Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial

May combine two claims.

The weight changes seen at 12 months in the intention-to-treat population of the present study are similar to those reported in a Counterweight-Plus feasibility study and in an audit of its use in routine primary care.

“The weight changes seen at 12 months in the intention-to-treat population of the present study are similar to those reported in a Counterweight-Plus feasibility study (-9•5 kg in intention-to-treat analyses with baseline observation carried forward [n=91]) 12 and in an audit of its use in routine primary care, including patients with type 2 diabetes (-10•5 kg in intention-to-treat analyses with im”

• cites [12] 12. Doherty A, Jackson D, Hammerla N, Plötz T, et al. Large Scale Population Assessment of Physical Activity Using Wrist Worn Accelerometers: The UK Biobank Study. PLoS One 2017 12(2):e0169649 sourceCould not verify

  The Methods and Results passages describe seven-day accelerometer monitoring in UK Biobank, not a weight-loss intervention. Searches for Counterweight-Plus, 12-month weight change, and the primary-care audit found no passage in our copy addressing the attributed comparison. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [19] 19. Franz M, Vanwormer JJ, Crain L et al. Weight-loss Outcomes: A Systematic Review and Meta- Analysis of Weight-loss Clinical Trials with a Minimum 1 year follow up. J AmDietAssoc 2007;107:1755-1767. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Physical activity and sleep were objectively measured over 7 days by use of wrist-worn triaxial accelerometers, and data were assessed with validated calibration and analysis algorithms.

“Physical activity and sleep were objectively measured over 7 days by use of wristworn triaxial accelerometers; data were assessed with validated calibration and analysis algorithms.13,14”

• cites [13] 13. van Hees VT, Sabia S, Anderson KN, et al. A Novel, Open Access Method to Assess Sleep Duration Using a Wrist-Worn Accelerometer. PLoS One.2015;10(11):e0142533. sourcePartly supported

  The Instrumentation section reports wrist-worn triaxial accelerometers, and Data Processing describes calibration methods and a sleep-analysis algorithm validated against polysomnography. But participants were asked to wear the devices for nine consecutive days, not seven; the paper also does not establish validation of a physical-activity analysis algorithm. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [14] 14. National Institute for Health and Care Excellence Type 2 diabetes in adults: management 2015 https://www.nice.org.uk/guidance/ng28 Accessed 30.10.2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim.

Practices agreeing to participate were randomly assigned (1:1) by the Robertson Centre for Biostatistics via a computer-generated list to intervention or control.

“Practices agreeing to participate were randomly assigned (1:1) by the Robertson Centre for Biostatistics (University of Glasgow, UK), via a computer-generated list, to provide either an evidence-based weight management programme (Counterweight-Plus; intervention) 12 or best-practice care by guidelines (control).”

• cites [12] 12. Doherty A, Jackson D, Hammerla N, Plötz T, et al. Large Scale Population Assessment of Physical Activity Using Wrist Worn Accelerometers: The UK Biobank Study. PLoS One 2017 12(2):e0169649 sourceCould not verify

  The Methods (Study Population; page unavailable) describe randomly selecting UK Biobank participants’ email addresses for accelerometer invitations, not randomly assigning practices to trial arms. Searches for the Robertson Centre and Counterweight-Plus found no passage addressing the claimed 1:1 allocation or weight-management intervention. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

May combine two claims.

Type 2 diabetes is strongly related to weight gain in adult life and accumulation of excess fat within the liver and pancreas.

“Type 2 diabetes is strongly related to weight gain in adult life and accumulation of excess fat within the liver and pancreas.”

• cites [4] 4. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011; 54: 2506-2514 sourcePartly supported

  The Discussion (page not provided) links type 2 diabetes to excess lipid accumulation in the liver and pancreas, describing this as a hypothesis consistent with the study’s findings. The paper does not establish the separate claim that type 2 diabetes is strongly related to weight gain in adult life; it studied weight loss after diagnosis, not adult-life weight gain. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

For participants who ceased to engage and did not attend their 12 month trial appointment, data from GP records within a window of plus or minus 3 months of the scheduled follow-up date were used if available, as pre-specified in the protocol.

“For participants who ceased to engage and did not attend their 12 month trial appointment, data from GP records (within a window of plus or minus 3 months of the scheduled follow-up date) were used if available, as pre-specified in the protocol.11”

• cites [11] 11. Lean M, Brosnahan N, McLoone P, et al. Feasibility and indicative results from a 12-month low-energy liquid diet treatment and maintenance programme for severe obesity. Br J Gen Pract 2013; 63: e115-124 sourcePartly supported

  The Outcome evaluations for analysis section says 12-month weights were taken within ±90 days of 365 days from baseline, and that weights for patients lost to follow-up were obtained opportunistically from health-professional measurements outside the study. It does not specify GP records, a missed trial appointment, or that this approach was pre-specified in a protocol. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Look AHEAD delivered a heavily supported programme in specialist centres, combining physical activity and dietary programme, and achieved a mean weight loss of 8.6 kg.

