Marcus Thuresson

Cardiovascular risk in post-myocardial infarction patients : nationwide real world data demonstrate the importance of a long-term perspective.

AIMS Long-term disease progression following myocardial infarction (MI) is not well understood. We examined the risk of subsequent cardiovascular events in patients discharged after MI in Sweden. METHODS AND RESULTS This was a retrospective, cohort study linking morbidity, mortality, and medication data from Swedish national registries. Of 108 315 patients admitted to hospital with a primary MI between 1 July 2006 and 30 June 2011 (index MI), 97 254 (89.8%) were alive 1 week after discharge and included in this study. The primary composite endpoint of risk for non-fatal MI, non-fatal stroke, or cardiovascular death was estimated for the first 365 days post-index MI and Day 366 to study completion. Risk and risk factors were assessed by Kaplan-Meier analysis and Cox proportional hazards modelling, respectively. Composite endpoint risk was 18.3% during the first 365 days post-index MI. Age [60-69 vs. <60 years: HR (95% CI): 1.37 (1.30-1.45); 70-79 vs. <60 years: 2.13 (2.03-2.24); >80 vs. <60 years: 3.96 (3.78-4.15)], prior MI [1.44 (1.40-1.49)], stroke [1.49 (1.44-1.54)], diabetes [1.37 (1.34-1.40)], heart failure [1.57 (1.53-1.62)] and no index MI revascularisation [1.88 (1.83-1.93)] were each independently associated with a higher risk of ischaemic events or death. For patients without a combined endpoint event during the first 365 days, composite endpoint risk was 20.0% in the following 36 months. CONCLUSIONS Risk of cardiovascular events appeared high beyond the first year post-MI, indicating a need for prolonged surveillance, particularly in patients with additional risk factors.

Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)

Background -Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose co-transporter-2 inhibitor (SGLT-2i) empagliflozin in type 2 diabetes patients with atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose lowering drugs (oGLDs) in six countries to determine if these benefits are seen in real-world practice, and across SGLT-2i class. Methods -Data were collected via medical claims, primary care/hospital records and national registries from the US, Norway, Denmark, Sweden, Germany and the UK. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios (HRs) for HHF, death and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany. Results -After propensity matching, there were 309,056 patients newly initiated on either SGLT-2i or oGLD (154,528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42% and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the two groups. There were 961 HHF cases during 190,164 person-years follow up (incidence rate [IR] 0.51/100 person-years). Of 215,622 patients in the US, Norway, Denmark, Sweden, and UK, death occurred in 1334 (IR 0.87/100 person-years), and HHF or death in 1983 (IR 1.38/100 person-years). Use of SGLT-2i, versus oGLDs, was associated with lower rates of HHF (HR 0.61; 95% CI 0.51-0.73; p<0.001); death (HR 0.49; 95% CI 0.41-0.57; p<0.001); and HHF or death (HR 0.54; 95% CI 0.48-0.60, p<0.001) with no significant heterogeneity by country. Conclusions -In this large multinational study, treatment with SGLT-2i versus oGLDs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of T2D patients in real-world practice (NCT02993614). Clinical Trial Registration -URL: ClinicalTrials.gov; Unique Identifier: NCT02993614.Background: Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class. Methods: Data were collected via medical claims, primary care/hospital records, and national registries from the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios for HHF, death, and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany. Results: After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the 2 groups. There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years). Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334 (incidence rate, 0.87/100 person-years), and HHF or death in 1983 (incidence rate, 1.38/100 person-years). Use of SGLT-2i, versus other glucose-lowering drugs, was associated with lower rates of HHF (hazard ratio, 0.61; 95% confidence interval, 0.51–0.73; P<0.001); death (hazard ratio, 0.49; 95% confidence interval, 0.41–0.57; P<0.001); and HHF or death (hazard ratio, 0.54; 95% confidence interval, 0.48–0.60; P<0.001) with no significant heterogeneity by country. Conclusions: In this large multinational study, treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02993614.

Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis

BACKGROUND In patients with type 2 diabetes and a high cardiovascular risk profile, the sodium-glucose co-transporter-2 (SGLT2) inhibitors empagliflozin and canagliflozin have been shown to lower cardiovascular morbidity and mortality. Using real-world data from clinical practice, we aimed to compare cardiovascular mortality and morbidity in new users of SGLT2 inhibitors versus new users of other glucose-lowering drugs, in a population with a broad cardiovascular risk profile. METHODS CVD-REAL Nordic was an observational analysis of individual patient-level data from the Prescribed Drug Registers, Cause of Death Registers, and National Patient Registers in Denmark, Norway, and Sweden. All patients who filled a prescription for glucose-lowering drugs between 2012 and 2015 were included and followed up until Dec 31, 2015. Patients were divided into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs. Each SGLT2 inhibitor user was matched with three users of other glucose-lowering drugs by use of propensity scores. Hazard ratios (HRs) were estimated by country (Cox survival model) and weighted averages were calculated. Cardiovascular outcomes investigated were cardiovascular mortality, major adverse cardiovascular events (cardiovascular mortality, myocardial infarction, and ischaemic or haemorrhagic stroke), hospital events for heart failure (inpatient or outpatient visit with a primary diagnosis of heart failure), non-fatal myocardial infarction, non-fatal stroke, and atrial fibrillation. We also assessed incidence of severe hypoglycaemia. FINDINGS Matched SGLT2 inhibitor (n=22 830) and other glucose-lowering drug (n=68 490) groups were well balanced at baseline, with a mean follow-up of 0·9 (SD 4·1) years (80 669 patient-years) and mean age of 61 (12·0) years; 40% (36 362 of 91 320) were women and prevalence of cardiovascular disease was 25% (22 686 of 91 320). 94% of the total SGLT2 inhibitor exposure time was for use of dapagliflozin, with 5% for empagliflozin, and 1% for canagliflozin. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with decreased risk of cardiovascular mortality (HR 0·53 [95% CI 0·40-0·71]), major adverse cardiovascular events (0·78 [0·69-0·87]), and hospital events for heart failure (0·70 [0·61-0·81]; p<0·0001 for all). We did not identify significant differences between use of SGLT2 inhibitors and use of other glucose-lowering drugs for non-fatal myocardial infarction, non-fatal stroke, or atrial fibrillation. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with a decreased risk of severe hypoglycaemia (HR 0·76 [0·65-0·90]; p=0·001). For cardiovascular mortality, the differences were similar for the 25% of individuals with cardiovascular disease at baseline and those without (HR 0·60 [0·42-0·85] vs 0·55 [0·34-0·90]), while for major adverse cardiovascular events the HR in the group with cardiovascular disease at baseline was 0·70 (0·59-0·83) versus 0·90 (0·76-1·07) in the group without. INTERPRETATION In a population of patients with type 2 diabetes and a broad cardiovascular risk profile, SGLT2 inhibitor use was associated with reduced cardiovascular disease and cardiovascular mortality compared with use of other glucose-lowering drugs-a finding consistent with the results of clinical trials in patients at high cardiovascular risk. FUNDING AstraZeneca.

Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: A multinational observational study.

To compare the sodium‐glucose‐cotransporter‐2 (SGLT‐2) inhibitor dapagliflozin with dipeptidyl peptidase‐4 (DPP‐4) inhibitors with regard to risk associations with major adverse cardiovascular (CV) events (MACE; non‐fatal myocardial infarction, non‐fatal stroke or cardiovascular mortality), hospitalization for heart failure (HHF), atrial fibrillation and severe hypoglycaemia in patients with type 2 diabetes (T2D) in a real‐world setting.Abstract To compare the sodium glucose-cotransporter-2-inhibitor (SGLT-2i) dapagliflozin versus dipeptidyl peptidase-4 inhibitors (DPP-4i) regarding risk associations of MACE (nonfatal myocardial infarction, nonfatal stroke or cardiovascular [CV] mortality), hospital events for heart failure (HHF), atrial fibrillation, and severe hypoglycemia for type 2 diabetes (T2D) patients in a real-world setting. All T2D patients dispensed with glucose lowering drugs (GLDs) during 2012-2015 were identified in nationwide registries in Denmark, Norway and Sweden. Patients were divided in two groups; new users of dapagliflozin and new users of DPP-4i, matched 1:3 by propensity score, calculated by patient characteristics, co-morbidities and drug treatment. Cox survival models estimated hazard ratio per country separately; a weighted average was calculated. After matching, a total of 40,908 T2D patients were identified as new users of dapagliflozin (n=10,227) or DPP-4i (n=30,681). The groups were well balanced at baseline; mean-age was 61 years and 23% had CV disease. Mean follow-up time was 0.95 years, with a total of 38,760 patient-years. Dapagliflozin was associated with lower risk of MACE, HHF and all-cause mortality compared to DPP-4i; hazard ratios (HRs): 0.79 (95% CI 0.67-0.94), 0.62 (0.50-0.77), and 0.44 (0.33-0.60), respectively. Numerically lower, but non-significant HRs were observed for myocardial infarction (0.91 [0.72-1.16]), stroke (0.79 [0.61-1.03]) and CV mortality (0.76 [0.53-1.08]) Atrial fibrillation and severe hypoglycemia showed neutral associations. Dapagliflozin was associated with lower risks of cardiovascular events and all-cause mortality compared to DPP-4i in a in a real-world clinical setting and broad T2D population.

