference (IV, Random, 95% CI) | ‐5.01 [‐37.78, 27.75] |
| 4.7.2 Correlation coefficient: 0.8 | 2 | 52 | Mean Difference (IV, Random, 95% CI) | ‐5.05 [‐19.99, 9.88] |
| 4.8 Postprandial blood glucose levels (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 4.8  Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 8: Postprandial blood glucose levels (mg/dL) | ||||
| 4.8.1 Correlation coefficient: 0 | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.8.2 Correlation coefficient: 0.8 | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.9 Serum insulin (microunits/mL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 4.9  Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 9: Serum insulin (microunits/mL) | ||||
| 4.9.1 Correlation coefficient: 0 | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.9.2 Correlation coefficient: 0.8 | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
Trial flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials (blank cells indicate that the particular outcome was not measured in some trials).
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial (blank cells indicate that the particular outcome was not measured in some trials)
Forest plot of comparison: 2 NNS versus placebo, outcome: 2.1 HbA1c (%).
Forest plot of comparison: 2 NNS versus placebo, outcome: 2.2 Body weight (kg).
Forest plot of comparison: 2 NNS versus placebo, outcome: 2.3 Adverse events (n/N).
Comparison 1: NNS versus sugar, Outcome 1: HbA1c (%)
Comparison 1: NNS versus sugar, Outcome 2: Body weight (kg)
Comparison 1: NNS versus sugar, Outcome 3: Total cholesterol (mg/dL)
Comparison 1: NNS versus sugar, Outcome 4: HDL cholesterol (mg/dL)
Comparison 1: NNS versus sugar, Outcome 5: LDL cholesterol (mg/dL)
Comparison 1: NNS versus sugar, Outcome 6: Triglycerides (mg/dL)
Comparison 1: NNS versus sugar, Outcome 7: Fasting blood glucose levels (mg/dL)
Comparison 1: NNS versus sugar, Outcome 8: Postprandial blood glucose levels (mg/dL)
Comparison 1: NNS versus sugar, Outcome 9: Serum insulin (microunits/mL)
Comparison 2: NNS versus placebo, Outcome 1: HbA1c (%)
Comparison 2: NNS versus placebo, Outcome 2: Body weight (kg)
Comparison 2: NNS versus placebo, Outcome 3: Adverse events (n/N)
Comparison 2: NNS versus placebo, Outcome 4: BMI (kg/m²)
Comparison 2: NNS versus placebo, Outcome 5: Total cholesterol (mg/dL)
Comparison 2: NNS versus placebo, Outcome 6: HDL cholesterol (mg/dL)
Comparison 2: NNS versus placebo, Outcome 7: LDL cholesterol (mg/dL)
Comparison 2: NNS versus placebo, Outcome 8: Triglycerides (mg/dL)
Comparison 2: NNS versus placebo, Outcome 9: Fasting blood glucose levels (mg/dL)
Comparison 2: NNS versus placebo, Outcome 10: Postprandial blood glucose levels (mg/dL)
Comparison 2: NNS versus placebo, Outcome 11: Serum insulin (microunits/mL)
Comparison 3: NNS versus another type of sweetener, Outcome 1: HbA1c (%)
Comparison 3: NNS versus another type of sweetener, Outcome 2: Total cholesterol (mg/dL)
Comparison 3: NNS versus another type of sweetener, Outcome 3: HDL cholesterol (mg/dL)
Comparison 3: NNS versus another type of sweetener, Outcome 4: LDL cholesterol (mg/dL)
Comparison 3: NNS versus another type of sweetener, Outcome 5: Triglycerides (mg/dL)
Comparison 3: NNS versus another type of sweetener, Outcome 6: Fasting glucose (mg/dL)
Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 1: HbA1c (%)
Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 2: Body weight (kg)
Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 3: Total cholesterol (mg/dL)
Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 4: HDL cholesterol (mg/dL)
Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 5: LDL cholesterol (mg/dL)
Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 6: Triglycerides (mg/dL)
Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 7: Fasting blood glucose levels (mg/dL)
Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 8: Postprandial blood glucose levels (mg/dL)
Comparison 4: Sensitivity analysis: NNS versus sugar, Outcome 9: Serum insulin (microunits/mL)
| Non‐nutritive sweeteners compared with sucrose, placebo, or a nutritive, low‐calorie sweetener for diabetes mellitus | ||||||
| Patient: people with diabetes mellitus Settings: outpatients Intervention: non‐nutritive sweeteners (aspartame, rebaudioside A, saccharin, sodium‐cyclamate, sucralose, steviol glycoside) Comparison: sucrose; placebo; nutritive, low‐calorie sweetener (tagatose) | ||||||
| Outcomes/Comparisions | Comparator | Non‐nutritive sweeteners | Relative effect | Number of participants | Certainty of the evidence | Comments |
|---|---|---|---|---|---|---|
| Health‐related quality of life | Not reported | |||||
| Diabetes complications | Not reported | |||||
| All‐cause mortality | Not reported | |||||
| Non‐serious adverse events (N) | ||||||
| NNS versus sugar | Not reported | |||||
| NNS versus placebo NNS: aspartame, rebaudioside A, steviol glycoside Follow‐up: 16 to 18 weeks | 356 per 1000 | 278 per 1000 (139 to 555) | RR 0.78 (0.39 to 1.56) | 231 (3) | ⊕⊝⊝⊝a | |
| NNS versus nutritive, low‐calorie sweetener | Not reported | |||||
| HbA1c (%) | ||||||
| NNS versus sugar NNS: aspartame, saccharin, sodium‐cyclamate Follow‐up: 4 to 6 weeks | The mean HbA1c ranged across control groups from 6.8% to 7.5% | The mean HbA1c in the NNS group was 0.4% higher (0.5% lower to 1.2% higher) | ‐ | 72 (3) | ⊕⊝⊝⊝b | |
| NNS versus placebo NNS: aspartame, rebaudioside A, steviol glycoside Follow‐up: 13 to 16 weeks | The mean final HbA1c ranged across control groups from 7.3% to 11.4% | The mean HbA1c in the NNS and placebo groups did not differ (MD 0%, −0.1% lower to 0.1% higher) | ‐ | 360 (4) | ⊕⊝⊝⊝c | The 95% prediction interval ranged between −0.3% and 0.3% |
| NNS versus nutritive, low‐calorie sweetener (tagatose) NNS: sucralose Follow‐up: 16 weeks | The mean HbA1c in the control group was 7.3% | The mean HbA1c in the NNS group was 0.3% higher (0.1% higher to 0.4% higher) | ‐ | 354 (1) | ⊕⊝⊝⊝d | |
| Body weight (kg) | ||||||
| NNS versus sugar NNS: aspartame, saccharin, sodium‐cyclamate Follow‐up: 4 to 6 weeks | The mean body weight in the control groups was 66.8 kg to 75.9 kg | The mean body weight in the intervention groups was 0.1 kg lower (2.7 kg lower to 2.6 kg higher) | ‐ | 72 (3) | ⊕⊝⊝⊝e | |
| NNS versus placebo NNS: aspartame, rebaudioside A Follow‐up: 12 to 16 weeks | The mean final body weight ranged across control groups from to 79.4 to 98.4 kg | The mean body weight in the intervention groups was 0.2 kg lower (1 kg lower to 0.6 kg higher) | ‐ | 184 (2) | ⊕⊝⊝⊝f | |
| NNS versus nutritive, low‐calorie sweetener | Not reported | |||||
| Socioeconomic effects | Not reported | |||||
| *The basis for the assumed risk (e.g. the median control group risk across trials) 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). | ||||||
| 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. | ||||||
| aDowngraded by one level because of inconsistency (no consistent direction of effect) and two levels because of serious imprecision (CI consistent with benefit and harm, small sample size, and small number of studies) ‐ see Appendix 18. | ||||||
| Sweetener | FDA (mg/kg body weight) (FDA 2015a ) | SCF/EFSA (mg/kg body weight) (Mortensen 2006 ) | JECFA (mg/kg body weight) (JECFA 2010 ) |
|---|---|---|---|
| ACE‐K | 15 | 9 | 15 |
| Advantame | 32.8 | 5 | 5 |
| Aspartame | 50 | 40 | 40 |
| Cyclamate | Not approved | 7 | 11 |
| Luo han guo fruit extracts | Not specified | Not specified | Not specified |