“Look AHEAD 21 delivered a heavily supported programme in specialist centres, combining physical activity and dietary programme, and achieved a mean weight loss of 8•6 kg.”

• cites [21] 21. Gregg EW, Chen H, Wagenknecht LE, Clark JM, Delahanty LM, Bantle J, et al. Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA : the journal of the American Medical Association. 2012;308(23):2489-96 sourcePartly supported

  The Study Design and Intervention sections describe 16 US research centers and frequent counseling combining dietary changes with increased physical activity. The Results report mean first-year weight loss of 8.6%, not 8.6 kg; the claimed unit is unsupported. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

The twin cycle hypothesis postulated that type 2 diabetes is caused specifically by excess fat within the liver and pancreas.

“The twin cycle hypothesis, 4 which postulated that type 2 diabetes is caused specifically by excess fat within the liver and pancreas, was tested by inducing negative energy balance with a 600-700 kcal/day diet.”

• cites [4] 4. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011; 54: 2506-2514 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

28% of all eligible individuals volunteered to participate, and 79% completed the intensive total diet replacement phase.

“28% of all eligible individuals volunteered to participate, 17 and 79% completed the intensive total diet replacement phase”

• cites [17] 17. Finer S, Robb P, Cowan K, Daly A, Robertson E, Farmer A. Top ten research priorities for type 2 diabetes: results from the Diabetes UK-James Lind Alliance Priority Setting Partnership. Lancet Online First DOI:http://dx.doi.org/10.1016/S2213-8587(17)30324-8 accessed 13.11.2017 sourceCould not verify

  The citation follows the 28% participation figure. The paper’s section on the priority-setting process reports responses to a research-priorities questionnaire, not the proportion of eligible individuals who volunteered for a diet-replacement intervention. Searches for the 28% figure and the total diet replacement phase found no supporting passage in our copy; no page number is available. (LLM, conf=0.77)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Bariatric surgery has dominated discussions of type 2 diabetes remission as the most effective way of producing major weight loss.

“Bariatric surgery has dominated discussions of type 2 diabetes remission as the most effective way of producing major weight loss.8,9,10”

• cites [8] 8. Sjostrom L. Review of the key results from the Swedish Obese Subjects (SOS) trial -a prospective controlled intervention study of bariatric surgery. J Intern Med 2013; 273: 219- 10.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [9] 9. Schauer PR, Burguera B, Ikramuddin S, et al.) Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Ann Surg 2003; 238: 467-484 sourceSupported
• cites [10] 10. Leslie WS, Ford I, Sattar N, et al. The Diabetes Remission Clinical Trial (DiRECT): protocol for a cluster randomised trial. BMC Fam Pract 2016; 17: 20 sourcePartly supported

  The Background and Discussion describe bariatric surgery as a way to achieve substantial weight loss and type 2 diabetes remission, and note that guidelines recommend it for obese patients with type 2 diabetes. They do not say it dominated discussions of remission or establish it as the most effective way to produce major weight loss; the paper also describes substantial weight loss through non-surgical diets. The indexed passages provide section labels but no page numbers. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

The sample had characteristics very similar to the general population of people with type 2 diabetes, so the results are likely to be generalisable.

“The sample had characteristics very similar to the general population of people with type 2 diabetes, so the results are likely to be generalisable.17”

• cites [17] 17. Finer S, Robb P, Cowan K, Daly A, Robertson E, Farmer A. Top ten research priorities for type 2 diabetes: results from the Diabetes UK-James Lind Alliance Priority Setting Partnership. Lancet Online First DOI:http://dx.doi.org/10.1016/S2213-8587(17)30324-8 accessed 13.11.2017 sourcePartly supported

  The paper’s section on the Priority Setting Partnership (page unavailable) reports broad reach among key target groups and expresses confidence that the process captured key research priorities. It does not compare respondents’ characteristics with those of the general population of people with type 2 diabetes, so the stated basis for generalisability is unsupported. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Sudden restoration of normoglycaemia can precipitate worsening of diabetic retinopathy, although this outcome is rare when early or no retinopathy is present.

“Sudden restoration of normoglycaemia can precipitate worsening of diabetic retinopathy, although this outcome is rare when early or no retinopathy is present.35”

• cites [35] 35. McCombie L, Leslie W, Taylor R, Kennon B, Sattar N, Lean MEJ. Beating type 2 diabetes into remission. BMJ 2017 358:j4030 https://doi.org/10.1136/bmj.j4030 accessed 13.11.2017 Age (years) 55•9 (7•3) 52•9 (7•6) Weight (kg) 98•8 (16•1) 101•0 (16•7) BMI (kg/•3) •5) Waist (cm) 106•9) 107•4) Systolic BP (mmHg) 137•2 (16•0) 132• sourceCould not verify

  The 'Potential metabolic value of remission' section (p. 2) says good glycaemic control improves microvascular outcomes, including retinopathy, but does not address transient worsening after sudden restoration of normoglycaemia. Searches for rapid glucose improvement and early retinopathy found no passage addressing the claimed risk or its rarity. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The benefits to individuals and the improved physical and psychological wellbeing accompanying substantial weight loss have previously been documented.

