A WHO key informant language survey of people with lived experiences of diabetes: Media misconceptions, values-based messaging, stigma, framings and communications considerations.

AIMS: This study aimed to learn from people with lived experiences of diabetes to raise the quality of diabetes communications. METHODS: An online key informant survey for people (18+) with a direct and/or adjacent (caregiver, friend, family-member etc.,) lived experience of diabetes. Through thematic analysis, we gathered insights on perceptions of media reporting on diabetes and communicating with accuracy, impact and without stigma. Descriptive analysis also investigated effective values for WHO to communicate diabetes with key audiences of policy-makers, funding partners and the general public. RESULTS: 918 respondents in 58 WHO Member States were analysed. Participants identified five key themes requiring more appropriate consideration in the media: accurately defining diabetes types, over-emphasis on sugar and lifestyle, negative impacts of diabetes stigma, burden of costs (financial, personal and interpersonal) and mental health. Irrespective of audience, key values-based messages identified as important for WHO to convey included: 'urgency', 'preventing suffering', 'improving wellbeing' and 'meaningful engagement' of people with lived experience. CONCLUSION: Learning from people with lived experience of diabetes identifies key diabetes communication considerations. Continued meaningful engagement of this group, including in WHO's work and the multistakeholder diffusion of this methodology to local contexts, could improve public discourse on diabetes and related policies.

(Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus.

BACKGROUND: People with type 1 diabetes mellitus (T1DM) need treatment with insulin for survival. Whether any particular type of (ultra-)long-acting insulin provides benefit especially regarding risk of diabetes complications and hypoglycaemia is unknown. OBJECTIVES: To compare the effects of long-term treatment with (ultra-)long-acting insulin analogues to NPH insulin (neutral protamine Hagedorn) or another (ultra-)long-acting insulin analogue in people with type 1 diabetes mellitus. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform and the reference lists of systematic reviews, articles and health technology assessment reports. We explored the US Food and Drug Administration (FDA) and European Medical Agency (EMA) web pages. We asked pharmaceutical companies, EMA and investigators for additional data and clinical study reports (CSRs). The date of the last search of all databases was 24 August 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of 24 weeks or more comparing one (ultra-)long-acting insulin to NPH insulin or another (ultra-)long-acting insulin in people with T1DM. DATA COLLECTION AND ANALYSIS: Two review authors assessed risk of bias using the new Cochrane 'Risk of bias' 2 (RoB 2) tool and extracted data. Our main outcomes were all-cause mortality, health-related quality of life (QoL), severe hypoglycaemia, non-fatal myocardial infarction/stroke (NFMI/NFS), severe nocturnal hypoglycaemia, serious adverse events (SAEs) and glycosylated haemoglobin A1c (HbA1c). We used a random-effects model to perform meta-analyses and calculated risk ratios (RRs) and odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) and 95% prediction intervals for effect estimates. We evaluated the certainty of the evidence applying the GRADE instrument. MAIN RESULTS: We included 26 RCTs. Two studies were unpublished. We obtained CSRs, clinical study synopses or both as well as medical reviews from regulatory agencies on 23 studies which contributed to better analysis of risk of bias and improved data extraction. A total of 8784 participants were randomised: 2428 participants were allocated to NPH insulin, 2889 participants to insulin detemir, 2095 participants to insulin glargine and 1372 participants to insulin degludec. Eight studies contributing 21% of all participants comprised children. The duration of the intervention varied from 24 weeks to 104 weeks. Insulin degludec versus NPH insulin: we identified no studies comparing insulin degludec with NPH insulin. Insulin detemir versus NPH insulin (9 RCTs): five deaths reported in two studies including adults occurred in the insulin detemir group (Peto OR 4.97, 95% CI 0.79 to 31.38; 9 studies, 3334 participants; moderate-certainty evidence). Three studies with 870 participants reported QoL showing no true beneficial or harmful effect for either intervention (low-certainty evidence). There was a reduction in severe hypoglycaemia in favour of insulin detemir: 171/2019 participants (8.5%) in the insulin detemir group compared with 138/1200 participants (11.5%) in the NPH insulin group experienced severe hypoglycaemia (RR 0.69, 95% CI 0.52 to 0.92; 8 studies, 3219 participants; moderate-certainty evidence). The 95% prediction interval ranged between 0.34 and 1.39. Only 1/331 participants in the insulin detemir group compared with 0/164 participants in the NPH insulin group experienced a NFMI (1 study, 495 participants; low-certainty evidence). No study reported NFS. A total of 165/2094 participants (7.9%) in the insulin detemir group compared with 102/1238 participants (8.2%) in the NPH insulin group experienced SAEs (RR 0.95, 95% CI 0.75 to 1.21; 9 studies, 3332 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 70/1823 participants (3.8%) in the insulin detemir group compared with 60/1102 participants (5.4%) in the NPH insulin group (RR 0.67, 95% CI 0.39 to 1.17; 7 studies, 2925 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin detemir with NPH insulin was 0.01%, 95% CI -0.1 to 0.1; 8 studies, 3122 participants; moderate-certainty evidence. Insulin glargine versus NPH insulin (9 RCTs): one adult died in the NPH insulin group (Peto OR 0.14, 95% CI 0.00 to 6.98; 8 studies, 2175 participants; moderate-certainty evidence). Four studies with 1013 participants reported QoL showing no true beneficial effect or harmful effect for either intervention (low-certainty evidence). Severe hypoglycaemia was observed in 122/1191 participants (10.2%) in the insulin glargine group compared with 145/1159 participants (12.5%) in the NPH insulin group (RR 0.84, 95% CI 0.67 to 1.04; 9 studies, 2350 participants; moderate-certainty evidence). No participant experienced a NFMI and one participant in the NPH insulin group experienced a NFS in the single study reporting this outcome (585 participants; low-certainty evidence). A total of 109/1131 participants (9.6%) in the insulin glargine group compared with 110/1098 participants (10.0%) in the NPH insulin group experienced SAEs (RR 1.08, 95% CI 0.63 to 1.84; 8 studies, 2229 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 69/938 participants (7.4%) in the insulin glargine group compared with 83/955 participants (8.7%) in the NPH insulin group (RR 0.83, 95% CI 0.62 to 1.12; 6 studies, 1893 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin glargine with NPH insulin was 0.02%, 95% CI -0.1 to 0.1; 9 studies, 2285 participants; moderate-certainty evidence. Insulin detemir versus insulin glargine (2 RCTs),insulin degludec versus insulin detemir (2 RCTs), insulin degludec versus insulin glargine (4 RCTs): there was no evidence of a clinically relevant difference for all main outcomes comparing (ultra-)long-acting insulin analogues with each other. For all outcomes none of the comparisons indicated differences in tests of interaction for children versus adults. AUTHORS' CONCLUSIONS: Comparing insulin detemir with NPH insulin for T1DM showed lower risk of severe hypoglycaemia in favour of insulin detemir (moderate-certainty evidence). However, the 95% prediction interval indicated inconsistency in this finding. Both insulin detemir and insulin glargine compared with NPH insulin did not show benefits or harms for severe nocturnal hypoglycaemia. For all other main outcomes with overall low risk of bias and comparing insulin analogues with each other, there was no true beneficial or harmful effect for any intervention. Data on patient-important outcomes such as QoL, macrovascular and microvascular diabetic complications were sparse or missing. No clinically relevant differences were found between children and adults.

Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus.

BACKGROUND: The term prediabetes is used to describe a population with an elevated risk of developing type 2 diabetes mellitus (T2DM). With projections of an increase in the incidence of T2DM, prevention or delay of the disease and its complications is paramount. It is currently unknown whether pioglitazone is beneficial in the treatment of people with increased risk of developing T2DM. OBJECTIVES: To assess the effects of pioglitazone for prevention or delay of T2DM and its associated complications in people at risk of developing T2DM. SEARCH METHODS: We searched CENTRAL, MEDLINE, Chinese databases, ICTRP Search Portal and ClinicalTrials.gov. We did not apply any language restrictions. Further, we investigated the reference lists of all included studies and reviews. We tried to contact all study authors. The date of the last search of databases was November 2019 (March 2020 for Chinese databases). SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a minimum duration of 24 weeks, and participants diagnosed with intermediate hyperglycaemia with no concomitant diseases, comparing pioglitazone as monotherapy or part of dual therapy with other glucose-lowering drugs, behaviour-changing interventions, placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts, read full-text articles and records, assessed risk of bias and extracted data. We performed meta-analyses with a random-effects model and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, with 95% confidence intervals (CIs) for effect estimates. We evaluated the certainty of the evidence with the GRADE. MAIN RESULTS: We included 27 studies with a total of 4186 randomised participants. The size of individual studies ranged between 43 and 605 participants and the duration varied between 6 and 36 months. We judged none of the included studies as having low risk of bias across all 'Risk of bias' domains. Most studies identified people at increased risk of T2DM by impaired fasting glucose or impaired glucose tolerance (IGT), or both. Our main outcome measures were all-cause mortality, incidence of T2DM, serious adverse events (SAEs), cardiovascular mortality, nonfatal myocardial infarction or stroke (NMI/S), health-related quality of life (QoL) and socioeconomic effects. The following comparisons mostly reported only a fraction of our main outcome set. Three studies compared pioglitazone with metformin. They did not report all-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects. Incidence of T2DM was 9/168 participants in the pioglitazone groups versus 9/163 participants in the metformin groups (RR 0.98, 95% CI 0.40 to 2.38; P = 0.96; 3 studies, 331 participants; low-certainty evidence). No SAEs were reported in two studies (201 participants; low-certainty evidence). One study compared pioglitazone with acarbose. Incidence of T2DM was 1/50 participants in the pioglitazone group versus 2/46 participants in the acarbose group (very low-certainty evidence). No participant experienced a SAE (very low-certainty evidence).One study compared pioglitazone with repaglinide. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 1/48 participants in the repaglinide group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). One study compared pioglitazone with a personalised diet and exercise consultation. All-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects were not reported. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 5/48 participants in the diet and exercise consultation group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). Six studies compared pioglitazone with placebo. No study reported on QoL or socioeconomic effects. All-cause mortality was 5/577 participants the in the pioglitazone groups versus 2/579 participants in the placebo groups (Peto odds ratio 2.38, 95% CI 0.54 to 10.50; P = 0.25; 4 studies, 1156 participants; very low-certainty evidence). Incidence of T2DM was 80/700 participants in the pioglitazone groups versus 131/695 participants in the placebo groups (RR 0.40, 95% CI 0.17 to 0.95; P = 0.04; 6 studies, 1395 participants; low-certainty evidence). There were 3/93 participants with SAEs in the pioglitazone groups versus 1/94 participants in the placebo groups (RR 3.00, 95% CI 0.32 to 28.22; P = 0.34; 2 studies, 187 participants; very low-certainty evidence). However, the largest study for this comparison did not distinguish between serious and non-serious adverse events. This study reported that 121/303 (39.9%) participants in the pioglitazone group versus 151/299 (50.5%) participants in the placebo group experienced an adverse event (P = 0.03). One study observed cardiovascular mortality in 2/181 participants in the pioglitazone group versus 0/186 participants in the placebo group (RR 5.14, 95% CI 0.25 to 106.28; P = 0.29; very low-certainty evidence). One study observed NMI in 2/303 participants in the pioglitazone group versus 1/299 participants in the placebo group (RR 1.97: 95% CI 0.18 to 21.65; P = 0.58; very low-certainty evidence). Twenty-one studies compared pioglitazone with no intervention. No study reported on cardiovascular mortality, NMI/S, QoL or socioeconomic effects. All-cause mortality was 11/441 participants in the pioglitazone groups versus 12/425 participants in the no-intervention groups (RR 0.85, 95% CI 0.38 to 1.91; P = 0.70; 3 studies, 866 participants; very low-certainty evidence). Incidence of T2DM was 60/1034 participants in the pioglitazone groups versus 197/1019 participants in the no-intervention groups (RR 0.31, 95% CI 0.23 to 0.40; P < 0.001; 16 studies, 2053 participants; moderate-certainty evidence). Studies reported SAEs in 16/610 participants in the pioglitazone groups versus 21/601 participants in the no-intervention groups (RR 0.71, 95% CI 0.38 to 1.32; P = 0.28; 7 studies, 1211 participants; low-certainty evidence). We identified two ongoing studies, comparing pioglitazone with placebo and with other glucose-lowering drugs. These studies, with 2694 participants. may contribute evidence to future updates of this review. AUTHORS' CONCLUSIONS: Pioglitazone reduced or delayed the development of T2DM in people at increased risk of T2DM compared with placebo (low-certainty evidence) and compared with no intervention (moderate-certainty evidence). It is unclear whether the effect of pioglitazone is sustained once discontinued. Pioglitazone compared with metformin neither showed advantage nor disadvantage regarding the development of T2DM in people at increased risk (low-certainty evidence). The data and reporting of all-cause mortality, SAEs, micro- and macrovascular complications were generally sparse. None of the included studies reported on QoL or socioeconomic effects.

Metformin may adversely affect orthostatic blood pressure recovery in patients with type 2 diabetes: substudy from the placebo-controlled Copenhagen Insulin and Metformin Therapy (CIMT) trial.

