Antidepressant utilisation and incidence of weight gain during 10 years’ follow-up

Objective To evaluate the long term association between antidepressant prescribing and body weight.

Design Population based cohort study.

Setting General practices contributing to the UK Clinical Practice Research Datalink, 2004-14.

Participants 136 762 men and 157 957 women with three or more records for body mass index (BMI).

Main outcome measures The main outcomes were antidepressant prescribing, incidence of ≥5% increase in body weight, and transition to overweight or obesity. Adjusted rate ratios were estimated from a Poisson model adjusting for age, sex, depression recording, comorbidity, coprescribing of antiepileptics or antipsychotics, deprivation, smoking, and advice on diet.

Results In the year of study entry, 17 803 (13.0%) men and 35 307 (22.4%) women with a mean age of 51.5 years (SD 16.6 years) were prescribed antidepressants. During 1 836 452 person years of follow-up, the incidence of new episodes of ≥5 weight gain in participants not prescribed antidepressants was 8.1 per 100 person years and in participants prescribed antidepressants was 11.2 per 100 person years (adjusted rate ratio 1.21, 95% confidence interval 1.19 to 1.22, P<0.001). The risk of weight gain remained increased during at least six years of follow-up. In the second year of treatment the number of participants treated with antidepressants for one year for one additional episode of ≥5% weight gain was 27 (95% confidence interval 25 to 29). In people who were initially of normal weight, the adjusted rate ratio for transition to overweight or obesity was 1.29 (1.25 to 1.34); in people who were initially overweight, the adjusted rate ratio for transition to obesity was 1.29 (1.25 to 1.33). Associations may not be causal, and residual confounding might contribute to overestimation of associations.

Conclusion Widespread utilisation of antidepressants may be contributing to long term increased risk of weight gain at population level. The potential for weight gain should be considered when antidepressant treatment is indicated.

Reference:  BMJ 2018;361:k1951


Severe and predominantly active atopic eczema in adulthood and long term risk of cardiovascular disease: population based cohort study

Objective To investigate whether adults with atopic eczema are at an increased risk of cardiovascular disease and whether the risk varies by atopic eczema severity and condition activity over time.

Design Population based matched cohort study.

Setting UK electronic health records from the Clinical Practice Research Datalink, Hospital Episode Statistics, and data from the Office for National Statistics, 1998–2015.

Participants Adults with a diagnosis of atopic eczema, matched (on age, sex, general practice, and calendar time) to up to five patients without atopic eczema.

Main outcome measures Cardiovascular outcomes (myocardial infarction, unstable angina, heart failure, atrial fibrillation, stroke, and cardiovascular death).

Results 387 439 patients with atopic eczema were matched to 1 528 477 patients without atopic eczema. The median age was 43 at cohort entry and 66% were female. Median follow-up was 5.1 years. Evidence of a 10% to 20% increased hazard for the non-fatal primary outcomes for patients with atopic eczema was found by using Cox regression stratified by matched set. There was a strong dose-response relation with severity of atopic eczema. Patients with severe atopic eczema had a 20% increase in the risk of stroke (hazard ratio 1.22, 99% confidence interval 1.01 to 1.48), 40% to 50% increase in the risk of myocardial infarction, unstable angina, atrial fibrillation, and cardiovascular death, and 70% increase in the risk of heart failure (hazard ratio 1.69, 99% confidence interval 1.38 to 2.06). Patients with the most active atopic eczema (active >50% of follow-up) were also at a greater risk of cardiovascular outcomes. Additional adjustment for cardiovascular risk factors as potential mediators partially attenuated the point estimates, though associations persisted for severe atopic eczema.

Conclusions Severe and predominantly active atopic eczema are associated with an increased risk of cardiovascular outcomes. Targeting cardiovascular disease prevention strategies among these patients should be considered.