“The benefits to individuals 32 and the improved physical and psychological wellbeing accompanying substantial weight loss have previously been documented.33”

• cites [32] 32. Rehackova L, Araujo-Soares V, Adamson AJ, Stevens S, Taylor R, Sniehotta FF. Acceptability of a Very Low Energy Diet in Type 2 Diabetes: Patient Experiences and Behaviour Regulation. Diabetic Med 2017; 34:1554-1567 sourcePartly supported

  The Changing management section (p. 1) links substantial weight loss in people with type 2 diabetes to longer life expectancy and remission, and says remission brings personal achievement and empowerment. These support physical and psychological benefits in that setting, but the paper does not document improved wellbeing from substantial weight loss for individuals generally. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [33] 33. The LookAHEAD Research Group. Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial. The Lancet Diabetes & Endocrinology 2016, 4: 913-921Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

Even if diabetes recurs, there might be a legacy effect of a period of good glucose control, as suggested in the UK Prospective Diabetes Study.

“Even if diabetes recurs, there might be a legacy effect of a period of good glucose control, as suggested in the UK Prospective Diabetes Study.35”

• cites [35] 35. McCombie L, Leslie W, Taylor R, Kennon B, Sattar N, Lean MEJ. Beating type 2 diabetes into remission. BMJ 2017 358:j4030 https://doi.org/10.1136/bmj.j4030 accessed 13.11.2017 Age (years) 55•9 (7•3) 52•9 (7•6) Weight (kg) 98•8 (16•1) 101•0 (16•7) BMI (kg/•3) •5) Waist (cm) 106•9) 107•4) Systolic BP (mmHg) 137•2 (16•0) 132• sourcePartly supported

  The ‘Potential metabolic value of remission’ section (p. 2) says good glycaemic control improves microvascular outcomes and notes that remission can decline over time. It does not say that benefits persist after diabetes recurs or attribute a legacy effect to the UK Prospective Diabetes Study. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

Remission was closely related to the degree of weight loss maintained at 12 months, with achievement in 86% of participants with at least 15 kg weight loss and 73% of those with weight loss of 10 kg or more.

“Remission was closely related to the degree of weight loss maintained at 12 months, with achievement in 86% of participants with at least 15 kg weight loss, and 73% of those with weight loss of 10 kg or more.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Two serious adverse events (biliary colic and abdominal pain), occurring in the same participant, were deemed potentially related to the intervention.

“Two serious adverse events (biliary colic and abdominal pain), occurring in the same participant, were deemed potentially related to the intervention.”

May combine two claims.

Most of these adverse events were of mild or moderate severity and dissipated over time.

“Most of these adverse events were of mild or moderate severity and dissipated over time (appendix p10).”

May combine two claims.

Remission varied with weight loss in the whole study population: none of 76 participants who gained weight, six (7%) of 89 who maintained 0-5 kg loss, 19 (34%) of 56 with 5-10 kg loss, 16 (57%) of 28 with 10-15 kg loss, and 31 (86%) of 36 who lost 15 kg or more.

“Remission varied with weight loss in the whole study population, with achievement in none of 76 participants who gained weight, six (7%) of 89 participants who maintained 0-5 kg weight loss, 19 (34%) of 56 participants with 5-10 kg loss, 16 (57%) of 28 participants with 10-15 kg loss, and 31 (86%) of 36 participants who lost 15 kg or more.”

May combine two claims.

Mean bodyweight fell by 10.0 kg (SD 8.0) in the intervention group and 1.0 kg (SD 3.7) in the control group; adjusted difference -8.8 kg (95% CI -10.3 to -7.3; p<0.0001).

“Mean bodyweight fell by 10•0 kg (SD 8•0) in the intervention group and 1•0 kg (3•7) in the control group (adjusted difference -8•8 kg, 95% CI -10•3 to -7•3; p<0•0001).”

• AssumptionThe authors state this as an assumption: Participants with missing primary outcome data were assumed not to have met the primary outcomes.

May combine two claims.

In per-protocol analysis, diabetes remission occurred in 65/127 (51.2%) intervention participants vs 6/147 (4.1%) control participants, OR 23.8 (95% CI 9.60-58.8), p<0.0001.

“Diabetes remission (HbA1c <48mmol/mol, off diabetic medication of ≥2 months) Intervention 65/127 (b) (51•2%) 23•8 (9•60, 58•8) p<0•0001 Control 6/147 (4•1%)”

May combine two claims.

At 12 months, HbA1c <42 mmol/mol was achieved by 40/138 (29.0%) intervention participants vs 7/148 (4.7%) control participants, OR 8.38 (95% CI 3.49-20.14), p<0.0001.

“HbA1c <42mmol/mol Intervention 40/138 (29•0%) 8•38 (3•49, 20•14) p<0•0001 Control 7/148 (4•7%)”

Probably not a substantial claim: may not pass S3 (load-bearing).

Similar patterns were recorded for BMI and weight change as a percentage of baseline weight.

“Similar patterns were recorded for BMI and weight change as a percentage of baseline weight (appendix p2).”

