The strengths of the study were its population based sampling, the objective method used to define metformin exposure, detailed dispensed prescribing histories available for patients, and adjustment ...for confounders. Because this is a pilot observational study, however, we must consider alternative explanations.
Abstract Aims/hypothesis Few studies have examined the clinical characteristics associated with changes in weight before and after diagnosis of type 2 diabetes. Using a large real-world cohort, we ...derived trajectories of BMI before and after diabetes diagnosis, and examined the clinical characteristics associated with these trajectories, including assessing the impact of pre-diagnosis weight change on post-diagnosis weight change. Methods We performed an observational cohort study using electronic medical records from individuals in the Scottish Care Information Diabetes Collaboration database. Two trajectories were calculated, based on observed BMI measurements between 3 years and 6 months before diagnosis and between 1 and 5 years after diagnosis. In the post-diagnosis trajectory, each BMI measurement was time-dependently adjusted for the effects of diabetes medications and HbA 1c change. Results A total of 2736 individuals were included in the study. There was a pattern of pre-diagnosis weight gain, with 1944 individuals (71%) gaining weight overall, and 875 (32%) gaining more than 0.5 kg/m 2 per year. This was followed by a pattern of weight loss after diagnosis, with 1722 individuals (63%) losing weight. Younger age and greater social deprivation were associated with increased weight gain before diagnosis. Pre-diagnosis weight change was unrelated to post-diagnosis weight change, but post-diagnosis weight loss was associated with older age, female sex, higher BMI, higher HbA 1c and weight gain during the peri-diagnosis period. When considering the peri-diagnostic period (defined as from 6 months before to 12 months after diagnosis), we identified 986 (36%) individuals who had a high HbA 1c at diagnosis but who lost weight rapidly and were most aggressively treated at 1 year; this subgroup had the best glycaemic control at 5 years. Conclusions/interpretation Average weight increases before diagnosis and decreases after diagnosis; however, there were significant differences across the population in terms of weight changes. Younger individuals gained weight pre-diagnosis, but, in older individuals, type 2 diabetes is less associated with weight gain, consistent with other drivers for diabetes aetiology in older adults. We have identified a substantial group of individuals who have a rapid deterioration in glycaemic control, together with weight loss, around the time of diagnosis, and who subsequently stabilise, suggesting that a high HbA 1c at diagnosis is not inevitably associated with a poor outcome and may be driven by reversible glucose toxicity. Graphical Abstract
Metformin is the most widely prescribed medication for the treatment of type 2 diabetes (T2D). However, gastrointestinal (GI) side effects develop in ~25% of patients treated with metformin, leading ...to the discontinuation of therapy in ~5% of cases. We hypothesized that reduced transport of metformin via organic cation transporter 1 (OCT1) could increase metformin concentration in the intestine, leading to increased risk of severe GI side effects and drug discontinuation. We compared the phenotype, carriage of reduced-function OCT1 variants, and concomitant prescribing of drugs known to inhibit OCT1 transport in 251 intolerant and 1,915 fully metformin-tolerant T2D patients. We showed that women and older people were more likely to be intolerant to metformin. Concomitant use of medications, known to inhibit OCT1 activity, was associated with intolerance (odds ratio OR 1.63 95% CI 1.22-2.17, P = 0.001) as was carriage of two reduced-function OCT1 alleles compared with carriage of one or no deficient allele (OR 2.41 95% CI 1.48-3.93, P < 0.001). Intolerance was over four times more likely to develop (OR 4.13 95% CI 2.09-8.16, P < 0.001) in individuals with two reduced-function OCT1 alleles who were treated with OCT1 inhibitors. Our results suggest that reduced OCT1 transport is an important determinant of metformin intolerance.
Aims
It is well established that low birthweight is associated with subsequent risk of type 2 diabetes (T2DM). The aim of our study was to use a large birth cohort linked to a national diabetes ...registry to investigate how birthweight impacts the phenotype at diagnosis of T2DM and the subsequent rate of glycaemic deterioration.
Methods
We linked the Walker Birth Cohort (48,000 births, 1952–1966, Tayside, Scotland) to the national diabetes registry in Scotland (SCI‐Diabetes). Birthweight was adjusted for gestational age. Simple linear regression was performed to assess the impact of the adjusted birthweight on the diabetes phenotype at diagnosis. This was then built up into a multiple regression model to allow for the adjustment of confounding variables. A cox proportional hazards model was then used to evaluate the impact of birthweight on diabetes progression.
Results
Lower birthweights were associated with a 293 day younger age of diagnosis of T2DM per 1 kg reduction in birthweight, p = 0.005; and a 1.29 kg/m2 lower BMI at diagnosis per 1 kg reduction in birthweight, p < 0.001. There was no significant association of birthweight on diabetes progression.
