OBJECTIVE
Insulin resistance (IR) may mediate heart failure (HF) development. We examined whether IR in people with newly diagnosed type 2 diabetes (T2D) increased their risk of a composite outcome ...of HF or death or of HF alone.
RESEARCH DESIGN AND METHODS
Insulin resistance (HOMA2-IR) values for UKPDS participants were derived from paired fasting plasma glucose (FPG) and insulin measures. Kaplan-Meier survival curves and multivariable survival models were used to evaluate associations between HOMA2-IR and HF/death or HF alone. We adjusted for potential confounders by including variables with univariate associations (P < 0.1) and by requiring a multivariable P < 0.05.
RESULTS
Of 5,102 UKPDS participants with newly diagnosed T2D, 4,344 had HOMA2-IR measurements. At enrollment, mean (SD) age was 52.5 (8.7) years, with HbA1c 7.2% (1.8%), and BMI 28.8 (5.5) kg/m2, and median (interquartile range) HOMA2-IR was 1.6 (1.1–2.2). HF/death occurred in 1,974 (45.4%) participants (235 first HF events, 1,739 deaths) over a median follow-up of 16.4 years. Multivariable independent associations with HF/death were older age and higher BMI, HOMA2-IR, FPG, waist-to-hip ratio, systolic blood pressure, LDL cholesterol, and heart rate as well as sex, race, smoking status, prior atrial fibrillation, and prior microalbuminuria. A doubling of HOMA2-IR was associated with a 5% greater risk of HF/death (relative risk RR 1.05 95% CI 1.01–1.12, P = 0.0029) and a 14% greater risk of HF (RR 1.14, 95% CI 1.02–1.27, P = 0.017).
CONCLUSIONS
Patients with newly diagnosed T2D and insulin resistance were more likely to develop HF or die than those more sensitive to insulin.
The incidence and prevalence of diabetes mellitus (DM) continue to grow markedly throughout the world, due primarily to the increase in type 2 DM (T2DM). Although improvements in DM and hypertension ...management have reduced the proportion of diabetic individuals who develop chronic kidney disease (CKD) and progress to end-stage renal disease (ESRD), the sheer increase in people developing DM will have a major impact on dialysis and transplant needs. This KDIGO conference addressed a number of controversial areas in the management of DM patients with CKD, including aspects of screening for CKD with measurements of albuminuria and estimated glomerular filtration rate (eGFR); defining treatment outcomes; glycemic management in both those developing CKD and those with ESRD; hypertension goals and management, including blockers of the renin–angiotensin–aldosterone system; and lipid management.
Aims/hypotheses
Current evidence indicates that statins increase the risk of incident diabetes; however, the relationship between statins and glycaemic control in people with established diabetes has ...not been well characterised. To address this question, we conducted a meta-analysis of randomised controlled trials (RCTs) of statins in patients with diabetes for whom there was available data on glycaemic control.
Methods
We identified studies published between January 1970 and November 2013 by searching electronic databases and reference lists. We included RCTs in which the intervention group received statins and the control group received placebo or standard treatment, with >200 participants enrolled, with the intervention lasting >12 weeks and with pre- and post-intervention HbA
1c
reported. We combined study-specific estimates using random-effects model meta-analysis.
Results
In a pooled analysis of nine trials involving 9,696 participants (4,980 statin, 4,716 control) and an average follow-up of 3.6 years, the mean HbA
1c
of participants randomised to statins was higher than those randomised to the control group: mean difference (95% CI) was 0.12% (0.04, 0.20) or 1.3 mmol/mol (0.4, 2.2);
p
= 0.003. There was moderate heterogeneity across the studies (
I
2
= 54%,
p
= 0.014) not explained by available study-level characteristics. This review was limited by the small number of studies, available data on only three statins and sparse reporting on changes in use of glucose-lowering medications.
Conclusions/interpretation
Statin treatment is associated with a modest increase in HbA
1c
in patients with diabetes.
The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed ...individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure.
We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from <120 to ≥170 mm Hg). The primary outcome was a major cardiovascular event (defined as a composite of fatal and non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring admission to hospital), analysed as per intention to treat.