May combine two claims.

Patients who completed the total diet replacement phase had greater weight loss than those who started but did not complete it; change during TDR was -14.5 kg vs -3.0 kg, difference -11.5 kg (95% CI -14.5 to -8.6), p<0.0001.

“Patients who completed the total diet replacement phase had greater weight loss, and those who completed the food reintroduction phase less weight gain, than did patients who started, but did not complete, each phase (figure 3, appendix p4).”

• Also stated in: § Imputation options: · plain

  “Change during TDR Mean (SD) [95% CI] -14•5 (6•0) [-15•5, -13•4] -3•0 (3•6) [-5•0, -1•0] -11•5 (-14•5, -8•6), p<0•0001”

Probably not a substantial claim: may not pass S3 (load-bearing).

During the TDR phase, constipation was the most common adverse effect, reported by 65 (46.8%) of 139 intervention participants.

“Constipation 65 (46•8) 30 (21•6) 24 (17•3) 11 (7•9) 18 (14•5) 14 (11•3) 4 (3•2) 0 (0•0) 6 (6•4) 2 (2•1) 2 (2•1) 2 (2•1)”

Probably not a substantial claim: may not pass S3 (load-bearing).

At 12 months, there was no significant difference between intervention and control in number of other prescribed medications (effect -0.08, 95% CI -0.49 to 0.33, p=0.7036).

“Number of other prescribed medications (not oral antidiabetic or antihypertensive) Intervention 148 3•5 (3•0) 4•0 (3•9) 0•5 (2•0) -0•08 (-0•49, 0•33) p=0•7036 (b) <0•01 Control 148 3•6 (3•4) 4•2 (3•7) 0•6 (1•4)”

Probably not a substantial claim: may not pass S3 (load-bearing).

Four participants in the intervention group who had diabetes remission had received a short rescue plan in the total diet replacement phase because of weight regain within 60 days of their 12 month assessment.

“Four participants in the intervention group who had diabetes remission had received a short rescue plan in the total diet replacement phase because of weight regain within 60 days of their 12 month assessment.”

May combine two claims.

68% of the intervention group remained off antihypertensive drugs at 12 months, with no increase in mean blood pressure.

“This approach resulted in 68% of the intervention group remaining off antihypertensive drugs at 12 months, with no increase in mean blood pressure.”

Probably not a substantial claim: may not pass S3 (load-bearing).

At 12 months, there was no significant difference between intervention and control in HDL cholesterol (relative difference 1.06, 95% CI 1.00-1.13, p=0.0563).

“HDL-cholesterol (mmol/l) Intervention 121 1•1 (0•3) 1•2 (0•4) 0•13 (0•25) 1•06 (1•00, 1•13) p=0•0563 0•15 Control 147 1•2 (0•3) 1•2 (0•3) 0•04 (0•21)”

Probably not a substantial claim: may not pass S3 (load-bearing).

At 12 months, there was no significant difference between intervention and control in diastolic blood pressure (effect -0.4, 95% CI -2.5 to 1.6, p=0.6863).

“Diastolic blood pressure (mmHg) Intervention 128 84•8 (10•2) 83•5 (9•5) -1•3 (10•3) -0•4 (-2•5, 1•6) p=0•6863 <0•01 Control 147 85•5 (8•8) 84•5 (8•9) -1•1 (10•1)”

Probably not a substantial claim: may not pass S3 (load-bearing).

At 12 months, there was no significant difference between intervention and control in total cholesterol (relative difference 1.03, 95% CI 0.97-1.10, p=0.2874).

“Total cholesterol (mmol/l) Intervention 121 4•3 (1•1) 4•5 (1•3) 0•23 (1•36) 1•03 (0•97, 1•10) p=0•2874 0•05 Control 147 4•3 (1•1) 4•3 (1•1) 0•07 (0•87)”

Probably not a substantial claim: may not pass S3 (load-bearing).

In year 1, 26 intervention participants withdrew from treatment, compared with 0 control participants.

“Control (n=115) Intervention (143) Reason for withdrawal 0 26 (0) No remission; patient decision 0 1 (3.8%)Medical reasons 0 2 (7.7%)Social reasons 0 8 (30.8%)Limited weight loss 0 3 (11.5%)Weight regain 0 1 (3.8%)Other 0 6 (23.1%)Not Known 0 5 (19.2%)”

May combine two claims.

The programme allowed almost half of participants to revert to a non-diabetic state, off antidiabetic drugs at 12 months, and 68% stopped antihypertensive medications with no rise in blood pressure.

“The programme allowed almost half of participants to revert to a non-diabetic state, off antidiabetic drugs at 12 months, and 68% stopped antihypertensive medications with no rise in blood pressure.”

May combine two claims.

At 12 months, diabetes remission occurred in 68 (46%) intervention participants and 6 (4%) control participants (odds ratio 19.7, 95% CI 7.8-49.8; p<0.0001).

“We recorded diabetes remission in 68 (46%) participants in the intervention group and six (4%) participants in the control group (odds ratio 19•7, 95% CI 7•8-49•8; p<0•0001, Fig 2).”