Conclusion
For the first time, we have shown that a lower birthweight is associated with younger onset of T2DM, with those with lower birthweight also being slimmer at diagnosis. These results suggest that lower birthweight impacts on T2DM phenotype via reduced beta‐cell function rather than insulin resistance.
Objective
To look at adverse outcomes for patients on liothyronine compared to l‐thyroxine. Some trials have examined the relative merits of liothyronine but none have looked at adverse outcomes in ...large numbers.
Study Design
An observational study of all patients prescribed thyroid hormone replacement in Tayside Scotland (population 400 000) from 1997 to 2014.
Patients
A study group of patients having ever used liothyronine (n = 400) was compared to those who had only used l‐thyroxine (n = 33 955). All patients were followed up until end‐point, death or leaving Tayside.
Measurements
Mortality rates and admissions with cardiovascular disease, atrial fibrillation, fractures, breast cancer and mental diseases were compared. Incident use of bisphosphonates, statins, antidepressants and antipsychotics was compared.
Results
Compared to patients only taking l‐thyroxine, those using liothyronine had no increased risk of cardiovascular disease hazard ratio (HR) 1·04; 95% CI 0·70–1·54, atrial fibrillation (HR 0·91: 0·47–1·75), or fractures (HR 0·79: 0·49–1·27) after adjusting for age. There was no difference in the number of prescriptions for bisphosphonates or statins. There was an increased risk of new prescriptions for antipsychotic medication (HR 2·26: 1·64–3·11 P < 0·0001) which was proportional to the number of liothyronine prescriptions. There was a non‐significant trend towards an increase in breast cancer and new use of antidepressant medications. During follow‐up, median TSH was higher for patients on l‐thyroxine alone (2·08 vs 1·07 mU/L; P < 0·001).
Conclusion
For patients taking long‐term liothyronine we did not identify any additional risk of atrial fibrillation, cardiovascular disease or fractures. There was an increased incident use of antipsychotic medication during follow‐up.
To evaluate the association between metformin use and anemia risk in type 2 diabetes, and the time-course for this, in a randomized controlled trial (RCT) and real-world population data.
Anemia was ...defined as a hemoglobin measure of <11 g/dL. In the RCTs A Diabetes Outcome Progression Trial (ADOPT;
= 3,967) and UK Prospective Diabetes Study (UKPDS;
= 1,473), logistic regression was used to model anemia risk and nonlinear mixed models for change in hematological parameters. In the observational Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) population (
= 3,485), discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk.
In ADOPT, compared with sulfonylureas, the odds ratio (OR) (95% CI) for anemia was 1.93 (1.10, 3.38) for metformin and 4.18 (2.50, 7.00) for thiazolidinediones. In UKPDS, compared with diet, the OR (95% CI) was 3.40 (1.98, 5.83) for metformin, 0.96 (0.57, 1.62) for sulfonylureas, and 1.08 (0.62, 1.87) for insulin. In ADOPT, hemoglobin and hematocrit dropped after metformin initiation by 6 months, with no further decrease after 3 years. In UKPDS, hemoglobin fell by 3 years in the metformin group compared with other treatments. At years 6 and 9, hemoglobin was reduced in all treatment groups, with no greater difference seen in the metformin group. In GoDARTS, each 1 g/day of metformin use was associated with a 2% higher annual risk of anemia.
Metformin use is associated with early risk of anemia in individuals with type 2 diabetes, a finding consistent across two RCTs and replicated in one real-world study. The mechanism for this early fall in hemoglobin is uncertain, but given the time course, is unlikely to be due to vitamin B
deficiency alone.
OBJECTIVE: The antidiabetic properties of metformin are mediated through its ability to activate the AMP-activated protein kinase (AMPK). Activation of AMPK can suppress tumor formation and inhibit ...cell growth in addition to lowering blood glucose levels. We tested the hypothesis that metformin reduces the risk of cancer in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: In an observational cohort study using record-linkage databases and based in Tayside, Scotland, U.K., we identified people with type 2 diabetes who were new users of metformin in 1994-2003. We also identified a set of diabetic comparators, individually matched to the metformin users by year of diabetes diagnosis, who had never used metformin. In a survival analysis we calculated hazard ratios for diagnosis of cancer, adjusted for baseline characteristics of the two groups using Cox regression. RESULTS: Cancer was diagnosed among 7.3% of 4,085 metformin users compared with 11.6% of 4,085 comparators, with median times to cancer of 3.5 and 2.6 years, respectively (P < 0.001). The unadjusted hazard ratio (95% CI) for cancer was 0.46 (0.40-0.53). After adjusting for sex, age, BMI, A1C, deprivation, smoking, and other drug use, there was still a significantly reduced risk of cancer associated with metformin: 0.63 (0.53-0.75). CONCLUSIONS: These results suggest that metformin use may be associated with a reduced risk of cancer. A randomized trial is needed to assess whether metformin is protective in a population at high risk for cancer.
