A new perspective on metformin therapy in type 1 diabetes

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Insulin 2 endocrinologydiseasesdrugs
lactic acidosis 1 endocrinologydiseases
metabolic syndrome 1 endocrinologydiseases
metformin 63 endocrinologydiseasesdrugs
vitamin B12 deficiency 3 endocrinologydiseases

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Select Drug Character Offset Drug Term Instance
Insulin 14809 individuals without diabetes but with established coronary heart disease [[37]], and the Copenhagen Insulin and Metformin Therapy (CIMT) trial reported no reduction in cIMT progression in insulin-treated people
Insulin 18434 (OR)0.568−No effect Weight (kg)84.0 ± 14.7−1.17<0.00010.274Sustained reduction by 1.17 kg Insulin dose (U/kg)0.65 ± 0.28−0.0050.5450.002After 6 months, reduced by 2 U/day (p = 0.045; post hoc
metformin 40 Title: DiabetologiaA new perspective on metformin therapy in type 1 diabetesRachel LivingstoneJames G. BoyleJohn R. Petrieon behalf of The REMOVAL Study
metformin 617 Recently-published findings from the REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL) trial suggest that metformin therapy in type 1 diabetes can reduce atherosclerosis progression, weight and LDL-cholesterol levels.
metformin 764 atherosclerosis progression, weight and LDL-cholesterol levels. This provides a new perspective on metformin therapy in type 1 diabetes and suggests a potential role for reducing the long-term risk of cardiovascular
metformin 2905 disease and improve life expectancy [[6], [7]].Diabetologists over previous decades have thought that metformin might be such a therapy, potentially mirroring its effects in type 2 diabetes in those with type 1 diabetes.
metformin 3220 recent REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL) study, the largest trial to date of metformin in the management of type 1 diabetes [[8], [9]].MetforminAs discussed by Sanchez-Rangel and Inzucchi
metformin 3369 [[8], [9]].MetforminAs discussed by Sanchez-Rangel and Inzucchi in this issue of Diabetologia [[10]], metformin hydrochloride is a simple and inexpensive biguanide molecule that is currently the first-line oral glucose-lowering
metformin 3716 driven by the UK Prospective Diabetes Study (UKPDS), published in 1998 [[13]]. Prior to the UKPDS, metformin was usually reserved for obese individuals and used with caution because of its similarity to another
metformin 4076 not withdrawn in the UK but was unavailable in the USA between 1977 and 1995. Key findings from the metformin substudy of the UKPDS were that obese participants with type 2 diabetes gained less weight than those
metformin 4401 infarction [[13], [14]].Perhaps because of such compelling evidence in type 2 diabetes, off-label use of metformin in type 1 diabetes is quite common in clinical practice. In a 2016 extract of population data from Scotland,
metformin 4602 data from Scotland, UK, 15% of adults with type 1 diabetes had received at least one prescription for metformin and 8% were using it currently [[9]]. If practice is similar elsewhere, it is likely that metformin
metformin 4702 metformin and 8% were using it currently [[9]]. If practice is similar elsewhere, it is likely that metformin is currently prescribed for thousands of people with type 1 diabetes worldwide. In France, in the form
metformin 4818 currently prescribed for thousands of people with type 1 diabetes worldwide. In France, in the form of metformin embonate, it has held a product license for use in type 1 diabetes since 1996. However, as discussed
metformin 5210 reported an improvement in euglycaemic–hyperinsulinaemic clamp-assessed insulin sensitivity when metformin was added to insulin therapy for 7 days in ten non-obese people with type 1 diabetes [[15]]. Two years
metformin 5631 3 weeks, in which no change in fasting glucose, body weight or insulin dose requirement was detected with metformin use, despite a significant improvement in seven-point capillary glucose profile [[16]].Small randomised