May combine two claims.

At 12 months, BMI decreased by 3.5 kg/m2 in intervention vs 0.4 kg/m2 in control, adjusted difference -3.0 (95% CI -3.5 to -2.5), p<0.0001.

“BMI (kg/m 2 ) Intervention 137 35•0 (4•5) 31•5 (4.9) -3•5 (2.8) -3•0 (-3•5, -2•5) p<0•0001 0•01 Control 148 34•2 (4•3) 33•8 (4•5) -0•4 (1.3)”

May combine two claims.

Patients who completed the food reintroduction phase had less weight gain than those who started but did not complete it; change during FR was 1.0 kg vs 3.2 kg, difference -2.7 kg (95% CI -4.3 to -1.1), p=0.0010.

“Patients who completed the total diet replacement phase had greater weight loss, and those who completed the food reintroduction phase less weight gain, than did patients who started, but did not complete, each phase (figure 3, appendix p4).”

• Also stated in: § Imputation options: · plain

  “Change during FR Mean (SD) [95% CI] 1•0 (3•2) [0•3, 1•6] 3•2 (2•3) [2•1, 4•3] -2•7 (-4•3, -1.1), p=0•0010”

Probably not a substantial claim: may not pass S3 (load-bearing).

At 12 months, weight during the WLM phase was 87.0 kg in completers vs 92.0 kg in non-completers, difference -5.0 kg (95% CI -11.6 to 1.7), p=0.1424.

“12 Months Mean (SD) 87•0 (15•1) 92•0 (17•2) -5•0 (-11•6, 1•7), p=0•1424”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In terms of lipids, only triglyceride concentrations declined, while baseline cholesterol values were suppressed under guideline-driven statin prescriptions.

“In terms of lipids, although only triglyceride concentrations declined, baseline cholesterol values were suppressed under guidelinedriven statin prescriptions.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Two of the 12 participants who received rescue plans within 60 days of their 12 month assessment achieved more than 15 kg weight loss.

“Two of the 12 participants who received rescue plans within 60 days of their 12 month assessment achieved more than 15 kg weight loss.”

May combine two claims.

Mean bodyweight fell by 10.0 kg in the intervention group and by 1.0 kg in the control group, with an adjusted difference of -8.8 kg (95% CI -10.3 to -7.3; p<0.0001).

“Mean bodyweight fell by 10•0 kg in the intervention group and by 1•0 kg in the control group (adjusted difference at -8•8 kg, 95% CI -10•3 to -7•3; p<0•0001; Table 2).”

May combine two claims.

At 12 months, HbA1c <48 mmol/mol was achieved by 71/138 (48.6%) intervention participants vs 23/148 (15.5%) control participants, OR 7.02 (95% CI 3.66-13.46), p<0.0001.

“All Patients HbA1c <48mmol/mol Intervention 71/138 (48•6%) 7•02 (3•66, 13•46) p<0•0001 Control 23/148 (15•5%)”

Probably not a substantial claim: may not pass S3 (load-bearing).

Change during the WLM phase was 1.9 kg in completers vs 2.4 kg in non-completers, difference -0.6 kg (95% CI -1.8 to 0.7), p=0.3809.

“Change during WLM Mean (SD) [95% CI] 1•9 (2•9) [1•2, 2•5] 2•4 (3•0) [1•3, 3•5] -0•6 (-1•8, 0•7), p=0•3809”

Probably not a substantial claim: may not pass S3 (load-bearing).

At 12 months, there was no significant difference between intervention and control in prescribed antidepressants (OR 1.40, 95% CI 0.79-2.49, p=0.2506).

“Control 91/148 (61.5%)Prescribed antidepressants Intervention 40/148 (27.0%) 1.40 (0.79, 2.49) p=0.2506”

May combine two claims.

At 12 months, percentage weight change from baseline was -9.9% in intervention vs -1.1% in control, adjusted difference -8.8% (95% CI -10.2 to -7.3), p<0.0001.

“Percentage weight change from baseline (a) Intervention 137 -9•9 (7•6) -8•8 (-10•2, -7•3) p<0•0001 0•01 Control 148 -1•1 (3•8)”

Classified as probably not a substantial claim. May combine two claims.

The planned primary analyses were done at the individual level, according to the intention-to-treat principle.

“The planned primary analyses were done at the individual level, according to the intention-to-treat principle.”

May combine two claims.

Liver insulin resistance and fat content normalised within 7 days, with first-phase insulin response and pancreas fat content normalising over 8 weeks, when negative energy balance was induced with a 600-700 kcal/day diet.

“Liver insulin resistance and fat content normalised within 7 days, with first-phase insulin response and pancreas fat content normalising over 8 weeks.5”

• cites [5] 5. Steven S, Hollingsworth KG, Al-Mrabeh A, et al. Very Low Calorie Diet and 6 Months of Weight Stability in Type 2 Diabetes: Pathophysiological Changes in Responders and Nonresponders. Diabetes Care 2016; 39: 158-165Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

Information about symptoms was collected only from participants in the intervention group.