Reference: BMJ 2018;361:k1786

Risk of stroke and transient ischaemic attack in patients with a diagnosis of resolved atrial fibrillation: retrospective cohort studies

Objectives To determine rates of stroke or transient ischaemic attack (TIA) and all cause mortality in patients with a diagnosis of “resolved” atrial fibrillation compared to patients with unresolved atrial fibrillation and without atrial fibrillation.

Design Two retrospective cohort studies.

Setting General practices contributing to The Health Improvement Network, 1 January 2000 to 15 May 2016.

Participants Adults aged 18 years or more with no previous stroke or TIA: 11 159 with resolved atrial fibrillation, 15 059 controls with atrial fibrillation, and 22 266 controls without atrial fibrillation.

Main outcome measures Primary outcome was incidence of stroke or TIA. Secondary outcome was all cause mortality.

Results Adjusted incidence rate ratios for stroke or TIA in patients with resolved atrial fibrillation were 0.76 (95% confidence interval 0.67 to 0.85, P<0.001) versus controls with atrial fibrillation and 1.63 (1.46 to 1.83, P<0.001) versus controls without atrial fibrillation. Adjusted incidence rate ratios for mortality in patients with resolved atrial fibrillation were 0.60 (0.56 to 0.65, P<0.001) versus controls with atrial fibrillation and 1.13 (1.06 to 1.21, P<0.001) versus controls without atrial fibrillation. When patients with resolved atrial fibrillation and documented recurrent atrial fibrillation were excluded the adjusted incidence rate ratio for stroke or TIA was 1.45 (1.26 to 1.67, P<0.001) versus controls without atrial fibrillation.

Conclusion Patients with resolved atrial fibrillation remain at higher risk of stroke or TIA than patients without atrial fibrillation. The risk is increased even in those in whom recurrent atrial fibrillation is not documented. Guidelines should be updated to advocate continued use of anticoagulants in patients with resolved atrial fibrillation.

Reference:  BMJ 2018;361:k1717


Cardiovascular disease risk prediction equations in 400 000 primary care patients in New Zealand: a derivation and validation study


Most cardiovascular disease risk prediction equations in use today were derived from cohorts established last century and with participants at higher risk but less socioeconomically and ethnically diverse than patients they are now applied to. We recruited a nationally representative cohort in New Zealand to develop equations relevant to patients in contemporary primary care and compared the performance of these new equations to equations that are recommended in the USA.


The PREDICT study automatically recruits participants in routine primary care when general practitioners in New Zealand use PREDICT software to assess their patients’ risk profiles for cardiovascular disease, which are prospectively linked to national ICD-coded hospitalisation and mortality databases. The study population included male and female patients in primary care who had no prior cardiovascular disease, renal disease, or congestive heart failure. New equations predicting total cardiovascular disease risk were developed using Cox regression models, which included clinical predictors plus an area-based deprivation index and self-identified ethnicity. Calibration and discrimination performance of the equations were assessed and compared with 2013 American College of Cardiology/American Heart Association Pooled Cohort Equations (PCEs). The additional predictors included in new PREDICT equations were also appended to the PCEs to determine whether they were independent predictors in the equations from the USA.


Outcome events were derived for 401 752 people aged 30–74 years at the time of their first PREDICT risk assessment between Aug 27, 2002, and Oct 12, 2015, representing about 90% of the eligible population. The mean follow-up was 4·2 years, and a third of participants were followed for 5 years or more. 15 386 (4%) people had cardiovascular disease events (1507 [10%] were fatal, and 8549 [56%] met the PCEs definition of hard atherosclerotic cardiovascular disease) during 1 685 521 person-years follow-up. The median 5-year risk of total cardiovascular disease events predicted by the new equations was 2·3% in women and 3·2% in men. Multivariable adjusted risk increased by about 10% per quintile of socioeconomic deprivation. Māori, Pacific, and Indian patients were at 13–48% higher risk of cardiovascular disease than Europeans, and Chinese or other Asians were at 25–33% lower risk of cardiovascular disease than Europeans. The PCEs overestimated of hard atherosclerotic cardiovascular disease by about 40% in men and by 60% in women, and the additional predictors in the new equations were also independent predictors in the PCEs. The new equations were significantly better than PCEs on all performance metrics.


