Clinical trials have shown cardiovascular benefits and potential risks from sodium glucose cotransporter 2 inhibitors (SGLT2i). Trials may have limited ability to address individual end points or ...safety concerns.
We performed a population-based cohort study among patients with type 2 diabetes mellitus with established cardiovascular disease newly initiated on antihyperglycemic agents within the US Department of Defense Military Health System between April 1, 2013, and December 31, 2016. Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite end point of all-cause mortality and hospitalization for heart failure event, major adverse cardiovascular events (defined as all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke), and individual end points were evaluated using conditional Cox models comparing new SGLT2i users with other antihyperglycemic agents. The exploratory safety end point was below-knee lower extremity amputation. Intent-to-treat and on-treatment analyses were performed.
After propensity matching, 25 258 patients were followed for a median of 1.6 years. Compared with non-SGLT2i, initiation of SGLT2i was associated with a lower rate of all-cause mortality and hospitalization for heart failure (1.73 versus 3.01 events per 100 person-years; HR, 0.57; 95% CI, 0.50-0.65) and major adverse cardiovascular events (2.31 versus 3.45 events per 100 person-years; HR, 0.67; 95% CI, 0.60-0.75). SGLT2i initiation was also associated with an ≈2-fold higher risk of below-knee lower extremity amputation (0.17 versus 0.09 events per 100 person-years; HR, 1.99; 95% CI, 1.12-3.51). Because of the disproportionate canagliflozin exposure in the database, the majority of amputations were observed on canagliflozin. Results were consistent in the on-treatment analysis.
In this high-risk cohort, initiation of SGLT2i was associated with lower risk of all-cause mortality, hospitalization for heart failure, and major adverse cardiovascular events and higher risk of below-knee lower extremity amputation. Findings underscore the potential benefit and risks to be aware of when initiating SGLT2i. It remains unclear whether the below-knee lower extremity amputation risk extends across the class of medication, because the study was not powered to make comparisons among individual treatments.
To determine whether the use of angiotensin converting enzyme inhibitors (ACEIs), compared with use of angiotensin receptor blockers, is associated with an increased risk of lung cancer.
Population ...based cohort study.
United Kingdom Clinical Practice Research Datalink.
A cohort of 992 061 patients newly treated with antihypertensive drugs between 1 January 1995 and 31 December 2015 was identified and followed until 31 December 2016.
Cox proportional hazards models were used to estimate adjusted hazard ratios with 95% confidence intervals of incident lung cancer associated with the time varying use of ACEIs, compared with use of angiotensin receptor blockers, overall, by cumulative duration of use, and by time since initiation.
The cohort was followed for a mean of 6.4 (SD 4.7) years, generating 7952 incident lung cancer events (crude incidence 1.3 (95% confidence interval 1.2 to 1.3) per 1000 person years). Overall, use of ACEIs was associated with an increased risk of lung cancer (incidence rate 1.6
1.2 per 1000 person years; hazard ratio 1.14, 95% confidence interval 1.01 to 1.29), compared with use of angiotensin receptor blockers. Hazard ratios gradually increased with longer durations of use, with an association evident after five years of use (hazard ratio 1.22, 1.06 to 1.40) and peaking after more than 10 years of use (1.31, 1.08 to 1.59). Similar findings were observed with time since initiation.
In this population based cohort study, the use of ACEIs was associated with an increased risk of lung cancer. The association was particularly elevated among people using ACEIs for more than five years. Additional studies, with long term follow-up, are needed to investigate the effects of these drugs on incidence of lung cancer.
Patients with acute heart failure are frequently or systematically hospitalized, often because the risk of adverse events is uncertain and the options for rapid follow-up are inadequate. Whether the ...use of a strategy to support clinicians in making decisions about discharging or admitting patients, coupled with rapid follow-up in an outpatient clinic, would affect outcomes remains uncertain.
In a stepped-wedge, cluster-randomized trial conducted in Ontario, Canada, we randomly assigned 10 hospitals to staggered start dates for one-way crossover from the control phase (usual care) to the intervention phase, which involved the use of a point-of-care algorithm to stratify patients with acute heart failure according to the risk of death. During the intervention phase, low-risk patients were discharged early (in ≤3 days) and received standardized outpatient care, and high-risk patients were admitted to the hospital. The coprimary outcomes were a composite of death from any cause or hospitalization for cardiovascular causes within 30 days after presentation and the composite outcome within 20 months.
A total of 5452 patients were enrolled in the trial (2972 during the control phase and 2480 during the intervention phase). Within 30 days, death from any cause or hospitalization for cardiovascular causes occurred in 301 patients (12.1%) who were enrolled during the intervention phase and in 430 patients (14.5%) who were enrolled during the control phase (adjusted hazard ratio, 0.88; 95% confidence interval CI, 0.78 to 0.99; P = 0.04). Within 20 months, the cumulative incidence of primary-outcome events was 54.4% (95% CI, 48.6 to 59.9) among patients who were enrolled during the intervention phase and 56.2% (95% CI, 54.2 to 58.1) among patients who were enrolled during the control phase (adjusted hazard ratio, 0.95; 95% CI, 0.92 to 0.99). Fewer than six deaths or hospitalizations for any cause occurred in low- or intermediate-risk patients before the first outpatient visit within 30 days after discharge.
