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

Advertisements

Cancer risk associated with chronic diseases and disease markers: prospective cohort study

Objectives To assess the independent and joint associations of major chronic diseases and disease markers with cancer risk and to explore the benefit of physical activity in reducing the cancer risk associated with chronic diseases and disease markers.

Design Prospective cohort study.

Setting Standard medical screening program in Taiwan.

Participants 405 878 participants, for whom cardiovascular disease markers (blood pressure, total cholesterol, and heart rate), diabetes, chronic kidney disease markers (proteinuria and glomerular filtration rate), pulmonary disease, and gouty arthritis marker (uric acid) were measured or diagnosed according to standard methods, were followed for an average of 8.7 years.

Main outcome measures Cancer incidence and cancer mortality.

Results A statistically significantly increased risk of incident cancer was observed for the eight diseases and markers individually (except blood pressure and pulmonary disease), with adjusted hazard ratios ranging from 1.07 to 1.44. All eight diseases and markers were statistically significantly associated with risk of cancer death, with adjusted hazard ratios ranging from 1.12 to 1.70. Chronic disease risk scores summarizing the eight diseases and markers were positively associated with cancer risk in a dose-response manner, with the highest scores associated with a 2.21-fold (95% confidence interval 1.77-fold to 2.75-fold) and 4.00-fold (2.84-fold to 5.63-fold) higher cancer incidence and cancer mortality, respectively. High chronic disease risk scores were associated with substantial years of life lost, and the highest scores were associated with 13.3 years of life lost in men and 15.9 years of life lost in women. The population attributable fractions of cancer incidence or cancer mortality from the eight chronic diseases and markers together were comparable to those from five major lifestyle factors combined (cancer incidence: 20.5% v 24.8%; cancer mortality: 38.9% v 39.7%). Among physically active (versus inactive) participants, the increased cancer risk associated with chronic diseases and markers was attenuated by 48% for cancer incidence and 27% for cancer mortality.

Conclusions Chronic disease is an overlooked risk factor for cancer, as important as five major lifestyle factors combined. In this study, chronic diseases contributed to more than one fifth of the risk for incident cancer and more than one third of the risk for cancer death. Physical activity is associated with a nearly 40% reduction in the cancer risk associated with chronic diseases.

Reference: BMJ 2018;360:k134

Migraine and risk of cardiovascular diseases: Danish population based matched cohort study

Objective To examine the risks of myocardial infarction, stroke (ischaemic and haemorrhagic), peripheral artery disease, venous thromboembolism, atrial fibrillation or atrial flutter, and heart failure in patients with migraine and in a general population comparison cohort.

Design Nationwide, population based cohort study.

Setting All Danish hospitals and hospital outpatient clinics from 1995 to 2013.

Participants 51 032 patients with migraine and 510 320 people from the general population matched on age, sex, and calendar year.

Main outcome measures Comorbidity adjusted hazard ratios of cardiovascular outcomes based on Cox regression analysis.

Results Higher absolute risks were observed among patients with incident migraine than in the general population across most outcomes and follow-up periods. After 19 years of follow-up, the cumulative incidences per 1000 people for the migraine cohort compared with the general population were 25 v 17 for myocardial infarction, 45 v 25 for ischaemic stroke, 11 v 6 for haemorrhagic stroke, 13 v 11 for peripheral artery disease, 27 v 18 for venous thromboembolism, 47 v 34 for atrial fibrillation or atrial flutter, and 19 v 18 for heart failure. Correspondingly, migraine was positively associated with myocardial infarction (adjusted hazard ratio 1.49, 95% confidence interval 1.36 to 1.64), ischaemic stroke (2.26, 2.11 to 2.41), and haemorrhagic stroke (1.94, 1.68 to 2.23), as well as venous thromboembolism (1.59, 1.45 to 1.74) and atrial fibrillation or atrial flutter (1.25, 1.16 to 1.36). No meaningful association was found with peripheral artery disease (adjusted hazard ratio 1.12, 0.96 to 1.30) or heart failure (1.04, 0.93 to 1.16). The associations, particularly for stroke outcomes, were stronger during the short term (0-1 years) after diagnosis than the long term (up to 19 years), in patients with aura than in those without aura, and in women than in men. In a subcohort of patients, the associations persisted after additional multivariable adjustment for body mass index and smoking.

Conclusions Migraine was associated with increased risks of myocardial infarction, ischaemic stroke, haemorrhagic stroke, venous thromboembolism, and atrial fibrillation or atrial flutter. Migraine may be an important risk factor for most cardiovascular diseases.

Reference: BMJ 2018;360:k96

Low cigarette consumption and risk of coronary heart disease and stroke: meta-analysis of 141 cohort studies in 55 study reports

Objective To use the relation between cigarette consumption and cardiovascular disease to quantify the risk of coronary heart disease and stroke for light smoking (one to five cigarettes/day).

Design Systematic review and meta-analysis.

Data sources Medline 1946 to May 2015, with manual searches of references.

Eligibility criteria for selecting studies Prospective cohort studies with at least 50 events, reporting hazard ratios or relative risks (both hereafter referred to as relative risk) compared with never smokers or age specific incidence in relation to risk of coronary heart disease or stroke.