We constructed a large prospective cohort study representing typical patients in primary care in New Zealand who were recommended for cardiovascular disease risk assessment. Most patients are now at low risk of cardiovascular disease, which explains why the PCEs based mainly on old cohorts substantially overestimate risk. Although the PCEs and many other equations will need to be recalibrated to mitigate overtreatment of the healthy majority, they also need new predictors that include measures of socioeconomic deprivation and multiple ethnicities to identify vulnerable high-risk subpopulations that might otherwise be undertreated.


Health Research Council of New Zealand, Heart Foundation of New Zealand, and Healthier Lives National Science Challenge.

Reference: The Lancet, Volume 391, No. 10133, p1897–1907, 12 May 2018

Relationship between Clinic and Ambulatory Blood-Pressure Measurements and Mortality


Evidence for the influence of ambulatory blood pressure on prognosis derives mainly from population-based studies and a few relatively small clinical investigations. This study examined the associations of blood pressure measured in the clinic (clinic blood pressure) and 24-hour ambulatory blood pressure with all-cause and cardiovascular mortality in a large cohort of patients in primary care.


We analyzed data from a registry-based, multicenter, national cohort that included 63,910 adults recruited from 2004 through 2014 in Spain. Clinic and 24-hour ambulatory blood-pressure data were examined in the following categories: sustained hypertension (elevated clinic and elevated 24-hour ambulatory blood pressure), “white-coat” hypertension (elevated clinic and normal 24-hour ambulatory blood pressure), masked hypertension (normal clinic and elevated 24-hour ambulatory blood pressure), and normotension (normal clinic and normal 24-hour ambulatory blood pressure). Analyses were conducted with Cox regression models, adjusted for clinic and 24-hour ambulatory blood pressures and for confounders.


During a median follow-up of 4.7 years, 3808 patients died from any cause, and 1295 of these patients died from cardiovascular causes. In a model that included both 24-hour and clinic measurements, 24-hour systolic pressure was more strongly associated with all-cause mortality (hazard ratio, 1.58 per 1-SD increase in pressure; 95% confidence interval [CI], 1.56 to 1.60, after adjustment for clinic blood pressure) than the clinic systolic pressure (hazard ratio, 1.02; 95% CI, 1.00 to 1.04, after adjustment for 24-hour blood pressure). Corresponding hazard ratios per 1-SD increase in pressure were 1.55 (95% CI, 1.53 to 1.57, after adjustment for clinic and daytime blood pressures) for nighttime ambulatory systolic pressure and 1.54 (95% CI, 1.52 to 1.56, after adjustment for clinic and nighttime blood pressures) for daytime ambulatory systolic pressure. These relationships were consistent across subgroups of age, sex, and status with respect to obesity, diabetes, cardiovascular disease, and antihypertensive treatment. Masked hypertension was more strongly associated with all-cause mortality (hazard ratio, 2.83; 95% CI, 2.12 to 3.79) than sustained hypertension (hazard ratio, 1.80; 95% CI, 1.41 to 2.31) or white-coat hypertension (hazard ratio, 1.79; 95% CI, 1.38 to 2.32). Results for cardiovascular mortality were similar to those for all-cause mortality.


Ambulatory blood-pressure measurements were a stronger predictor of all-cause and cardiovascular mortality than clinic blood-pressure measurements. White-coat hypertension was not benign, and masked hypertension was associated with a greater risk of death than sustained hypertension. (Funded by the Spanish Society of Hypertension and others.)

Reference: N Engl J Med 2018; 378:1509-1520

Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study

Objective To assess whether the use of dipeptidyl peptidase-4 inhibitors is associated with the incidence of inflammatory bowel disease in patients with type 2 diabetes.