| Neohesperidine DC | Not approved | 5 | Not evaluated |
| Neotame | 0.3 | 2 | 2 |
| Saccharin | 15 | 5 | 5 |
| Sucralose | 5 | 15 | 15 |
| Steviol glycosides | 4 | 4 | 4 |
| Thaumatin | Not approved | Not specified | Not specified |
| ACE‐K: acesulfame potassium; DC: dihydrochalcone; EFSA: European Food Safety Authority;FDA: US Food and Drug Administration; JECFA: Joint FAO/WHO Expert Committee on Food Additives; SCF: Scientific Committee on Food (European Commission). | |||
| Trial ID (trial design) | Intervention(s) and comparator(s) | Description of power and sample size calculation | Screened/eligible (N) | Randomised (N) | Analysed (primary outcome) (N) | Finishing trial (N) | Randomised finishing trial (%) | Follow‐up |
|---|---|---|---|---|---|---|---|---|
| Ensor 2015 (parallel RCT) | I: Splenda 1.5 g 3 times a day, dissolved in 125 to 250 mL water | ‐ | ‐ | 253 | 184a | 119 | ‐ | 12 months |
| C: D‐tagatose 15 g 3 times a day, dissolved in 125 to 250 mL water | 241 | 172a | 85 | ‐ | ||||
| 494 | 356 | 204 | 41.3 | |||||
| (parallel RCT) | I: steviol glycoside capsules 250 mg 3 times a day (92% purity) | "Power analysis were also conducted to determine whether the samples were large enough to allow for the detection of a clinically significant change between baseline and post treatment levels within the control and treatment groups. A clinically significant difference was defined based on the range of 'normal' values for each of the parameters considered." | ‐ | ‐ | 8 + 15b | 23b | ‐ | 3 months |
| C: placebo capsules 3 times a day | ‐ | 8 + 15b | 23b | ‐ | ||||
| total: | 53 | 46 | 46 | 86.8 | ||||
| (parallel RCT) | I: rebaudioside A 250 mg 4 times a day in capsules (97% purity) | "The study was designed to provide 90% power (α = 0.05, two‐sided) to detect a 0.5% difference in HbA1c response between treatment groups, assuming a standard deviation of 0.8%." | 175 | 60 | 60 | 58 | 96.7 | 16 weeks |
| C: placebo capsules 4 times a day (microcrystalline cellulose) | 62 | 62 | 58 | 93.5 | ||||
| total: | 122 | 122 | 116 | 95.1 | ||||
| (parallel RCT) | I: sucralose 667 mg daily in capsules | "The number of subjects was based on achieving at least 90% power to detect a 0.6 treatment group difference in percent HbA1c change from baseline. Post‐study analysis showed that the study provided more than 99.99% power to detect this difference, and more than 90% to detect a difference of 0.3." | ‐ | 67 | 65c | 63 | 94 | 17 weeks |
| C: placebo (cellulose) capsules | 69 | 68c | 65 | 94.2 | ||||
| total: | 136 | 133c | 128 | 94.1 | ||||
| (cross‐over RCT) | I: aspartame 162 mg daily, added to the usual diet | ‐ | ‐ | ‐ | 9 | 9 | ‐ | 6 weeks |
| C: sucrose 45 g daily, added to the usual diet | ‐ | 9 | 9 | ‐ | ||||
| total: | 9 | 9 | 9 | 100 | ||||
| (cross‐over RCT) | I: saccharin and starch 30 g daily, added to the usual diet | ‐ | ‐ | 17 | 17 | 17 | 100 | 6 weeks |
| C: sucrose 28 g daily, added to the usual diet | 17 | 17 | 17 | 100 | ||||
| total: | 17 | 17 | 17 | 100 | ||||
| (cross‐over RCT) | I: sodium‐cyclamate, ad libitum (348 ± 270 mg/day) | ‐ | 10 | 10 | 10 | 10 | 100 | 4 weeks |
| C: sucrose, ad libitum (24 ± 13 g/day) | 10 | 10 | 10 | 100 | ||||
| total: | 10 | 10 | 10 | 100 | ||||
| (parallel RCT) | I: aspartame 2.7 g daily, in capsules | ‐ | 63 | 30 | 29 | 29 | 96.7 | 18 weeks |
| C: placebo (cornstarch) 1.8 g daily in capsules | 33 | 33 | 33 | 100 | ||||
| total: | 63 | 62 | 62 | 98.4 | ||||
| (parallel RCT) | I: aspartame 300 mg capsules, 2 capsules 3 times daily added to the usual diet | ‐ | ‐ | ‐ | ‐ | 36 | ‐ | 13 weeks |
| C: matched placebo | ‐ | ‐ | 33 | ‐ | ||||
| total: | 75 | ‐ | 69 | 92 | ||||
| Grand total | All interventions | 437d | 364e | |||||