Type 2 diabetes (T2D) is a complex chronic disease characterized by considerable phenotypic heterogeneity. In this study, we applied a reverse graph embedding method to routinely collected data from ...23,137 Scottish patients with newly diagnosed diabetes to visualize this heterogeneity and used partitioned diabetes polygenic risk scores to gain insight into the underlying biological processes. Overlaying risk of progression to outcomes of insulin requirement, chronic kidney disease, referable diabetic retinopathy and major adverse cardiovascular events, we show how these risks differ by patient phenotype. For example, patients at risk of retinopathy are phenotypically different from those at risk of cardiovascular events. We replicated our findings in the UK Biobank and the ADOPT clinical trial, also showing that the pattern of diabetes drug monotherapy response differs for different drugs. Overall, our analysis highlights how, in a European population, underlying phenotypic variation drives T2D onset and affects subsequent diabetes outcomes and drug response, demonstrating the need to incorporate these factors into personalized treatment approaches for the management of T2D.
The pathophysiology of type 2 diabetes differs markedly by ethnicity.
A systematic review and meta-analysis was conducted to assess the impact of ethnicity on the glucose-lowering efficacy of the ...newer oral agents, sodium-glucose cotransporter 2 inhibitors (SGLT-2i), glucagon-like peptide 1 receptor agonists (GLP-1RA), and dipeptidyl peptidase 4 inhibitors (DPP-4i), using evidence from randomized clinical trials (RCTs).
A literature search was conducted in PubMed of all randomized, placebo-controlled trials of DPP-4i, SGLT-2i, and GLP-1RA. The search strategy was developed based on Medical Subject Headings (MeSH) terms and keywords.
A total of 64 studies that qualified for meta-analysis after full-text review based on predefined inclusion and exclusion criteria-RCTs with at least 50 patients in each arm, >70% of population from Asian or white group, duration ≥24 weeks, and publication up to March 2019-were selected for systematic review and meta-analysis.
Data extraction was done for aggregated study-level data by two independent researchers. Absolute changes in HbA
(%) from baseline to 24 weeks between the drug and placebo were considered as the primary end point of the study.
Change in HbA
was evaluated by computing mean differences and 95% CIs between treatment and placebo arms.
The study is based on summarized data and could not be separated based on East Asians and South Asians.
The glucose-lowering efficacy of SGLT-2i, and to a lesser extent DPP-4i, was greater in studies of predominantly Asian ethnicity compared with studies of predominantly white ethnicity. There was no difference seen by ethnicity for GLP-1RA.
Aims/hypothesis
There is considerable variability in how diabetes progresses after diagnosis. Progression modelling has largely focused on ‘time to failure’ methods, yet determining a ‘coefficient of ...failure’ has many advantages. We derived a rate of glycaemic deterioration in type 2 diabetes, using a large real-world cohort, and aimed to investigate the clinical, biochemical, pharmacological and immunological variables associated with fast and slow rates of glycaemic deterioration.
Methods
An observational cohort study was performed using the electronic medical records from participants in the Genetics of Diabetes Audit and Research in Tayside Study (GoDARTS). A model was derived based on an individual’s observed HbA
1c
measures from the first eligible HbA
1c
after the diagnosis of diabetes through to the study end (defined as insulin initiation, death, leaving the area or end of follow-up). Each HbA
1c
measure was time-dependently adjusted for the effects of non-insulin glucose-lowering drugs, changes in BMI and corticosteroid use. GAD antibody (GADA) positivity was defined as GAD titres above the 97.5th centile of the population distribution.
Results
The mean (95% CI) glycaemic deterioration for type 2 diabetes and GADA-positive individuals was 1.4 (1.3, 1.4) and 2.8 (2.4, 3.3) mmol/mol HbA
1c
per year, respectively. A younger age of diagnosis, lower HDL-cholesterol concentration, higher BMI and earlier calendar year of diabetes diagnosis were independently associated with higher rates of glycaemic deterioration in individuals with type 2 diabetes. The rate of deterioration in those diagnosed at over 70 years of age was very low, with 66% having a rate of deterioration of less than 1.1 mmol/mol HbA
1c
per year, and only 1.5% progressing more rapidly than 4.4 mmol/mol HbA
1c
per year.
Conclusions/interpretation
We have developed a novel approach for modelling the progression of diabetes in observational data across multiple drug combinations. This approach highlights how glycaemic deterioration in those diagnosed at over 70 years of age is minimal, supporting a stratified approach to diabetes management.
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