Data extraction/synthesis MOOSE guidelines were followed. For each study, the relative risk was estimated for smoking one, five, or 20 cigarettes per day by using regression modelling between risk and cigarette consumption. Relative risks were adjusted for at least age and often additional confounders. The main measure was the excess relative risk for smoking one cigarette per day (RR1_per_day−1) expressed as a proportion of that for smoking 20 cigarettes per day (RR20_per_day−1), expected to be about 5% assuming a linear relation between risk and consumption (as seen with lung cancer). The relative risks for one, five, and 20 cigarettes per day were also pooled across all studies in a random effects meta-analysis. Separate analyses were done for each combination of sex and disorder.

Results The meta-analysis included 55 publications containing 141 cohort studies. Among men, the pooled relative risk for coronary heart disease was 1.48 for smoking one cigarette per day and 2.04 for 20 cigarettes per day, using all studies, but 1.74 and 2.27 among studies in which the relative risk had been adjusted for multiple confounders. Among women, the pooled relative risks were 1.57 and 2.84 for one and 20 cigarettes per day (or 2.19 and 3.95 using relative risks adjusted for multiple factors). Men who smoked one cigarette per day had 46% of the excess relative risk for smoking 20 cigarettes per day (53% using relative risks adjusted for multiple factors), and women had 31% of the excess risk (38% using relative risks adjusted for multiple factors). For stroke, the pooled relative risks for men were 1.25 and 1.64 for smoking one or 20 cigarettes per day (1.30 and 1.56 using relative risks adjusted for multiple factors). In women, the pooled relative risks were 1.31 and 2.16 for smoking one or 20 cigarettes per day (1.46 and 2.42 using relative risks adjusted for multiple factors). The excess risk for stroke associated with one cigarette per day (in relation to 20 cigarettes per day) was 41% for men and 34% for women (or 64% and 36% using relative risks adjusted for multiple factors). Relative risks were generally higher among women than men.

Conclusions Smoking only about one cigarette per day carries a risk of developing coronary heart disease and stroke much greater than expected: around half that for people who smoke 20 per day. No safe level of smoking exists for cardiovascular disease. Smokers should aim to quit instead of cutting down to significantly reduce their risk of these two common major disorders.

Reference:  BMJ 2018;360:j5855

Improving adherence to healthy dietary patterns, genetic risk, and long term weight gain: gene-diet interaction analysis in two prospective cohort studies

Objective To investigate whether improving adherence to healthy dietary patterns interacts with the genetic predisposition to obesity in relation to long term changes in body mass index and body weight.

Design Prospective cohort study.

Setting Health professionals in the United States.

Participants 8828 women from the Nurses’ Health Study and 5218 men from the Health Professionals Follow-up Study.

Exposure Genetic predisposition score was calculated on the basis of 77 variants associated with body mass index. Dietary patterns were assessed by the Alternate Healthy Eating Index 2010 (AHEI-2010), Dietary Approach to Stop Hypertension (DASH), and Alternate Mediterranean Diet (AMED).

Main outcome measures Five repeated measurements of four year changes in body mass index and body weight over follow-up (1986 to 2006).

Results During a 20 year follow-up, genetic association with change in body mass index was significantly attenuated with increasing adherence to the AHEI-2010 in the Nurses’ Health Study (P=0.001 for interaction) and Health Professionals Follow-up Study (P=0.005 for interaction). In the combined cohorts, four year changes in body mass index per 10 risk allele increment were 0.07 (SE 0.02) among participants with decreased AHEI-2010 score and −0.01 (0.02) among those with increased AHEI-2010 score, corresponding to 0.16 (0.05) kg versus −0.02 (0.05) kg weight change every four years (P<0.001 for interaction). Viewed differently, changes in body mass index per 1 SD increment of AHEI-2010 score were −0.12 (0.01), −0.14 (0.01), and −0.18 (0.01) (weight change: −0.35 (0.03), −0.36 (0.04), and −0.50 (0.04) kg) among participants with low, intermediate, and high genetic risk, respectively. Similar interaction was also found for DASH but not for AMED.

Conclusions These data indicate that improving adherence to healthy dietary patterns could attenuate the genetic association with weight gain. Moreover, the beneficial effect of improved diet quality on weight management was particularly pronounced in people at high genetic risk for obesity.

Reference: BMJ 2018;360:j5644

The effect of physical activity on mortality and cardiovascular disease in 130 000 people from 17 high-income, middle-income, and low-income countries: the PURE study

Association of Broad- vs Narrow-Spectrum Antibiotics With Treatment Failure, Adverse Events, and Quality of Life in Children With Acute Respiratory Tract Infections

Question  Does treatment with broad-spectrum antibiotics result in better clinical or patient-centered outcomes than narrow-spectrum antibiotics for children with acute respiratory tract infections?

Findings  In a retrospective cohort of 30 159 children with acute otitis media, group A streptococcal pharyngitis, and acute sinusitis, treatment with broad-spectrum vs narrow-spectrum antibiotics was not associated with treatment failure but was associated with higher rates of adverse events (3.7% vs 2.7%, respectively). In a prospective cohort of 2472 children, receipt of broad-spectrum vs narrow-spectrum antibiotics was associated with a slightly worse child quality of life and higher rates of adverse events (35.6% vs 25.1%, respectively).

Meaning  Use of broad-spectrum vs narrow-spectrum antibiotics was not associated with better clinical or patient-centered outcomes in children with acute respiratory tract infections.

Reference: JAMA. 2017;318(23):2325-2336.