| All comparators | 432d | 333e | ||||||
| All interventions and comparators | 979d | 661e | ||||||
| ‐: denotes not reported C: comparator; HbA1c: glycosylated haemoglobin A1c; I: intervention; RCT: randomised controlled trial. aWe provided numbers for the intention‐to‐treat analysis. Authors also performed a per‐protocol analysis, with 119 participants in the Splenda and 85 in the tagatose group. | ||||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 HbA1c (%) Show forest plot | 3 | 72 | Mean Difference (IV, Random, 95% CI) | 0.35 [‐0.54, 1.24] |
| 1.2 Body weight (kg) Show forest plot | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐0.07 [‐2.72, 2.59] |
| 1.3 Total cholesterol (mg/dL) Show forest plot | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐0.77 [‐11.10, 9.56] |
| 1.4 HDL cholesterol (mg/dL) Show forest plot | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.09 [‐5.59, 3.42] |
| 1.5 LDL cholesterol (mg/dL) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.6 Triglycerides (mg/dL) Show forest plot | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.52 [‐14.96, 11.91] |
| 1.7 Fasting blood glucose levels (mg/dL) Show forest plot | 2 | 52 | Mean Difference (IV, Random, 95% CI) | ‐5.02 [‐28.31, 18.26] |
| 1.8 Postprandial blood glucose levels (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.9 Serum insulin (microunits/mL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 HbA1c (%) Show forest plot | 4 | 360 | Mean Difference (IV, Random, 95% CI) | ‐0.00 [‐0.13, 0.13] |
| 2.1.1 Studies with final value scores | 2 | 108 | Mean Difference (IV, Random, 95% CI) | ‐0.11 [‐0.51, 0.28] |
| 2.1.2 Studies with change‐from‐baseline scores | 2 | 252 | Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.13, 0.17] |
| 2.2 Body weight (kg) Show forest plot | 2 | 184 | Mean Difference (IV, Random, 95% CI) | ‐0.19 [‐1.01, 0.63] |
| 2.2.1 Studies with final value scores | 1 | 62 | Mean Difference (IV, Random, 95% CI) | 0.90 [‐6.82, 8.62] |
| 2.2.2 Studies with change‐from‐baseline scores | 1 | 122 | Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐1.02, 0.62] |
| 2.3 Adverse events (n/N) Show forest plot | 3 | 231 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.39, 1.56] |
| 2.4 BMI (kg/m²) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.5 Total cholesterol (mg/dL) Show forest plot | 3 | 228 | Mean Difference (IV, Random, 95% CI) | 1.99 [‐4.82, 8.80] |
| 2.5.1 Studies with final value scores | 2 | 106 | Mean Difference (IV, Random, 95% CI) | 3.75 [‐10.83, 18.32] |
| 2.5.2 Studies with change‐from‐baseline scores | 1 | 122 | Mean Difference (IV, Random, 95% CI) | 1.50 [‐6.20, 9.20] |
| 2.6 HDL cholesterol (mg/dL) Show forest plot | 2 | 168 | Mean Difference (IV, Random, 95% CI) | ‐0.39 [‐2.17, 1.39] |
| 2.6.1 Studies with final value score | 1 | 46 | Mean Difference (IV, Random, 95% CI) | ‐0.32 [‐4.99, 4.35] |
| 2.6.2 Studies with change‐from‐baseline scores | 1 | 122 | Mean Difference (IV, Random, 95% CI) | ‐0.40 [‐2.32, 1.52] |
| 2.7 LDL cholesterol (mg/dL) Show forest plot | 2 | 168 | Mean Difference (IV, Random, 95% CI) | 3.09 [‐2.90, 9.08] |
| 2.7.1 Studies with final values | 1 | 46 | Mean Difference (IV, Random, 95% CI) | 1.04 [‐11.45, 13.53] |
| 2.7.2 Studies with change‐from‐baseline scores | 1 | 122 | Mean Difference (IV, Random, 95% CI) | 3.70 [‐3.13, 10.53] |
| 2.8 Triglycerides (mg/dL) Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 2.8.1 Studies with final value scores | 2 | 106 | Mean Difference (IV, Random, 95% CI) | 18.47 [‐6.78, 43.72] |
| 2.9 Fasting blood glucose levels (mg/dL) Show forest plot | 5 | 384 | Mean Difference (IV, Random, 95% CI) | 2.24 [‐11.60, 16.07] |
| 2.9.1 Studies with final value scores | 4 | 251 | Mean Difference (IV, Random, 95% CI) | 1.07 [‐23.65, 25.79] |