metformin 5838 randomised trials: the 2000sThe early studies described above did not ignite enthusiasm for research on metformin in type 1 diabetes in the 1990s. It was more than a decade later, after the publication of the UKPDS,
metformin 6223 participants with type 1 diabetes achieved non-sustained improvements in HbA1c and weight at 3 months with metformin use, reverting to baseline by 6 months [[17]]. The full paper was not published until 15 years later
metformin 6500 double-blind placebo-controlled trial, in which 62 adults with type 1 diabetes were randomised to receive metformin or placebo, showing a reduction in insulin dose requirement without an improvement in HbA1c when metformin
metformin 6607 metformin or placebo, showing a reduction in insulin dose requirement without an improvement in HbA1c when metformin was added to continuous subcutaneous insulin infusion therapy for 6 months [[19]]. The following year
metformin 6952 randomising 30 adolescent individuals with type 1 diabetes, reported improvements in HbA1c after 3 months of metformin use (by 0.6% [6.6 mmol/mol] and 0.9% [9.9 mmol/mol], respectively); only the Canadian study demonstrated
metformin 7709 trial in which 100 individuals with type 1 diabetes and suboptimal glycaemic control were randomised to metformin or placebo for 1 year at the Steno Diabetes Center (Copenhagen, Denmark). There was no improvement
metformin 7833 1 year at the Steno Diabetes Center (Copenhagen, Denmark). There was no improvement in HbA1c with metformin , but reductions in insulin dose requirement, weight and LDL-cholesterol (by 5.7 U, 1.74 kg and 0·3 mmol/l,
metformin 8155 adjustment for a statistically significant imbalance in concomitant statin use (used in 49% of the metformin group and 27% of the placebo group) [[25]]. Around 40% of participants in both groups reported gastrointestinal
metformin 8475 with at least one episode of severe hypoglycaemia was numerically, but not statistically, higher with metformin compared with placebo but the rate of severe hypoglycaemia complicated by coma (n = 6 with metformin;
metformin 8578 metformin compared with placebo but the rate of severe hypoglycaemia complicated by coma (n = 6 with metformin ; n = 1 with placebo) approached statistical significance.Systematic review: 2010In our systematic
metformin 9115 heterogeneity. We noted a significant reduction in insulin dose requirement (6.6 U/day, p < 0.001) with metformin , and weight reduction in some trials, but no consistent evidence for HbA1c reduction. We found no information
metformin 9537 Institute for Health and Care Excellence (NICE) replicated our meta-analysis and went on to recommend metformin for adults with type 1 diabetes and a BMI ≥25 kg/m2 who ‘want to improve glucose control while
metformin 9766 effective insulin dose’ [[27]]. The ‘recommendations for research’ included further studies on metformin in type 1 diabetes, although outcomes of interest were not specified.The ADA followed, stating that
metformin 9886 diabetes, although outcomes of interest were not specified.The ADA followed, stating that ‘adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in overweight/obese
metformin 10290 have poor glycaemic control [[3]], following these recommendations would have led to a sharp rise in metformin prescribing in type 1 diabetes.Lessons from type 2 diabetes?Types 1 and 2 diabetes are conditions with
metformin 10771 Netherlands, published in 2000, demonstrated reductions in HbA1c, weight and insulin dose requirement when metformin was added to treatment for 5 months in insulin-treated type 2 diabetes [[29]]. This was followed, in
metformin 11445 striking 40% reduction in cardiovascular events, a pre-specified secondary outcome, in those randomised to metformin . HbA1c, insulin dose requirement and weight gain were also reduced (by 0.4%, 20 U/day and 3 kg, respectively).