Data for 344 716 participants from 48 randomised clinical trials were available for this analysis. Pre-randomisation mean systolic/diastolic blood pressures were 146/84 mm Hg in participants with previous cardiovascular disease (n=157 728) and 157/89 mm Hg in participants without previous cardiovascular disease (n=186 988). There was substantial spread in participants' blood pressure at baseline, with 31 239 (19·8%) of participants with previous cardiovascular disease and 14 928 (8·0%) of individuals without previous cardiovascular disease having a systolic blood pressure of less than 130 mm Hg. The relative effects of blood pressure-lowering treatment were proportional to the intensity of systolic blood pressure reduction. After a median 4·15 years' follow-up (Q1–Q3 2·97–4·96), 42 324 participants (12·3%) had at least one major cardiovascular event. In participants without previous cardiovascular disease at baseline, the incidence rate for developing a major cardiovascular event per 1000 person-years was 31·9 (95% CI 31·3–32·5) in the comparator group and 25·9 (25·4–26·4) in the intervention group. In participants with previous cardiovascular disease at baseline, the corresponding rates were 39·7 (95% CI 39·0–40·5) and 36·0 (95% CI 35·3–36·7), in the comparator and intervention groups, respectively. Hazard ratios (HR) associated with a reduction of systolic blood pressure by 5 mm Hg for a major cardiovascular event were 0·91, 95% CI 0·89–0·94 for partipants without previous cardiovascular disease and 0·89, 0·86–0·92, for those with previous cardiovascular disease. In stratified analyses, there was no reliable evidence of heterogeneity of treatment effects on major cardiovascular events by baseline cardiovascular disease status or systolic blood pressure categories.
In this large-scale analysis of randomised trials, a 5 mm Hg reduction of systolic blood pressure reduced the risk of major cardiovascular events by about 10%, irrespective of previous diagnoses of cardiovascular disease, and even at normal or high–normal blood pressure values. These findings suggest that a fixed degree of pharmacological blood pressure lowering is similarly effective for primary and secondary prevention of major cardiovascular disease, even at blood pressure levels currently not considered for treatment. Physicians communicating the indication for blood pressure lowering treatment to their patients should emphasise its importance on reducing cardiovascular risk rather than focusing on blood pressure reduction itself.
British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School.
On April 10, 2019, the National Institute for Health and Care Excellence (NICE) published guidance1 that recommends daratumumab with bortezomib and dexamethasone within the Cancer Drugs Fund (CDF) as ...an option for treating relapsed multiple myeloma in people who have had one previous treatment, but only under the conditions in the managed access agreement.2 NICE appraised daratumumab with bortezomib and dexamethasone as a single technology appraisal. ...line treatment options include bortezomib retreatment, if bortezomib has been used as first-line treatment, and bortezomib with dexamethasone, or carfilzomib with dexamethasone, if thalidomide has been used as first-line treatment. The ERG considered the difference between the company's utility values before and after progression (0·03) to be implausibly small, so it preferred utility values from ENDEAVOR even though these were not from the main trial or derived from EQ-5D, the preferred quality-of-life measure in the NICE methods guide.7 Based on the company's exponential curve to predict long-term overall survival with daratumumab with bortezomib and dexamethasone and utility values from CASTOR, the incremental cost-effectiveness ratio (ICER) lay between £30 000 and £40 000 per quality-adjusted life-year (QALY) gained compared with bortezomib with dexamethasone.