BACKGROUND: Metformin has been shown to have both neuroprotective and neurodegenerative effects. The aim of this study was to investigate the effect of metformin in combination with insulin on cardiovascular autonomic neuropathy (CAN) and distal peripheral neuropathy (DPN) in individuals with type 2 diabetes (T2DM). METHODS: The study is a sub-study of the CIMT trial, a randomized placebo-controlled trial with a 2 × 3 factorial design, where 412 patients with T2DM were randomized to 18 months of metformin or placebo in addition to open-labelled insulin. Outcomes were measures of CAN: Changes in heart rate response to deep breathing (beat-to-beat), orthostatic blood pressure (OBP) and heart rate and vibration detection threshold (VDT) as a marker DPN. Serum levels of vitamin B12 and methyl malonic acid (MMA) were analysed. RESULTS: After 18 months early drop in OBP (30 s after standing) was increased in the metformin group compared to placebo: systolic blood pressure drop increased by 3.4 mmHg (95% CI 0.6; 6.2, p = 0.02) and diastolic blood pressure drop increased by 1.3 mmHg (95% CI 0.3; 2.6, p = 0.045) compared to placebo. Beat-to-beat variation decreased in the metformin group by 1.1 beats per minute (95% CI - 2.4; 0.2, p = 0.10). Metformin treatment did not affect VDT group difference - 0.33 V (95% CI - 1.99; 1.33, p = 0.39) or other outcomes. Changes in B12, MMA and HbA1c did not confound the associations. CONCLUSIONS: Eighteen months of metformin treatment in combination with insulin compared with insulin alone increased early drop in OBP indicating an adverse effect of metformin on CAN independent of vitamin B12, MMA HbA1c. Trial registration The protocol was approved by the Regional Committee on Biomedical Research Ethics (H-D-2007-112), the Danish Medicines Agency and registered with ClinicalTrials.gov (NCT00657943).

Metformin monotherapy for adults with type 2 diabetes mellitus.

BACKGROUND: Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified. OBJECTIVES: To assess the effects of metformin monotherapy in adults with T2DM. SEARCH METHODS: We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017). SELECTION CRITERIA: We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument. MAIN RESULTS: We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD). Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions. Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD. Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trials no NFMI occurred and in one trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 25/1456 participants (1.7%) in the thiazolidinedione group. One trial reported no NFS occurred. No trial reported on HRQoL or ESRD. Three trials compared metformin with dipeptidyl peptidase-4 inhibitors (one trial each with saxagliptin, sitagliptin, vildagliptin with altogether 1977 participants). There was no substantial difference between the interventions for all-cause mortality, SAE, CVM, NFMI and NFS (very low-certainty evidence for all outcomes). One trial compared metformin with a glucagon-like peptide-1 analogue (very low-certainty evidence for all reported outcomes). There was no substantial difference between the interventions for all-cause mortality, CVM, NFMI and NFS. One or more SAEs were reported in 16/268 (6.0%) of the participants allocated to metformin compared with 35/539 (6.5%) of the participants allocated to a glucagon-like peptide-1 analogue. HRQoL or ESRD were not reported. One trial compared metformin with meglitinide and two trials compared metformin with no intervention. No deaths or SAEs occurred (very low-certainty evidence) no other patient-important outcomes were reported. No trial compared metformin with placebo or a behaviour changing interventions. Four ongoing trials with 5824 participants are likely to report one or more of our outcomes of interest and are estimated to be completed between 2018 and 2024. Furthermore, 24 trials with 2369 participants are awaiting assessment. AUTHORS' CONCLUSIONS: There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes.

Effect of Metformin vs. Placebo in Combination with Insulin Analogues on Bone Markers P1NP and CTX in Patients with Type 2 Diabetes Mellitus.

Preclinical studies have shown a potential osteoanabolic effect of metformin but human studies of how metformin affects bone turnover are few. A post hoc sub-study analysis of an 18-month multicenter, placebo-controlled, double-blinded trial in type 2 diabetes mellitus (T2DM), randomizing participants to metformin versus placebo both in combination with different insulin analogue regimens (Metformin + Insulin vs. Placebo + Insulin). Patients were not treatment naive at baseline, 83% had received metformin, 69% had received insulin, 57.5% had received the combination of metformin and insulin before entering the study. Bone formation and resorption were assessed by measuring, N-terminal propeptide of type I procollagen (P1NP) and C-terminal telopeptide of type I collagen (CTX) at baseline and end of study. The influence of gender, age, smoking, body mass index (BMI), T2DM duration, glycosylated hemoglobin A1c (HbA1c), c-reactive protein (CRP) and insulin dosage was also included in the analyses. The levels of bone formation marker P1NP and bone resorption marker CTX increased significantly in both groups during the trial. P1NP increased less in the Metformin + Insulin compared to the placebo + insulin group (p = 0.001) (between group difference change), while the increases in CTX levels (p = 0.11) were not different. CRP was inversely associated (p = 0.012) and insulin dosage (p = 0.011) was positively related with change in P1NP levels. BMI (p = 0.002) and HbA1C (p = 0.037) were inversely associated with change in CTX levels. During 18 months of treatment with metformin or placebo, both in combination with insulin, bone turnover increased in both groups. But the pattern was different as the bone formation marker (P1NP) increased less during Metformin + Insulin treatment, while change in bone resorption (CTX) was not significantly different between the two groups.

Metformin for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus.

BACKGROUND: The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether metformin can prevent or delay T2DM and its complications in people with increased risk of developing T2DM is unknown. OBJECTIVES: To assess the effects of metformin for the prevention or delay of T2DM and its associated complications in persons at increased risk for the T2DM. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was March 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of one year or more comparing metformin with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or standard care in people with impaired glucose tolerance, impaired fasting glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or combinations of these. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles and records, assessed risk of bias and extracted outcome data independently. We used a random-effects model to perform meta-analysis and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 20 RCTs randomising 6774 participants. One trial contributed 48% of all participants. The duration of intervention in the trials varied from one to five years. We judged none of the trials to be at low risk of bias in all 'Risk of bias' domains. Our main outcome measures were all-cause mortality, incidence of T2DM, serious adverse events (SAEs), cardiovascular mortality, non-fatal myocardial infarction or stroke, health-related quality of life and socioeconomic effects.The following comparisons mostly reported only a fraction of our main outcome set. Fifteen RCTs compared metformin with diet and exercise with or without placebo: all-cause mortality was 7/1353 versus 7/1480 (RR 1.11, 95% CI 0.41 to 3.01; P = 0.83; 2833 participants, 5 trials; very low-quality evidence); incidence of T2DM was 324/1751 versus 529/1881 participants (RR 0.50, 95% CI 0.38 to 0.65; P < 0.001; 3632 participants, 12 trials; moderate-quality evidence); the reporting of SAEs was insufficient and diverse and meta-analysis could not be performed (reported numbers were 4/118 versus 2/191; 309 participants; 4 trials; very low-quality evidence); cardiovascular mortality was 1/1073 versus 4/1082 (2416 participants; 2 trials; very low-quality evidence). One trial reported no clear difference in health-related quality of life after 3.2 years of follow-up (very low-quality evidence). Two trials estimated the direct medical costs (DMC) per participant for metformin varying from $220 to $1177 versus $61 to $184 in the comparator group (2416 participants; 2 trials; low-quality evidence). Eight RCTs compared metformin with intensive diet and exercise: all-cause mortality was 7/1278 versus 4/1272 (RR 1.61, 95% CI 0.50 to 5.23; P = 0.43; 2550 participants, 4 trials; very low-quality evidence); incidence of T2DM was 304/1455 versus 251/1505 (RR 0.80, 95% CI 0.47 to 1.37; P = 0.42; 2960 participants, 7 trials; moderate-quality evidence); the reporting of SAEs was sparse and meta-analysis could not be performed (one trial reported 1/44 in the metformin group versus 0/36 in the intensive exercise and diet group with SAEs). One trial reported that 1/1073 participants in the metformin group compared with 2/1079 participants in the comparator group died from cardiovascular causes. One trial reported that no participant died due to cardiovascular causes (very low-quality evidence). Two trials estimated the DMC per participant for metformin varying from $220 to $1177 versus $225 to $3628 in the comparator group (2400 participants; 2 trials; very low-quality evidence). Three RCTs compared metformin with acarbose: all-cause mortality was 1/44 versus 0/45 (89 participants; 1 trial; very low-quality evidence); incidence of T2DM was 12/147 versus 7/148 (RR 1.72, 95% CI 0.72 to 4.14; P = 0.22; 295 participants; 3 trials; low-quality evidence); SAEs were 1/51 versus 2/50 (101 participants; 1 trial; very low-quality evidence). Three RCTs compared metformin with thiazolidinediones: incidence of T2DM was 9/161 versus 9/159 (RR 0.99, 95% CI 0.41 to 2.40; P = 0.98; 320 participants; 3 trials; low-quality evidence). SAEs were 3/45 versus 0/41 (86 participants; 1 trial; very low-quality evidence). Three RCTs compared metformin plus intensive diet and exercise with identical intensive diet and exercise: all-cause mortality was 1/121 versus 1/120 participants (450 participants; 2 trials; very low-quality evidence); incidence of T2DM was 48/166 versus 53/166 (RR 0.55, 95% CI 0.10 to 2.92; P = 0.49; 332 participants; 2 trials; very low-quality evidence). One trial estimated the DMC of metformin plus intensive diet and exercise to be $270 per participant compared with $225 in the comparator group (94 participants; 1 trial; very-low quality evidence). One trial in 45 participants compared metformin with a sulphonylurea. The trial reported no patient-important outcomes. For all comparisons there were no data on non-fatal myocardial infarction, non-fatal stroke or microvascular complications. We identified 11 ongoing trials which potentially could provide data of interest for this review. These trials will add a total of 17,853 participants in future updates of this review. AUTHORS' CONCLUSIONS: Metformin compared with placebo or diet and exercise reduced or delayed the risk of T2DM in people at increased risk for the development of T2DM (moderate-quality evidence). However, metformin compared to intensive diet and exercise did not reduce or delay the risk of T2DM (moderate-quality evidence). Likewise, the combination of metformin and intensive diet and exercise compared to intensive diet and exercise only neither showed an advantage or disadvantage regarding the development of T2DM (very low-quality evidence). Data on patient-important outcomes such as mortality, macrovascular and microvascular diabetic complications and health-related quality of life were sparse or missing.