metformin 11573 dose requirement and weight gain were also reduced (by 0.4%, 20 U/day and 3 kg, respectively). That metformin could provide cardiovascular protection in insulin-treated individuals with type 2 diabetes provided
metformin 12140 continuing uncertainty, in 2010 the US type 1 diabetes charity JDRF decided to prioritise funding for metformin as adjunct therapy in type 1 diabetes. The first of the multicentre trials to emerge (in 2016) was a
metformin 12520 [73 mmol/mol]) and high insulin dose requirements (mean, 1.1 U/kg) [[32]]. HbA1c was reduced at 3 months with metformin (by 0.3% [3.3 mmol/mol]) but this was not sustained at the end of the 6 month trial (similar findings
metformin 12827 pre-specified outcomes, insulin dose requirement was reduced by 25% from baseline in 23% of participants taking metformin (compared with 1% in the placebo group) and BMI was reduced by 10% or more in 24% of participants taking
metformin 12942 (compared with 1% in the placebo group) and BMI was reduced by 10% or more in 24% of participants taking metformin (compared with 7% in the placebo group) [[33]]. No changes were observed in cholesterol levels. The
metformin 13121 observed in cholesterol levels. The researchers concluded that their results did not support prescribing metformin to overweight adolescent individuals with type 1 diabetes to improve glycaemic control and, by implication,
metformin 13540 it was an international effort that aimed to address the lack of cardiovascular data in the area of metformin use in type 1 diabetes by conducting a double-blind, placebo-controlled trial to test whether 3 years
metformin 13656 type 1 diabetes by conducting a double-blind, placebo-controlled trial to test whether 3 years of metformin treatment (1000 mg twice daily) added to titrated insulin therapy (towards target HbA1c, 7.0% [53.0 mmol/mol])
metformin 14453 outcomes over 30 years [[2]]. Prior to REMOVAL, small studies had reported a reduction of cIMT with metformin use in the metabolic syndrome and type 2 diabetes [[35], [36]]. However, while REMOVAL was under way,
metformin 14678 Atherosclerosis: MEtformin for insulin ResistAnce (CAMERA) trial reported no impact of 18 months of metformin treatment on cIMT in individuals without diabetes but with established coronary heart disease [[37]],
metformin 15061 REMOVAL study, progression of the primary outcome, mean far wall cIMT, was not significantly reduced with metformin therapy. Mean cIMT is often used in studies of people without diabetes to reduce variability as it excludes
metformin 15433 maximal far wall cIMT, pre-specified in REMOVAL because of its use in the DCCT/EDIC study, was reduced by metformin by twice as much as in the EDIC study over less than half the period of follow-up, despite more than
metformin 15805 [[40]]. This was an exciting and positive finding but it is premature to conclude that the effect of metformin on cIMT in the REMOVAL study might translate into clinical outcomes, as the contribution of reduced
metformin 16195 vascular structure, results of the REMOVAL study demonstrated a sustained reduction in weight with metformin (by 1.2 kg), as well as modest reductions in insulin dose requirement (by about 2 U/day from the 6-month
metformin 16490 prevalence of statin use [[9]] (see Table 1). There was no increase in hypoglycaemia and no effect of metformin on reactive hyperaemia index, a measure of small vessel endothelial function. Estimated GFR was acutely
metformin 16633 measure of small vessel endothelial function. Estimated GFR was acutely increased upon initiation of metformin (by 4 ml min−1 1.73m−2), an unexpected finding that requires further investigation, although it
metformin 16885 evidence [[41]]. Around a quarter of individuals (twice the rate of those taking placebo) discontinued metformin over 3 years, suggesting that about one in eight had genuine intolerance with the majority being attributable
metformin 17119 gastrointestinal adverse effects. Biochemical vitamin B12 deficiency was more than doubled over 3 years with metformin use (12%) vs placebo (5%). These findings contribute to a body of evidence that treatment with metformin
metformin 17224 metformin use (12%) vs placebo (5%). These findings contribute to a body of evidence that treatment with metformin reduces vitamin B12 concentration, suggesting monitoring during long-term use [[28]], particularly in