Design Population based cohort study.

Setting More than 700 general practices contributing data to the United Kingdom Clinical Practice Research Datalink.

Participants A cohort of 141 170 patients, at least 18 years of age, starting antidiabetic drugs between 1 January 2007 and 31 December 2016, with follow-up until 30 June 2017.

Main outcome measures Adjusted hazard ratios for incident inflammatory bowel disease associated with use of dipeptidyl peptidase-4 inhibitors overall, by cumulative duration of use, and by time since initiation, estimated using time dependent Cox proportional hazards models. Use of dipeptidyl peptidase-4 inhibitors was modelled as a time varying variable and compared with use of other antidiabetic drugs, with exposures lagged by six months to account for latency and diagnostic delays.

Results During 552 413 person years of follow-up, 208 incident inflammatory bowel disease events occurred (crude incidence rate of 37.7 (95% confidence interval 32.7 to 43.1) per 100 000 person years). Overall, use of dipeptidyl peptidase-4 inhibitors was associated with an increased risk of inflammatory bowel disease (53.4 v34.5 per 100 000 person years; hazard ratio 1.75, 95% confidence interval 1.22 to 2.49). Hazard ratios gradually increased with longer durations of use, reaching a peak after three to four years of use (hazard ratio 2.90, 1.31 to 6.41) and decreasing after more than four years of use (1.45, 0.44 to 4.76). A similar pattern was observed with time since starting dipeptidyl peptidase-4 inhibitors. These findings remained consistent in several sensitivity analyses.

Conclusions In this first population based study, the use of dipeptidyl peptidase-4 inhibitors was associated with an increased risk of inflammatory bowel disease. Although these findings need to be replicated, physicians should be aware of this possible association.

Reference: BMJ 2018;360:k872

Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: population based cohort study

Objective To evaluate the cardiovascular safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus, in direct comparisons with DPP-4 inhibitors (DPP-4i), GLP-1 receptor agonists (GLP-1RA), or sulfonylureas, as used in routine practice.

Design Population based retrospective cohort study.

Setting Nationwide sample of patients with type 2 diabetes from a large de-identified US commercial healthcare database (Optum Clinformatics Datamart).

Participants Three pairwise 1:1 propensity score matched cohorts of patients with type 2 diabetes 18 years and older who initiated canagliflozin or a comparator non-gliflozin antidiabetic agent (ie, a DPP-4i, a GLP-1RA, or a sulfonylurea) between April 2013 and September 2015.

Main outcome measures The primary outcomes were heart failure admission to hospital and a composite cardiovascular endpoint (comprised of being admitted to hospital for acute myocardial infarction, ischemic stroke, or hemorrhagic stroke). Hazard ratios and 95% confidence intervals were estimated in each propensity score matched cohort controlling for more than 100 baseline characteristics.

Results During a 30 month period, the hazard ratio for heart failure admission to hospital associated with canagliflozin was 0.70 (95% confidence interval 0.54 to 0.92) versus a DPP-4i (n=17 667 pairs), 0.61 (0.47 to 0.78) versus a GLP-1RA (20 539), and 0.51 (0.38 to 0.67) versus a sulfonylurea (17 354 ). The hazard ratio for the composite cardiovascular endpoint associated with canagliflozin was 0.89 (0.68 to 1.17) versus a DPP-4i, 1.03 (0.79 to 1.35) versus a GLP-1RA, and 0.86 (0.65 to 1.13) versus a sulfonylurea. Results were similar in sensitivity analyses further adjusting for baseline hemoglobin A1c levels and in subgroups of patients with and without prior cardiovascular disease or heart failure.

Conclusions In this large cohort study, canagliflozin was associated with a lower risk of heart failure admission to hospital and with a similar risk of myocardial infarction or stroke in direct comparisons with three different classes of non-gliflozin diabetes treatment alternatives as used in routine care.

Reference: BMJ 2018;360:k119