Adding exercise to usual care in patients with hypertension, type 2 diabetes mellitus and/or cardiovascular disease: a protocol for a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Hypertension, type 2 diabetes mellitus and cardiovascular disease are among the leading causes of mortality globally. Exercise is one of the commonly recommended interventions/preventions for hypertension, type 2 diabetes mellitus and cardiovascular disease. However, the previous reviews have shown conflicting evidence on the effects of exercise. Our objective is to assess the beneficial and harmful effects of adding exercise to usual care for people with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. METHODS: This protocol for a systematic review was undertaken using the recommendations of The Cochrane Collaboration, the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) and the eight-step assessment procedure suggested by Jakobsen et al. We plan to include all relevant randomised clinical trials and cluster-randomised trials assessing the effects of adding exercise to usual care for people with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP) and BIOSIS. We will systematically assess the risks of random errors using Trial Sequential Analysis as well as risks of bias of all included trials. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). DISCUSSION: The present systematic review will have the potential to aid patients, clinicians and decision-makers recommending exercise and thereby, benefit patients with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019142313.

Metformin and second- or third-generation sulphonylurea combination therapy for adults with type 2 diabetes mellitus.

BACKGROUND: The number of people with type 2 diabetes mellitus (T2DM) is increasing worldwide. The combination of metformin and sulphonylurea (M+S) is a widely used treatment. Whether M+S shows better or worse effects in comparison with other antidiabetic medications for people with T2DM is still controversial. OBJECTIVES: To assess the effects of metformin and sulphonylurea (second- or third-generation) combination therapy for adults with type 2 diabetes mellitus. SEARCH METHODS: We updated the search of a recent systematic review from the Agency for Healthcare Research and Quality (AHRQ). The updated search included CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and WHO ICTRP. The date of the last search was March 2018. We searched manufacturers' websites and reference lists of included trials, systematic reviews, meta-analyses and health technology assessment reports. We asked investigators of the included trials for information about additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) randomising participants 18 years old or more with T2DM to M+S compared with metformin plus another glucose-lowering intervention or metformin monotherapy with a treatment duration of 52 weeks or more. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles and records, assessed risk of bias and extracted outcome data independently. We used a random-effects model to perform meta-analysis, and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the certainty of the evidence using the GRADE instrument. MAIN RESULTS: We included 32 RCTs randomising 28,746 people. Treatment duration ranged between one to four years. We judged none of these trials as low risk of bias for all 'Risk of bias' domains. Most important events per person were all-cause and cardiovascular mortality, serious adverse events (SAE), non-fatal stroke (NFS), non-fatal myocardial infarction (MI) and microvascular complications. Most important comparisons were as follows:Five trials compared M+S (N = 1194) with metformin plus a glucagon-like peptide 1 analogue (N = 1675): all-cause mortality was 11/1057 (1%) versus 11/1537 (0.7%), risk ratio (RR) 1.15 (95% confidence interval (CI) 0.49 to 2.67); 3 trials; 2594 participants; low-certainty evidence; cardiovascular mortality 1/307 (0.3%) versus 1/302 (0.3%), low-certainty evidence; serious adverse events (SAE) 128/1057 (12.1%) versus 194/1537 (12.6%), RR 0.90 (95% CI 0.73 to 1.11); 3 trials; 2594 participants; very low-certainty evidence; non-fatal myocardial infarction (MI) 2/549 (0.4%) versus 6/1026 (0.6%), RR 0.57 (95% CI 0.12 to 2.82); 2 trials; 1575 participants; very low-certainty evidence.Nine trials compared M+S (N = 5414) with metformin plus a dipeptidyl-peptidase 4 inhibitor (N = 6346): all-cause mortality was 33/5387 (0.6%) versus 26/6307 (0.4%), RR 1.32 (95% CI 0.76 to 2.28); 9 trials; 11,694 participants; low-certainty evidence; cardiovascular mortality 11/2989 (0.4%) versus 9/3885 (0.2%), RR 1.54 (95% CI 0.63 to 3.79); 6 trials; 6874 participants; low-certainty evidence; SAE 735/5387 (13.6%) versus 779/6307 (12.4%), RR 1.07 (95% CI 0.97 to 1.18); 9 trials; 11,694 participants; very low-certainty evidence; NFS 14/2098 (0.7%) versus 8/2995 (0.3%), RR 2.21 (95% CI 0.74 to 6.58); 4 trials; 5093 participants; very low-certainty evidence; non-fatal MI 15/2989 (0.5%) versus 13/3885 (0.3%), RR 1.45 (95% CI 0.69 to 3.07); 6 trials; 6874 participants; very low-certainty evidence; one trial in 64 participants reported no microvascular complications were observed (very low-certainty evidence).Eleven trials compared M+S (N = 3626) with metformin plus a thiazolidinedione (N = 3685): all-cause mortality was 123/3300 (3.7%) versus 114/3354 (3.4%), RR 1.09 (95% CI 0.85 to 1.40); 6 trials; 6654 participants; low-certainty evidence; cardiovascular mortality 37/2946 (1.3%) versus 41/2994 (1.4%), RR 0.78 (95% CI 0.36 to 1.67); 4 trials; 5940 participants; low-certainty evidence; SAE 666/3300 (20.2%) versus 671/3354 (20%), RR 1.01 (95% CI 0.93 to 1.11); 6 trials; 6654 participants; very low-certainty evidence; NFS 20/1540 (1.3%) versus 16/1583 (1%), RR 1.29 (95% CI 0.67 to 2.47); P = 0.45; 2 trials; 3123 participants; very low-certainty evidence; non-fatal MI 25/1841 (1.4%) versus 21/1877 (1.1%), RR 1.21 (95% CI 0.68 to 2.14); P = 0.51; 3 trials; 3718 participants; very low-certainty evidence; three trials (3123 participants) reported no microvascular complications (very low-certainty evidence).Three trials compared M+S (N = 462) with metformin plus a glinide (N = 476): one person died in each intervention group (3 trials; 874 participants; low-certainty evidence); no cardiovascular mortality (2 trials; 446 participants; low-certainty evidence); SAE 34/424 (8%) versus 27/450 (6%), RR 1.68 (95% CI 0.54 to 5.21); P = 0.37; 3 trials; 874 participants; low-certainty evidence; no NFS (1 trial; 233 participants; very low-certainty evidence); non-fatal MI 2/215 (0.9%) participants in the M+S group; 2 trials; 446 participants; low-certainty evidence; no microvascular complications (1 trial; 233 participants; low-certainty evidence).Four trials compared M+S (N = 2109) with metformin plus a sodium-glucose co-transporter 2 inhibitor (N = 3032): all-cause mortality was 13/2107 (0.6%) versus 19/3027 (0.6%), RR 0.96 (95% CI 0.44 to 2.09); 4 trials; 5134 participants; very low-certainty evidence; cardiovascular mortality 4/1327 (0.3%) versus 6/2262 (0.3%), RR 1.22 (95% CI 0.33 to 4.41); 3 trials; 3589 participants; very low-certainty evidence; SAE 315/2107 (15.5%) versus 375/3027 (12.4%), RR 1.02 (95% CI 0.76 to 1.37); 4 trials; 5134 participants; very low-certainty evidence; NFS 3/919 (0.3%) versus 7/1856 (0.4%), RR 0.87 (95% CI 0.22 to 3.34); 2 trials; 2775 participants; very low-certainty evidence; non-fatal MI 7/890 (0.8%) versus 8/1374 (0.6%), RR 1.43 (95% CI 0.49 to 4.18; 2 trials); 2264 participants; very low-certainty evidence; amputation of lower extremity 1/437 (0.2%) versus 1/888 (0.1%); very low-certainty evidence.Trials reported more hypoglycaemic episodes with M+S combination compared to all other metformin-antidiabetic agent combinations. Results for M+S versus metformin monotherapy were inconclusive. There were no RCTs comparing M+S with metformin plus insulin. We identified nine ongoing trials and two trials are awaiting assessment. Together these trials will include approximately 16,631 participants. AUTHORS' CONCLUSIONS: There is inconclusive evidence whether M+S combination therapy compared with metformin plus another glucose-lowering intervention results in benefit or harm for most patient-important outcomes (mortality, SAEs, macrovascular and microvascular complications) with the exception of hypoglycaemia (more harm for M+S combination). No RCT reported on health-related quality of life.

Lipid-Lowering Agents in Older Individuals: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: The efficacy of lipid-lowering agents on patient-important outcomes in older individuals is unclear. METHODS: We included randomized trials that enrolled individuals aged 65 years or older and that included at least 1 year of follow-up.Pairs of reviewers selected and appraised the trials. RESULTS: We included 23 trials that enrolled 60,194 elderly patients. For primary prevention, statins reduced the risk of coronary artery disease [CAD; relative risk (RR): 0.79, 95% CI: 0.68 to 0.91] and myocardial infarction (MI; RR: 0.45, 95% CI: 0.31 to 0.66) but not all-cause or cardiovascular mortality or stroke. These effects were imprecise in patients with diabetes, but there was no significant interaction between diabetes status and the intervention effect. For secondary prevention, statins reduced all-cause mortality (RR: 0.80, 95% CI: 0.73 to 0.89), cardiovascular mortality (RR: 0.68, 95% CI: 0.58 to 0.79), CAD (RR: 0.68, 95% CI: 0.61 to 0.77), MI (RR: 0.68, 95% CI: 0.59 to 0.79), and revascularization (RR: 0.68, 95% CI: 0.61 to 0.77). Intensive (vs less-intensive) statin therapy reduced the risk of CAD and heart failure. Niacin did not reduce the risk of revascularization, and fibrates did not reduce the risk of stroke, cardiovascular mortality, or CAD. CONCLUSION: High-certainty evidence supports statin use for secondary prevention in older individuals. Evidence for primary prevention is less certain. Data in older individuals with diabetes are limited; however, no empirical evidence has shown a significant difference based on diabetes status.

Development of type 2 diabetes mellitus in people with intermediate hyperglycaemia.