AbstractObjectiveTo compare the effectiveness of three commonly prescribed oral antidiabetic drugs added to metformin for people with type 2 diabetes mellitus requiring second line treatment in ...routine clinical practice.DesignCohort study emulating a comparative effectiveness trial (target trial).SettingLinked primary care, hospital, and death data in England, 2015-21.Participants75 739 adults with type 2 diabetes mellitus who initiated second line oral antidiabetic treatment with a sulfonylurea, DPP-4 inhibitor, or SGLT-2 inhibitor added to metformin.Main outcome measuresPrimary outcome was absolute change in glycated haemoglobin A1c (HbA1c) between baseline and one year follow-up. Secondary outcomes were change in body mass index (BMI), systolic blood pressure, and estimated glomerular filtration rate (eGFR) at one year and two years, change in HbA1c at two years, and time to ≥40% decline in eGFR, major adverse kidney event, hospital admission for heart failure, major adverse cardiovascular event (MACE), and all cause mortality. Instrumental variable analysis was used to reduce the risk of confounding due to unobserved baseline measures.Results75 739 people initiated second line oral antidiabetic treatment with sulfonylureas (n=25 693, 33.9%), DPP-4 inhibitors (n=34 464 ,45.5%), or SGLT-2 inhibitors (n=15 582, 20.6%). SGLT-2 inhibitors were more effective than DPP-4 inhibitors or sulfonylureas in reducing mean HbA1c values between baseline and one year. After the instrumental variable analysis, the mean differences in HbA1c change between baseline and one year were −2.5 mmol/mol (95% confidence interval (CI) −3.7 to −1.3) for SGLT-2 inhibitors versus sulfonylureas and −3.2 mmol/mol (−4.6 to −1.8) for SGLT-2 inhibitors versus DPP-4 inhibitors. SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in reducing BMI and systolic blood pressure. For some secondary endpoints, evidence for SGLT-2 inhibitors being more effective was lacking—the hazard ratio for MACE, for example, was 0.99 (95% CI 0.61 to 1.62) versus sulfonylureas and 0.91 (0.51 to 1.63) versus DPP-4 inhibitors. SGLT-2 inhibitors had reduced hazards of hospital admission for heart failure compared with DPP-4 inhibitors (0.32, 0.12 to 0.90) and sulfonylureas (0.46, 0.20 to 1.05). The hazard ratio for a ≥40% decline in eGFR indicated a protective effect versus sulfonylureas (0.42, 0.22 to 0.82), with high uncertainty in the estimated hazard ratio versus DPP-4 inhibitors (0.64, 0.29 to 1.43).ConclusionsThis emulation study of a target trial found that SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in lowering mean HbA1c, BMI, and systolic blood pressure and in reducing the hazards of hospital admission for heart failure (v DPP-4 inhibitors) and kidney disease progression (v sulfonylureas), with no evidence of differences in other clinical endpoints.
The effects of pharmacological blood-pressure-lowering on cardiovascular outcomes in individuals aged 70 years and older, particularly when blood pressure is not substantially increased, is ...uncertain. We compared the effects of blood-pressure-lowering treatment on the risk of major cardiovascular events in groups of patients stratified by age and blood pressure at baseline.
We did a meta-analysis using individual participant-level data from randomised controlled trials of pharmacological blood-pressure-lowering versus placebo or other classes of blood-pressure-lowering medications, or between more versus less intensive treatment strategies, which had at least 1000 persons-years of follow-up in each treatment group. Participants with previous history of heart failure were excluded. Data were obtained from the Blood Pressure Lowering Treatment Triallists' Collaboration. We pooled the data and categorised participants into baseline age groups (<55 years, 55–64 years, 65–74 years, 75–84 years, and ≥85 years) and blood pressure categories (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg systolic blood pressure and from <70 mm Hg to ≥110 mm Hg diastolic). We used a fixed effects one-stage approach and applied Cox proportional hazard models, stratified by trial, to analyse the data. The primary outcome was defined as either a composite of fatal or non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring hospital admission.
We included data from 358 707 participants from 51 randomised clinical trials. The age of participants at randomisation ranged from 21 years to 105 years (median 65 years IQR 59–75), with 42 960 (12·0%) participants younger than 55 years, 128 437 (35·8%) aged 55–64 years, 128 506 (35·8%) 65–74 years, 54 016 (15·1%) 75–84 years, and 4788 (1·3%) 85 years and older. The hazard ratios for the risk of major cardiovascular events per 5 mm Hg reduction in systolic blood pressure for each age group were 0·82 (95% CI 0·76–0·88) in individuals younger than 55 years, 0·91 (0·88–0·95) in those aged 55–64 years, 0·91 (0·88–0·95) in those aged 65–74 years, 0·91 (0·87–0·96) in those aged 75–84 years, and 0·99 (0·87–1·12) in those aged 85 years and older (adjusted pinteraction=0·050). Similar patterns of proportional risk reductions were observed for a 3 mm Hg reduction in diastolic blood pressure. Absolute risk reductions for major cardiovascular events varied by age and were larger in older groups (adjusted pinteraction=0·024). We did not find evidence for any clinically meaningful heterogeneity of relative treatment effects across different baseline blood pressure categories in any age group.
Pharmacological blood pressure reduction is effective into old age, with no evidence that relative risk reductions for prevention of major cardiovascular events vary by systolic or diastolic blood pressure levels at randomisation, down to less than 120/70 mm Hg. Pharmacological blood pressure reduction should, therefore, be considered an important treatment option regardless of age, with the removal of age-related blood-pressure thresholds from international guidelines.
British Heart Foundation, National Institute of Health Research Oxford Biomedical Research Centre, Oxford Martin School.
PDF