metformin 17536 disease.Table 1Summary of REMOVAL study outcomesOutcomesBaseline (mean ± SD)Difference or ratio ( metformin vs placebo)Main effect (p value)Treatment-by-visit interactiona (p value)Effect of metformin over 3 years:
metformin 17629 ratio (metformin vs placebo)Main effect (p value)Treatment-by-visit interactiona (p value)Effect of metformin over 3 years: clinical interpretationPrimary outcome Mean cIMT(mm)0.782 ± 0.162−0.0050.166−No
metformin 19512 arbitrary units; eGFR, estimated GFR; IRR, incidence rate ratioAs in other studies of type 1 diabetes and metformin , HbA1c was only transiently improved by metformin and reverted to baseline over the first 6 months
metformin 19562 rate ratioAs in other studies of type 1 diabetes and metformin, HbA1c was only transiently improved by metformin and reverted to baseline over the first 6 months of use, probably as insulin doses were down-titrated
metformin 19744 insulin doses were down-titrated by patients in an effort to avoid hypoglycaemia [[9]]. The effect of metformin on maximal cIMT was, therefore, consistent with an anti-atherosclerotic effect independent of glucose
metformin 20213 vascular tissues [[44]] or improvement in aspects of endothelial function [[31], [45]]. Alternatively, metformin can inhibit AGE formation by a pathway independent of AMPK [[46]]. The contrasting results between the
metformin 20394 contrasting results between the REMOVAL study and the CAMERA study [[37]] suggest that an effect of metformin on atherosclerosis progression may be specific to diabetes. In the CIMT trial, as acknowledged by the
metformin 20540 be specific to diabetes. In the CIMT trial, as acknowledged by the authors, the lack of an effect of metformin on cIMT in type 2 diabetes may have been due to a lack of statistical power [[36]].Summary and conclusionsThe
metformin 20721 power [[36]].Summary and conclusionsThe recent larger trials provide a new perspective on the use of metformin in type 1 diabetes. Although there is evidence that metformin can limit insulin dose requirement, there
metformin 20783 provide a new perspective on the use of metformin in type 1 diabetes. Although there is evidence that metformin can limit insulin dose requirement, there is little evidence to support the recommendation by current
metformin 21072 type 1 diabetes who are overweight or obese.Ideally there should be a cardiovascular outcome trial of metformin in type 1 diabetes but this would involve studying several thousand individuals over at least 5 years,
metformin 21632 outcome-based trial is completed, clinicians and people with type 1 diabetes will have to decide whether metformin will be of benefit on the basis of existing evidence. The results of the REMOVAL study suggest that
metformin 21742 will be of benefit on the basis of existing evidence. The results of the REMOVAL study suggest that metformin can reduce weight and LDL-cholesterol and might reduce atherosclerosis progression, over 3 years in
Select Disease Character Offset Disease Term Instance
lactic acidosis 3945 phenformin, that was withdrawn from use in 1977 owing to concerns regarding a potential increased risk of lactic acidosis . Metformin was not withdrawn in the UK but was unavailable in the USA between 1977 and 1995. Key findings
metabolic syndrome 14474 30 years [[2]]. Prior to REMOVAL, small studies had reported a reduction of cIMT with metformin use in the metabolic syndrome and type 2 diabetes [[35], [36]]. However, while REMOVAL was under way, the Carotid Atherosclerosis:
vitamin B12 deficiency 17055 genuine intolerance with the majority being attributable to gastrointestinal adverse effects. Biochemical vitamin B12 deficiency was more than doubled over 3 years with metformin use (12%) vs placebo (5%). These findings contribute
vitamin B12 deficiency 18972 cIMT(mm)0.918 ± 0.196−0.0130.0093−Significant reduction in progression of atherosclerosis Occurrence of vitamin B12 deficiency (<150 pmol/l)−2.76 (HR)0.0094−Risk of vitamin B12 deficiency more than doubled vs placeboData were
vitamin B12 deficiency 19038 of atherosclerosis Occurrence of vitamin B12 deficiency (<150 pmol/l)−2.76 (HR)0.0094−Risk of vitamin B12 deficiency more than doubled vs placeboData were analysed by ANCOVA other than for carotid outcomes (repeated measures

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