BACKGROUND: Intermediate hyperglycaemia (IH) is characterised by one or more measurements of elevated blood glucose concentrations, such as impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and elevated glycosylated haemoglobin A1c (HbA1c). These levels are higher than normal but below the diagnostic threshold for type 2 diabetes mellitus (T2DM). The reduced threshold of 5.6 mmol/L (100 mg/dL) fasting plasma glucose (FPG) for defining IFG, introduced by the American Diabetes Association (ADA) in 2003, substantially increased the prevalence of IFG. Likewise, the lowering of the HbA1c threshold from 6.0% to 5.7% by the ADA in 2010 could potentially have significant medical, public health and socioeconomic impacts. OBJECTIVES: To assess the overall prognosis of people with IH for developing T2DM, regression from IH to normoglycaemia and the difference in T2DM incidence in people with IH versus people with normoglycaemia. SEARCH METHODS: We searched MEDLINE, Embase, ClincialTrials.gov and the International Clinical Trials Registry Platform (ICTRP) Search Portal up to December 2016 and updated the MEDLINE search in February 2018. We used several complementary search methods in addition to a Boolean search based on analytical text mining. SELECTION CRITERIA: We included prospective cohort studies investigating the development of T2DM in people with IH. We used standard definitions of IH as described by the ADA or World Health Organization (WHO). We excluded intervention trials and studies on cohorts with additional comorbidities at baseline, studies with missing data on the transition from IH to T2DM, and studies where T2DM incidence was evaluated by documents or self-report only. DATA COLLECTION AND ANALYSIS: One review author extracted study characteristics, and a second author checked the extracted data. We used a tailored version of the Quality In Prognosis Studies (QUIPS) tool for assessing risk of bias. We pooled incidence and incidence rate ratios (IRR) using a random-effects model to account for between-study heterogeneity. To meta-analyse incidence data, we used a method for pooling proportions. For hazard ratios (HR) and odds ratios (OR) of IH versus normoglycaemia, reported with 95% confidence intervals (CI), we obtained standard errors from these CIs and performed random-effects meta-analyses using the generic inverse-variance method. We used multivariable HRs and the model with the greatest number of covariates. We evaluated the certainty of the evidence with an adapted version of the GRADE framework. MAIN RESULTS: We included 103 prospective cohort studies. The studies mainly defined IH by IFG5.6 (FPG mmol/L 5.6 to 6.9 mmol/L or 100 mg/dL to 125 mg/dL), IFG6.1 (FPG 6.1 mmol/L to 6.9 mmol/L or 110 mg/dL to 125 mg/dL), IGT (plasma glucose 7.8 mmol/L to 11.1 mmol/L or 140 mg/dL to 199 mg/dL two hours after a 75 g glucose load on the oral glucose tolerance test, combined IFG and IGT (IFG/IGT), and elevated HbA1c (HbA1c5.7: HbA1c 5.7% to 6.4% or 39 mmol/mol to 46 mmol/mol; HbA1c6.0: HbA1c 6.0% to 6.4% or 42 mmol/mol to 46 mmol/mol). The follow-up period ranged from 1 to 24 years. Ninety-three studies evaluated the overall prognosis of people with IH measured by cumulative T2DM incidence, and 52 studies evaluated glycaemic status as a prognostic factor for T2DM by comparing a cohort with IH to a cohort with normoglycaemia. Participants were of Australian, European or North American origin in 41 studies; Latin American in 7; Asian or Middle Eastern in 50; and Islanders or American Indians in 5. Six studies included children and/or adolescents.Cumulative incidence of T2DM associated with IFG5.6, IFG6.1, IGT and the combination of IFG/IGT increased with length of follow-up. Cumulative incidence was highest with IFG/IGT, followed by IGT, IFG6.1 and IFG5.6. Limited data showed a higher T2DM incidence associated with HbA1c6.0 compared to HbA1c5.7. We rated the evidence for overall prognosis as of moderate certainty because of imprecision (wide CIs in most studies). In the 47 studies reporting restitution of normoglycaemia, regression ranged from 33% to 59% within one to five years follow-up, and from 17% to 42% for 6 to 11 years of follow-up (moderate-certainty evidence).Studies evaluating the prognostic effect of IH versus normoglycaemia reported different effect measures (HRs, IRRs and ORs). Overall, the effect measures all indicated an elevated risk of T2DM at 1 to 24 years of follow-up. Taking into account the long-term follow-up of cohort studies, estimation of HRs for time-dependent events like T2DM incidence appeared most reliable. The pooled HR and the number of studies and participants for different IH definitions as compared to normoglycaemia were: IFG5.6: HR 4.32 (95% CI 2.61 to 7.12), 8 studies, 9017 participants; IFG6.1: HR 5.47 (95% CI 3.50 to 8.54), 9 studies, 2818 participants; IGT: HR 3.61 (95% CI 2.31 to 5.64), 5 studies, 4010 participants; IFG and IGT: HR 6.90 (95% CI 4.15 to 11.45), 5 studies, 1038 participants; HbA1c5.7: HR 5.55 (95% CI 2.77 to 11.12), 4 studies, 5223 participants; HbA1c6.0: HR 10.10 (95% CI 3.59 to 28.43), 6 studies, 4532 participants. In subgroup analyses, there was no clear pattern of differences between geographic regions. We downgraded the evidence for the prognostic effect of IH versus normoglycaemia to low-certainty evidence due to study limitations because many studies did not adequately adjust for confounders. Imprecision and inconsistency required further downgrading due to wide 95% CIs and wide 95% prediction intervals (sometimes ranging from negative to positive prognostic factor to outcome associations), respectively.This evidence is up to date as of 26 February 2018. AUTHORS' CONCLUSIONS: Overall prognosis of people with IH worsened over time. T2DM cumulative incidence generally increased over the course of follow-up but varied with IH definition. Regression from IH to normoglycaemia decreased over time but was observed even after 11 years of follow-up. The risk of developing T2DM when comparing IH with normoglycaemia at baseline varied by IH definition. Taking into consideration the uncertainty of the available evidence, as well as the fluctuating stages of normoglycaemia, IH and T2DM, which may transition from one stage to another in both directions even after years of follow-up, practitioners should be careful about the potential implications of any active intervention for people 'diagnosed' with IH.