“Information about symptoms was collected only from participants in the intervention group.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All models were adjusted for the minimisation variables (study centre and practice list size).

“All models were adjusted for the minimisation variables (study centre and practice list size).”

Probably not a substantial claim: may not pass S3 (load-bearing).

The large numbers of people with type 2 diabetes makes it impossible to offer surgery to all people, even if this approach were financially possible and palatable to everyone.

“The large numbers of people with type 2 diabetes makes it impossible to offer surgery to all people, even if this approach were financially possible and palatable to everyone.”

May combine two claims.

Bariatric surgery comes at a high financial cost and with the risk of long-term problems, such as post-prandial hypoglycaemia and micronutrient deficiencies that restrict acceptability.

“However, this option comes at a high financial cost and with the risk of long-term problems, such as post-prandial hypoglycaemia, and micronutrient deficiencies that restrict acceptability.25,26”

• cites [25] 25. Vecht J, Masclee AA, Lamers CB. The dumping syndrome. Current insights into pathophysiology, diagnosis and treatment. Scand J Gastroenterol Suppl 1997; 223: 21-27Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [26] 26. White MG, Shaw JAM, Taylor R. Type 2 diabetes: The pathologic basis of reversible beta-cell dysfunction. Diabetes Care 2016; 39: 2080-2088 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Outcomes were compared between groups with mixed-effects regression models, with adjustment for GP practice as a random effect.

“Outcomes were compared between groups with mixed-effects regression models, with adjustment for GP practice as a random effect.”

May combine two claims.

The Counterbalance study reported similar weight loss, but was intensively managed with very low calorie diet in a research centre.

“The Counterbalance study 6 reported similar weight loss, but was intensively managed with very low calorie diet in a research centre.”

• cites [6] 6. Henry RR, Schaeffer L, Olefsky JM. Glycaemic effects of intensive caloric restriction and isocaloric refeeding in non-insulin dependent diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 1985; 61: 917-925 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Wing and colleagues reported improvement of HbA1c, from a higher baseline level than DiRECT, after a very low calorie diet intervention under specialist supervision, with mean weight loss at 12 months of 8.6 kg.

“More than 25 years ago, Wing and colleagues 24 reported improvement of HbA1c, from a higher baseline level than DiRECT, after a very low calorie diet intervention under specialist supervision, with mean weight loss at 12 months of 8•6 kg.”

• cites [24] 24. Meier JJ, Butler AE, Galasso R, Butler PC. Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased beta-cell turnover. Diabetes Care 2006; 29: 1554-1559 sourceNot checked — no full text of the source

May combine two claims.

23 (8%) participants were lost to follow-up at 12 months, with 128 (86%) intervention and 147 (99%) control participants attending the 12 month study assessment.

“23 (8%) participants were lost to follow-up at 12 months, with 128 (86%) participants in the intervention group and 147 (99%) participants in the control group attending the 12 month study assessment.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A nurse or dietitian in each intervention practice was given 8 h structured training by study research dietitians experienced in Counterweight-Plus, following a standard protocol to minimise variability and maintain fidelity across all practices.

“A nurse or dietitian (as available locally) in each intervention practice was given a total of 8 h structured training by the study research dietitians experienced in Counterweight-Plus.Training followed a standard protocol, to minimise variability and maintain fidelity across all practices.”

May combine two claims.

Data for the first primary outcome (weight loss ≥15 kg) were available for 285 (96%) participants, and for the second primary outcome (diabetes remission) for 290 (97%) participants.

“Thus, data for the first primary outcome (weight loss ≥15kg) were available for 285 (96%) participants (n=137 intervention and n=148 control), and for the second primary outcome (diabetes remission) for 290 (97%) participants (n=142 and n=148, respectively).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Randomisation was stratified to maintain balance for practice list size (>5700 or ≤5700) across intervention groups within each study region.

“Randomisation was stratified to maintain balance for practice list size (>5700 or ≤5700) across intervention groups within each study region.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Antihypertensive drugs were withdrawn because blood pressure rapidly decreases upon commencement of a low energy diet.

“Antihypertensive drugs were withdrawn because blood pressure rapidly decreases upon commencement of a low energy diet.6”

• cites [6] 6. Henry RR, Schaeffer L, Olefsky JM. Glycaemic effects of intensive caloric restriction and isocaloric refeeding in non-insulin dependent diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 1985; 61: 917-925 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Sample-size calculations indicated that recruitment of 280 participants would be required to achieve 80% power.

“Sample-size calculations indicated that recruitment of 280 participants would be required to achieve 80% power.”

May combine two claims.

In the intervention group, six (4%) participants consented but never engaged with the intervention, and 26 (17%) participants withdrew from treatment during the first 12 months.

“In the intervention group, six (4%) participants consented, but thereafter never engaged with the intervention, and 26 (17%) participants withdrew from treatment during the first 12 months (n=15 during total diet replacement, n=6 during stepped food reintroduction, and n=5 during weight loss maintenance).”

May combine two claims.