Among patients with acute heart failure who were seeking emergency care, the use of a hospital-based strategy to support clinical decision making and rapid follow-up led to a lower risk of the composite of death from any cause or hospitalization for cardiovascular causes within 30 days than usual care. (Funded by the Ontario SPOR Support Unit and others; COACH ClinicalTrials.gov number, NCT02674438.).
Despite current established therapy, heart failure (HF) remains a leading cause of hospitalization and mortality worldwide. Novel therapeutic targets are therefore needed to improve the prognosis of ...patients with HF. The EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) demonstrated significant reductions in mortality and HF hospitalization risk in patients with type 2 diabetes mellitus (T2D) and cardiovascular disease with the antihyperglycemic agent, empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor. The CANVAS trial (Canagliflozin Cardiovascular Assessment Study) subsequently reported a reduction in 3-point major adverse cardiovascular events and HF hospitalization risk. Although SGLT2 inhibition may have potential application beyond T2D, including HF, the mechanisms responsible for the cardioprotective effects of SGLT2 inhibitors remain incompletely understood. SGLT2 inhibition promotes natriuresis and osmotic diuresis, leading to plasma volume contraction and reduced preload, and decreases in blood pressure, arterial stiffness, and afterload as well, thereby improving subendocardial blood flow in patients with HF. SGLT2 inhibition is also associated with preservation of renal function. Based on data from mechanistic studies and clinical trials, large clinical trials with SGLT2 inhibitors are now investigating the potential use of SGLT2 inhibition in patients who have HF with and without T2D. Accordingly, in this review, we summarize the key pharmacodynamic effects of SGLT2 inhibitors and the clinical evidence that support the rationale for the use of SGLT2 inhibitors in patients with HF who have T2D. Because these favorable effects presumably occur independent of blood glucose lowering, we also explore the potential use of SGLT2 inhibition in patients without T2D with HF or at risk of HF, such as in patients with coronary artery disease or hypertension. Finally, we provide a detailed overview and summary of ongoing cardiovascular outcome trials with SGLT2 inhibitors.
Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point.
A total of 16 492 patients ...with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07-1.51; P=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15-1.88; P=0.002), with no significant difference thereafter (time-varying interaction, P=0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate ≤60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin (P for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups.
In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease.
http://www.clinicaltrials.gov. Unique identifier: NCT01107886.
Patients with acute myocardial infarction (MI) are at risk for developing heart failure (HF) and subsequently are at an increased risk of mortality. Sodium-glucose cotransporter-2 inhibitors have ...been proven to improve outcomes in patients with HF with reduced ejection fraction, and, in the case of empagliflozin, in HF with preserved ejection fraction even without diabetes, but their efficacy and safety in the post-MI population has not yet been evaluated.
The EMPACT-MI trial will evaluate the safety and efficacy of empagliflozin compared with placebo in patients hospitalized for MI with or at high risk of new onset HF, in addition to standard care. EMPACT-MI is a streamlined, multinational, randomized, double-blind, placebo-controlled trial randomizing 5,000 participants at approximately 480 centers in 22 countries. Eligible patients presenting with spontaneous MI must have new signs or symptoms of pulmonary congestion requiring treatment or new left ventricular dysfunction (LVEF<45%), and at least 1 additional risk factor for development of future HF. Eligible and consenting patients are randomized to empagliflozin 10mg or placebo daily in addition to standard of care within 14 days of hospital admission for MI. The primary composite end point is time to first hospitalization for HF or all-cause mortality.
EMPACT-MI will inform clinical practice regarding the role of empagliflozin in patients after an MI with high-risk for the development of future HF and mortality.
Objectives The purpose of the study was to investigate whether fertility therapy might contribute to subsequent cardiovascular disease. Background Fertility medications are used for 1% of births yet ...may also lead to endothelial injury with long-term adverse consequences for the mother. Methods A population-based cohort analysis was performed of women who gave birth in Ontario, Canada, between July 1, 1993, and March 31, 2010, distinguishing those who did and did not receive fertility therapy in the 2 years before delivery. Cox proportional models were derived to estimate hazard ratios with and without adjustment for baseline characteristics. The primary outcome was a composite cardiovascular endpoint of death, nonfatal coronary ischemia, stroke, transient ischemic attack, thromboembolism, or heart failure. Results Among 1,186,753 women who delivered during the study period, 6,979 gave birth after fertility therapy. After 9.7 years of median follow-up, women who delivered after fertility therapy had fewer cardiovascular events than controls (103 vs. 117 events per 100,000 person-years), equivalent to an unadjusted hazard ratio of 0.96 (95% confidence interval: 0.72 to 1.29, p = 0.79) and an adjusted hazard ratio of 0.55 (95% confidence interval: 0.41 to 0.74, p < 0.0001). An apparent relative lower risk was observed across all age and income groups. Women who received fertility therapy also had lower risk-adjusted all-cause mortality, thromboembolic events, subsequent depression, alcoholism, and self-harm (p < 0.01 for each). Conclusions Successful fertility therapy was not associated with an increased risk of cardiovascular disease later in life.
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