Diet, physical activity or both for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus.

BACKGROUND: The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether diet, physical activity or both can prevent or delay T2DM and its associated complications in at-risk people is unknown. OBJECTIVES: To assess the effects of diet, physical activity or both on the prevention or delay of T2DM and its associated complications in people at increased risk of developing T2DM. SEARCH METHODS: This is an update of the Cochrane Review published in 2008. We searched the CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, ICTRP Search Portal and reference lists of systematic reviews, articles and health technology assessment reports. The date of the last search of all databases was January 2017. We continuously used a MEDLINE email alert service to identify newly published studies using the same search strategy as described for MEDLINE up to September 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of two years or more. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology for data collection and analysis. We assessed the overall quality of the evidence using GRADE. MAIN RESULTS: We included 12 RCTs randomising 5238 people. One trial contributed 41% of all participants. The duration of the interventions varied from two to six years. We judged none of the included trials at low risk of bias for all 'Risk of bias' domains.Eleven trials compared diet plus physical activity with standard or no treatment. Nine RCTs included participants with impaired glucose tolerance (IGT), one RCT included participants with IGT, impaired fasting blood glucose (IFG) or both, and one RCT included people with fasting glucose levels between 5.3 to 6.9 mmol/L. A total of 12 deaths occurred in 2049 participants in the diet plus physical activity groups compared with 10 in 2050 participants in the comparator groups (RR 1.12, 95% CI 0.50 to 2.50; 95% prediction interval 0.44 to 2.88; 4099 participants, 10 trials; very low-quality evidence). The definition of T2DM incidence varied among the included trials. Altogether 315 of 2122 diet plus physical activity participants (14.8%) developed T2DM compared with 614 of 2389 comparator participants (25.7%) (RR 0.57, 95% CI 0.50 to 0.64; 95% prediction interval 0.50 to 0.65; 4511 participants, 11 trials; moderate-quality evidence). Two trials reported serious adverse events. In one trial no adverse events occurred. In the other trial one of 51 diet plus physical activity participants compared with none of 51 comparator participants experienced a serious adverse event (low-quality evidence). Cardiovascular mortality was rarely reported (four of 1626 diet plus physical activity participants and four of 1637 comparator participants (the RR ranged between 0.94 and 3.16; 3263 participants, 7 trials; very low-quality evidence). Only one trial reported that no non-fatal myocardial infarction or non-fatal stroke had occurred (low-quality evidence). Two trials reported that none of the participants had experienced hypoglycaemia. One trial investigated health-related quality of life in 2144 participants and noted that a minimal important difference between intervention groups was not reached (very low-quality evidence). Three trials evaluated costs of the interventions in 2755 participants. The largest trial of these reported an analysis of costs from the health system perspective and society perspective reflecting USD 31,500 and USD 51,600 per quality-adjusted life year (QALY) with diet plus physical activity, respectively (low-quality evidence). There were no data on blindness or end-stage renal disease.One trial compared a diet-only intervention with a physical-activity intervention or standard treatment. The participants had IGT. Three of 130 participants in the diet group compared with none of the 141 participants in the physical activity group died (very low-quality evidence). None of the participants died because of cardiovascular disease (very low-quality evidence). Altogether 57 of 130 diet participants (43.8%) compared with 58 of 141 physical activity participants (41.1%) group developed T2DM (very low-quality evidence). No adverse events were recorded (very low-quality evidence). There were no data on non-fatal myocardial infarction, non-fatal stroke, blindness, end-stage renal disease, health-related quality of life or socioeconomic effects.Two trials compared physical activity with standard treatment in 397 participants. One trial included participants with IGT, the other trial included participants with IGT, IFG or both. One trial reported that none of the 141 physical activity participants compared with three of 133 control participants died. The other trial reported that three of 84 physical activity participants and one of 39 control participants died (very low-quality evidence). In one trial T2DM developed in 58 of 141 physical activity participants (41.1%) compared with 90 of 133 control participants (67.7%). In the other trial 10 of 84 physical activity participants (11.9%) compared with seven of 39 control participants (18%) developed T2DM (very low-quality evidence). Serious adverse events were rarely reported (one trial noted no events, one trial described events in three of 66 physical activity participants compared with one of 39 control participants - very low-quality evidence). Only one trial reported on cardiovascular mortality (none of 274 participants died - very low-quality evidence). Non-fatal myocardial infarction or stroke were rarely observed in the one trial randomising 123 participants (very low-quality evidence). One trial reported that none of the participants in the trial experienced hypoglycaemia. One trial investigating health-related quality of life in 123 participants showed no substantial differences between intervention groups (very low-quality evidence). There were no data on blindness or socioeconomic effects. AUTHORS' CONCLUSIONS: There is no firm evidence that diet alone or physical activity alone compared to standard treatment influences the risk of T2DM and especially its associated complications in people at increased risk of developing T2DM. However, diet plus physical activity reduces or delays the incidence of T2DM in people with IGT. Data are lacking for the effect of diet plus physical activity for people with intermediate hyperglycaemia defined by other glycaemic variables. Most RCTs did not investigate patient-important outcomes.

Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus.

BACKGROUND: The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether dipeptidyl-peptidase (DPP)-4 inhibitors or glucagon-like peptide (GLP)-1 analogues are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown. OBJECTIVES: To assess the effects of DPP-4 inhibitors and GLP-1 analogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials; MEDLINE; PubMed; Embase; ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform; and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was January 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing DPP-4 inhibitors and GLP-1 analogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles and records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses, we planned to use a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall quality of the evidence using the GRADE instrument. MAIN RESULTS: We included seven completed RCTs; about 98 participants were randomised to a DPP-4 inhibitor as monotherapy and 1620 participants were randomised to a GLP-1 analogue as monotherapy. Two trials investigated a DPP-4 inhibitor and five trials investigated a GLP-1 analogue. A total of 924 participants with data on allocation to control groups were randomised to a comparator group; 889 participants were randomised to placebo and 33 participants to metformin monotherapy. One RCT of liraglutide contributed 85% of all participants. The duration of the intervention varied from 12 weeks to 160 weeks. We judged none of the included trials at low risk of bias for all 'Risk of bias' domains and did not perform meta-analyses because there were not enough trials.One trial comparing the DPP-4 inhibitor vildagliptin with placebo reported no deaths (very low-quality evidence). The incidence of T2DM by means of WHO diagnostic criteria in this trial was 3/90 participants randomised to vildagliptin versus 1/89 participants randomised to placebo (very low-quality evidence). Also, 1/90 participants on vildagliptin versus 2/89 participants on placebo experienced a serious adverse event (very low-quality evidence). One out of 90 participants experienced congestive heart failure in the vildagliptin group versus none in the placebo group (very low-quality evidence). There were no data on non-fatal myocardial infarction, stroke, health-related quality of life or socioeconomic effects reported.All-cause and cardiovascular mortality following treatment with GLP-1 analogues were rarely reported; one trial of exenatide reported that no participant died. Another trial of liraglutide 3.0 mg showed that 2/1501 in the liraglutide group versus 2/747 in the placebo group died after 160 weeks of treatment (very low-quality evidence).The incidence of T2DM following treatment with liraglutide 3.0 mg compared to placebo after 160 weeks was 26/1472 (1.8%) participants randomised to liraglutide versus 46/738 (6.2%) participants randomised to placebo (very low-quality evidence). The trial established the risk for (diagnosis of) T2DM as HbA1c 5.7% to 6.4% (6.5% or greater), fasting plasma glucose 5.6 mmol/L or greater to 6.9 mmol/L or less (7.0 mmol/L or greater) or two-hour post-load plasma glucose 7.8 mmol/L or greater to 11.0 mmol/L (11.1 mmol/L). Altogether, 70/1472 (66%) participants regressed from intermediate hyperglycaemia to normoglycaemia compared with 268/738 (36%) participants in the placebo group. The incidence of T2DM after the 12-week off-treatment extension period (i.e. after 172 weeks) showed that five additional participants were diagnosed T2DM in the liraglutide group, compared with one participant in the placebo group. After 12-week treatment cessation, 740/1472 (50%) participants in the liraglutide group compared with 263/738 (36%) participants in the placebo group had normoglycaemia.One trial used exenatide and 2/17 participants randomised to exenatide versus 1/16 participants randomised to placebo developed T2DM (very low-quality evidence). This trial did not provide a definition of T2DM. One trial reported serious adverse events in 230/1524 (15.1%) participants in the liraglutide 3.0 mg arm versus 96/755 (12.7%) participants in the placebo arm (very low quality evidence). There were no serious adverse events in the trial using exenatide. Non-fatal myocardial infarction was reported in 1/1524 participants in the liraglutide arm and in 0/55 participants in the placebo arm at 172 weeks (very low-quality evidence). One trial reported congestive heart failure in 1/1524 participants in the liraglutide arm and in 1/755 participants in the placebo arm (very low-quality evidence). Participants receiving liraglutide compared with placebo had a small mean improvement in the physical component of the 36-item Short Form scale showing a difference of 0.87 points (95% CI 0.17 to 1.58; P = 0.02; 1 trial; 1791 participants; very low-quality evidence). No trial evaluating GLP-1-analogues reported data on stroke, microvascular complications or socioeconomic effects. AUTHORS' CONCLUSIONS: There is no firm evidence that DPP-4 inhibitors or GLP-1 analogues compared mainly with placebo substantially influence the risk of T2DM and especially its associated complications in people at increased risk for the development of T2DM. Most trials did not investigate patient-important outcomes.

Insulin secretagogues for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus.