Remission of type 2 diabetes was not the primary outcome in Look AHEAD, but was observed in 11.5% of participants after 1 year and 7.5% after 4 years, with 9.2% achieving remission for at least 2 years.

“Remission of type 2 diabetes was not the primary outcome in Look AHEAD, but was observed in 11•5% of participants after 1 year and 7•5% after 4 years, with 9•2% achieving remission for at least 2 years.22”

• cites [22] 22. Uusitupa MIJ. Early Lifestyle Intervention in Patients with Non-insulin-dependent Diabetes Mellitus and Impaire Glucose Tolerance. Annals of Med 28: 445-449; 2006 http://dx.doi.org/10.3109/07853899608999106 accessed 13.11.201 sourceNot checked — no full text of the source

Classified as probably not a substantial claim. May combine two claims.

The co-primary outcomes were analysed hierarchically, with the weight loss outcome first and no adjustment of p values for multiple comparisons.

“The co-primary outcomes were analysed in a hierarchical manner, the weight loss outcome first, with no adjustment of the p values for multiple comparisons.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

“The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Models of continuous outcomes were also adjusted for the baseline measurement of the outcome.

“Models of continuous outcomes were also adjusted for the baseline measurement of the outcome.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Findings from Franz and colleagues' meta-analysis showed an average weight change of about 10 kg at 12 months from interventions with very low calorie diets.

“Findings from Franz and colleagues' meta-analysis 20 showed an average weight change of about 10 kg at 12 months from interventions with very low calorie diets.”

• cites [20] 20. LookAhead Research Group. Eight-year weight losses with an intensive lifestyle intervention: the look AHEAD study. Obesity 2014; 22: 5-13Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

A Finnish study showed improved glucose control and reduced use of diabetes medication after years 1 and 2 of a lifestyle intervention.

“A Finnish study 23 showed improved glucose control and reduced use of diabetes medication after years 1 and 2 of a lifestyle intervention.”

• cites [23] 23. Wing RR, Marcus MD, Salata R, Epstein LH, Miaskiewicz S, Blair EH. Effects of a very-low- calorie diet on long-term glycemic control in obese type 2 diabetic subjects. Arch Intern Med. 1991;151(7):1334-40. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Participants, carers, and research assistants who collected outcome data were aware of group allocation.

“Due to the nature of the lifestyle intervention being examined, participants, carers, and research assistants who collected outcome data were aware of group allocation; however, allocation was concealed from the study statistician in charge of developing and conducting the statistical analysis programme (AM).”

May combine two claims.

The primary care practice was the unit of randomisation to enable consistent management of type 2 diabetes within practices and avoid contamination between treatment groups.

“The primary care practice was the unit of randomisation to enable consistent management of type 2 diabetes within practices and avoid contamination between treatment groups.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Allocation was concealed from the study statistician in charge of developing and conducting the statistical analysis programme.

“Due to the nature of the lifestyle intervention being examined, participants, carers, and research assistants who collected outcome data were aware of group allocation; however, allocation was concealed from the study statistician in charge of developing and conducting the statistical analysis programme (AM).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The strengths of the study include a well-defined evidence-based intervention and a robust cluster-randomised study design, managed by a well-established clinical trials unit.

“The strengths of the study include a well-defined evidence-based intervention and a robust cluster-randomised study design, managed by a well-established clinical trials unit.”

Classified as probably not a substantial claim.

Intervention effects for binary outcomes were estimated using mixed effects logistic regression models adjusted for randomised group, study centre, practice list size, and GP practice as a random effect.

“Intervention effects reported as estimated odds ratios (Intervention:Control), based on mixed effects logistic regression model, adjusted for randomised group, study centre (Tyneside, Scotland), and practice list size (≤5700, >5700) as fixed effects, and GP practice as a random effect.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

There were limitations to the data that could be collected in the routine primary care setting; therefore, detailed body composition was not assessed.

“There were limitations to the data that could be collected in the routine primary care setting; therefore, detailed body composition was not assessed.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The data for physical activity should be viewed with caution because they were based on around half of all participants in each group for whom the data were complete.

“The data for physical activity should be viewed with caution because they were based on around half of all participants in each group for whom the data were complete.”

May combine two claims.

Information about serious adverse events was collected in both groups retrospectively at the 12 month assessments, and only two events, in the same participant, might have been related to the intervention.

“We did collect information about serious adverse events in both groups, retrospectively at the 12 month assessments, and recorded only two, in the same participant, that might have been related to the intervention.”

May combine two claims.

It is not possible to exclude some contamination of the control group, with deliberate weight loss as a result of media publicity about the intervention during the study; such contamination would have tended to attenuate the effects of the intervention.

“It is not possible to exclude some contamination of the control group, with deliberate weight loss as a result of media publicity about the intervention during the study.Such contamination would have tended to attenuate the effects of the intervention.”

Classified as probably not a substantial claim.

Intervention effects for continuous outcomes were estimated using mixed effects linear regression models adjusted for randomised group, baseline value, study centre, practice list size, and GP practice as a random effect.