| 2.9.2 Studies with change‐from‐baseline scores | 1 | 133 | Mean Difference (IV, Random, 95% CI) | 3.96 [‐7.30, 15.22] |
| 2.10 Postprandial blood glucose levels (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.10.1 Studies with final value scores | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.11 Serum insulin (microunits/mL) Show forest plot | 2 | 152 | Mean Difference (IV, Random, 95% CI) | ‐2.51 [‐5.39, 0.37] |
| 2.11.1 Studies with final value scores | 1 | 30 | Mean Difference (IV, Random, 95% CI) | ‐3.70 [‐11.13, 3.73] |
| 2.11.2 Studies with change‐from‐baseline scores | 1 | 122 | Mean Difference (IV, Random, 95% CI) | ‐2.30 [‐5.42, 0.82] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 HbA1c (%) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.2 Total cholesterol (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.3 HDL cholesterol (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.4 LDL cholesterol (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.5 Triglycerides (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.6 Fasting glucose (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 HbA1c (%) Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 4.1.1 Correlation coefficient: 0 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | 0.36 [‐0.52, 1.24] |
| 4.1.2 Correlation coefficient: 0.8 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | 0.34 [‐0.57, 1.26] |
| 4.2 Body weight (kg) Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 4.2.1 Correlation coefficient: 0 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐0.06 [‐3.81, 3.68] |
| 4.2.2 Correlation coefficient: 0.8 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐0.07 [‐1.75, 1.61] |
| 4.3 Total cholesterol (mg/dL) Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 4.3.1 Correlation coefficient: 0 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐0.87 [‐15.35, 13.62] |
| 4.3.2 Correlation coefficient: 0.8 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.38 [‐10.21, 7.46] |
| 4.4 HDL cholesterol (mg/dL) Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 4.4.1 Correlation coefficient: 0 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.10 [‐7.40, 5.21] |
| 4.4.2 Correlation coefficient: 0.8 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.06 [‐3.98, 1.86] |
| 4.5 LDL cholesterol (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.5.1 Correlation coefficient: 0 | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.5.2 Correlation coefficient: 0.8 | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.6 Triglycerides (mg/dL) Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 4.6.1 Correlation coefficient: 0 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.53 [‐19.91, 16.84] |
| 4.6.2 Correlation coefficient: 0.8 | 3 | 72 | Mean Difference (IV, Random, 95% CI) | ‐1.49 [‐10.75, 7.77] |
| 4.7 Fasting blood glucose levels (mg/dL) Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 4.7.1 Correlation coefficient: 0 | 2 | 52 | Mean Difference (IV, Random, 95% CI) | ‐5.01 [‐37.78, 27.75] |
| 4.7.2 Correlation coefficient: 0.8 | 2 | 52 | Mean Difference (IV, Random, 95% CI) | ‐5.05 [‐19.99, 9.88] |
| 4.8 Postprandial blood glucose levels (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.8.1 Correlation coefficient: 0 | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.8.2 Correlation coefficient: 0.8 | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.9 Serum insulin (microunits/mL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.9.1 Correlation coefficient: 0 | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.9.2 Correlation coefficient: 0.8 | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