BACKGROUND: The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether insulin secretagogues (sulphonylureas and meglitinide analogues) are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown. OBJECTIVES: To assess the effects of insulin secretagogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was April 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing insulin secretagogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles/records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We carried out trial sequential analyses (TSAs) for all outcomes that could be meta-analysed. We assessed the overall quality of the evidence by using the GRADE instrument. MAIN RESULTS: We included six RCTs with 10,018 participants; 4791 participants with data on allocation to intervention groups were randomised to a second- or third-generation sulphonylurea or a meglitinide analogue as monotherapy and 29 participants were randomised to a second-generation sulphonylurea plus metformin. Three trials investigated a second-generation sulphonylurea, two trials investigated a third-generation sulphonylurea and one trial a meglitinide analogue. A total of 4873 participants with data on allocation to control groups were randomised to a comparator group; 4820 participants were randomised to placebo, 23 to diet and exercise, and 30 participants to metformin monotherapy. One RCT of nateglinide contributed 95% of all participants. The duration of the intervention varied from six months to five years. We judged none of the included trials as at low risk of bias for all 'Risk of bias' domains.All-cause and cardiovascular mortality following sulphonylurea (glimepiride) treatment were rarely observed (very low-quality evidence). The RR for incidence of T2DM comparing glimepiride monotherapy with placebo was 0.75; 95% CI 0.54 to 1.04; P = 0.08; 2 trials; 307 participants; very low-quality evidence. One of the trials reporting on the incidence of T2DM did not define the diagnostic criteria used. The other trial diagnosed T2DM as two consecutive fasting blood glucose values ≥ 6.1 mmol/L. TSA showed that only 4.5% of the diversity-adjusted required information size was accrued so far. No trial reported data on serious adverse events, non-fatal myocardial infarction (MI), non-fatal stroke, congestive heart failure (HF), health-related quality of life or socioeconomic effects.One trial with a follow-up of five years compared a meglitinide analogue (nateglinide) with placebo. A total of 310/4645 (6.7%) participants allocated to nateglinide died compared with 312/4661 (6.7%) participants allocated to placebo (hazard ratio (HR) 1.00; 95% CI 0.85 to 1.17; P = 0.98; moderate-quality evidence). The two main criteria for diagnosing T2DM were a fasting plasma glucose level ≥ 7.0 mmol/L or a 2-hour post challenge glucose ≥ 11.1 mmol/L. T2DM developed in 1674/4645 (36.0%) participants in the nateglinide group and in 1580/4661 (33.9%) in the placebo group (HR 1.07; 95% CI 1.00 to 1.15; P = 0.05; moderate-quality evidence). One or more serious adverse event was reported in 2066/4602 (44.9%) participants allocated to nateglinide compared with 2089/4599 (45.6%) participants allocated to placebo. A total of 126/4645 (2.7%) participants allocated to nateglinide died because of cardiovascular disease compared with 118/4661 (2.5%) participants allocated to placebo (HR 1.07; 95% CI 0.83 to 1.38; P = 0.60; moderate-quality evidence). Comparing participants receiving nateglinide with those receiving placebo for the outcomes MI, non-fatal stroke and HF gave the following event rates: MI 116/4645 (2.5%) versus 122/4661 (2.6%), stroke 100/4645 (2.2%) versus 110/4661 (2.4%) and numbers hospitalised for HF 85/4645 (1.8%) versus 100/4661 (2.1%) - (HR 0.85; 95% CI 0.64 to 1.14; P = 0.27). The quality of the evidence was moderate for all these outcomes. Health-related quality of life or socioeconomic effects were not reported. AUTHORS' CONCLUSIONS: There is insufficient evidence to demonstrate whether insulin secretagogues compared mainly with placebo reduce the risk of developing T2DM and its associated complications in people at increased risk for the development of T2DM. Most trials did not investigate patient-important outcomes.

Sodium-glucose cotransporter (SGLT) 2 inhibitors for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus.

BACKGROUND: Sodium-glucose cotransporter (SGLT) 2 inhibitors were recently approved as glucose-lowering interventions in people with type 2 diabetes mellitus (T2DM). Potential beneficial or harmful effects of SGLT 2 inhibitors in people at risk for the development of T2DM are unknown. OBJECTIVES: To assess the effects of SGLT 2 inhibitors focusing on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose or moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PubMed, EMBASE, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of ongoing for information about additional trials. The date of the last search of all databases was January 2016. SELECTION CRITERIA: Randomised controlled trials (RCTs) of any duration comparing SGLT 2 inhibitors with any glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts, assessed quality and extracted data independently. We resolved discrepancies by consensus or the involvement of a third author. MAIN RESULTS: We could not include any RCT in this systematic review. One trial was published in two abstracts, but did not provide separate information of the participants with impaired glucose tolerance, impaired fasting glucose or both. We identified two ongoing trials, both evaluating the effects of dapagliflozin (and metformin) in people at risk for the development of type 2 diabetes and a follow-up of 24 to 26 weeks. Both trials will mainly report on surrogate outcome measures with some data on adverse effects and health-related quality of life. AUTHORS' CONCLUSIONS: Due to lack of data it is not possible to conclude whether SGLT 2 inhibitors prevent or delay the diagnosis of T2DM and its associated complications.

Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus-the randomised, blinded Copenhagen Insulin and Metformin Therapy (CIMT) trial.

OBJECTIVE: To assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes in carotid intima-media thickness (IMT) in patients with type 2 diabetes. DESIGN AND SETTING: Investigator-initiated, randomised, placebo-controlled trial with a 2 × 3 factorial design conducted at eight hospitals in Denmark. PARTICIPANTS AND INTERVENTIONS: 412 participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥ 7.5% (≥ 58 mmol/mol); body mass index >25 kg/m2) were in addition to open-labelled insulin treatment randomly assigned 1:1 to 18 months blinded metformin (1 g twice daily) versus placebo, aiming at an HbA1c ≤ 7.0% (≤ 53 mmol/mol). OUTCOMES: The primary outcome was change in the mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight and hypoglycaemic and serious adverse events were other prespecified outcomes. RESULTS: Change in the mean carotid IMT did not differ significantly between the groups (between-group difference 0.012 mm (95% CI -0.003 to 0.026), p=0.11). HbA1c was more reduced in the metformin group (between-group difference -0.42% (95% CI -0.62% to -0.23%), p<0.001)), despite the significantly lower insulin dose at end of trial in the metformin group (1.04 IU/kg (95% CI 0.94 to 1.15)) compared with placebo (1.36 IU/kg (95% CI 1.23 to 1.51), p<0.001). The metformin group gained less weight (between-group difference -2.6 kg (95% CI -3.3 to -1.8), p<0.001). The groups did not differ with regard to number of patients with severe or non-severe hypoglycaemic or other serious adverse events, but the metformin group had more non-severe hypoglycaemic episodes (4347 vs 3161, p<0.001). CONCLUSIONS: Metformin in combination with insulin did not reduce carotid IMT despite larger reduction in HbA1c, less weight gain, and smaller insulin dose compared with placebo plus insulin. However, the trial only reached 46% of the planned sample size and lack of power may therefore have affected our results. TRIAL REGISTRATION NUMBER: NCT00657943; Results.