“Intervention effects reported as estimated mean differences (Intervention-Control), based on mixed effects linear regression model, adjusted for randomised group, baseline value (a) , study centre (Tyneside, Scotland), and practice list size (≤5700, >5700) as fixed effects, and GP practice as a random effect.”

May combine two claims.

Weight loss leads to a rapid and marked fall in blood pressure, with risk of postural hypotension if antihypertensive drugs are continued.

“Weight loss leads to a rapid and marked fall in blood pressure, with risk of postural hypotension if antihypertensive drugs are continued.”

• cites [6] 6. Henry RR, Schaeffer L, Olefsky JM. Glycaemic effects of intensive caloric restriction and isocaloric refeeding in non-insulin dependent diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 1985; 61: 917-925 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

The dropout rate of 25% in the intervention group was an indication of non-acceptability for this proportion, but should be considered in relation to the overall effectiveness of the programme for a much greater proportion.

“The dropout rate of 25% in the intervention group was an indication of non-acceptability for this proportion, but should be considered in relation to the overall effectiveness of the programme for a much greater proportion.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study was funded by Diabetes UK, the formula diet was donated by Cambridge Weight Plan, and neither organisation had any input into the study design, data analysis or interpretation.

“This study was funded as a Strategic Research Initiative by Diabetes UK (award number 13/0004691).The formula diet was donated by Cambridge Weight Plan.Neither organisation had any input into the study design, data analysis or interpretation.”

May combine two claims.

The study design stipulated data collection from the control group only at baseline and 12 months, so intercurrent adverse events could not be assessed.

“The study design stipulated data collection from the control group only at baseline and 12 months, so intercurrent adverse events could not be assessed.”

May combine two claims.

Antidiabetic medications were stopped in the intervention group but not in the control group; withdrawal might have been possible in some control participants, but the study design was a comparison of the entire programme with current standard of care under current guidelines.

“Antidiabetic medications were stopped in the intervention group, but not in the control group.Withdrawal of antidiabetic medications might have been possible in some participants in the control group, but the study design was a comparison of the entire programme with current standard of care, under current guidelines.”

May combine two claims.

The racial and ethnic characteristics, while typical of the populations of Scotland and Tyneside, do not allow for unqualified extrapolation to other groups, such as south Asians, who tend to develop diabetes with less weight gain.

“The racial and ethnic characteristics, while typical of the populations of Scotland and Tyneside, do not allow for unqualified extrapolation to other groups, such as south Asians, who tend to develop diabetes with less weight gain.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Differences in change during each treatment phase were derived from a linear regression model adjusted for weight at the start of the phase.

“Differences in the change during each phase derived from a linear regression model of the change in weight, adjusted for weight at the start of the phase”

Classified as probably not a substantial claim.

The present study was not designed or powered to evaluate effects on complications of diabetes.

“The present study was not designed or powered to evaluate effects on complications of diabetes.”

May combine two claims.

The sample size exceeded the need for statistical power, and the remission rate of 46% greatly exceeded the level of 22% considered clinically important.

“The sample size exceeded the need for statistical power, and the remission rate of 46% greatly exceeded the level of 22% considered clinically important.”

May combine two claims.

Because the unit of randomisation was the primary care centre, participants were aware of their planned allocation; however, negligible bias seemed to result from this design on the basis of baseline group characteristics.

“Because the unit of randomisation was the primary care centre, participants were aware of their planned allocation to the control or intervention group; however, negligible bias seemed to result from this design on the basis of baseline group characteristics.”

May combine two claims.

A carryover acute effect of the rescue plans suppressing HbA1c in these participants cannot be excluded, but any such effect would have been very small and unlikely to affect the study conclusions.

“We cannot exclude a carryover acute effect of the rescue plans suppressing HbA1c in these participants, but believe any such effect would have been very small and unlikely to affect the study conclusions.”

May combine two claims.

The conclusions reported here apply to people with type 2 diabetes diagnosed within the previous 6 years, and existing evidence has shown that remission is less likely with longer durations of disease.

“The conclusions reported here apply to people with type 2 diabetes diagnosed within the previous 6 years, and existing evidence has shown that remission is less likely with longer durations of disease.6,8”

• cites [6] 6. Henry RR, Schaeffer L, Olefsky JM. Glycaemic effects of intensive caloric restriction and isocaloric refeeding in non-insulin dependent diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 1985; 61: 917-925 sourceNot checked — no full text of the source
• cites [8] 8. Sjostrom L. Review of the key results from the Swedish Obese Subjects (SOS) trial -a prospective controlled intervention study of bariatric surgery. J Intern Med 2013; 273: 219- 10.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

For per-protocol analyses, no assumptions were made about missing values.

“For per protocol analyses, no assumptions were made about missing values.”

May combine two claims.

Given that few control participants achieved remission, the planned subgroup analyses using logistic regression models with interaction terms were highly underpowered, so the odds ratios presented relate to achievement of the outcome in the intervention group only.

“Given that few in the control group achieved this outcome, the planned analyses using logistic regression models with interaction terms were highly underpowered, so the odds ratios presented here relate to achievement of the outcome in the Intervention group only, for each subgroup relative to the reference group”