Novel oral glucose‐lowering drugs are associated with lower risk of all‐cause mortality, cardiovascular events and severe hypoglycaemia compared with insulin in patients with type 2 diabetes

To investigate the association of novel oral glucose‐lowering drugs (GLDs), compared with that of insulin, with risk of all‐cause mortality, cardiovascular disease (CVD) and severe hypoglycaemia.

Population study of disease burden, management, and treatment of bipolar disorder in Sweden: a retrospective observational registry study.

The aim of the study was to describe temporal changes in bipolar disorder during 20 years within the Swedish population and to investigate clinical and socioeconomic characteristics, drug treatment, and mortality among patients with bipolar disorder.

Incidence, prevalence and mortality of type 2 diabetes requiring glucose-lowering treatment, and associated risks of cardiovascular complications: a nationwide study in Sweden, 2006–2013

Aims/hypothesisThe global diabetes epidemic affects countries differently. We aimed to describe trends in the incidence and prevalence of type 2 diabetes mellitus requiring glucose-lowering treatment, together with associated life expectancy and risks of significant clinical complications.MethodsData on patients with type 2 diabetes who filled a prescription for any glucose-lowering drug (GLD) during the period 2006–2013 were extracted from the Swedish Prescribed Drug Register, Cause of Death Register and Swedish National Patient Register.ResultsIn 2013, the prevalence of GLD-treated type 2 diabetes was 4.4% (n = 352,436) and the incidence was 399 per 100,000 population (n = 30,620). During 2006–2013, the prevalence increased by 61% while the incidence remained relatively stable; the prevalence of cardiovascular disease (CVD, 34% in 2013) and microvascular disease (16% in 2013) was also stable. Insulin use increased by 29% while sulfonylurea use declined by 55%. Compared with the general population, patients with type 2 diabetes had increased risk of myocardial infarction, stroke and all-cause mortality, with age-standardised risks of ∼1.7-, 1.5- and 1.3-fold, respectively. These risks declined over time. Life-years lost due to diabetes was most pronounced at younger ages and improved in women over time from 2006 to 2013.Conclusions/interpretationThe prevalence of type 2 diabetes requiring GLD treatment in Sweden increased substantially in recent years, while the incidence remained stable. Use of sulfonylurea declined while insulin use increased. The high prevalence of diabetes-related comorbidities, increased risk of complications and life-years lost highlights the need for optimised and new preventive strategies in patients with type 2 diabetes.

Sulphonylurea compared to DPP-4 inhibitors in combination with metformin carries increased risk of severe hypoglycemia, cardiovascular events, and all-cause mortality

AIMS There are safety concerns related to sulphonylurea treatment. The objective of this nationwide study was to compare the risk of cardiovascular disease (CVD), all-cause mortality and severe hypoglycemia in patients with type 2 diabetes (T2D) starting second-line treatment with either metformin+sulphonylurea or metformin+dipeptidyl peptidase-4 inhibitor (DPP-4i). METHODS All patients with T2D in Sweden who initiated second-line treatment with metformin+sulphonylurea or metformin+DPP-4i during 2006-2013 (n=40,736 and 12,024, respectively) were identified in this nationwide study. The Swedish Prescribed Drug Register and the Cause of Death and National Patient Registers were used, and Cox survival models adjusted for age, sex, fragility, prior CVD, and CVD-preventing drugs were applied to estimate risks of events. Propensity score adjustments and matching methods were used to test the results. RESULTS Of 52,760 patients; 77% started metformin+SU and 23% metformin+DPP-4i. Crude incidences for severe hypoglycemia, CVD, and all-cause mortality in the SU cohort were 2.0, 19.6, and 24.6 per 1000 patient-years and in the DPP-4i cohort were 0.8, 7.6, and 14.9 per 1000 patient-years, respectively. Sulphonylurea compared with DPP4i was associated with higher risk of subsequent severe hypoglycemia, fatal and nonfatal CVD, and all-cause mortality; adjusted HR (95% CI): 2.07 (1.11-3.86); 1.17 (1.01-1.37); and 1.25 (1.02-1.54), respectively. Results were confirmed by additional propensity-adjusted and matched analyses. Among the SU drugs, glibenclamide had the highest risks. CONCLUSIONS Metformin+SU treatment was associated with an increased risk of subsequent severe hypoglycemia, cardiovascular events, and all-cause mortality compared with metformin+DPP4i. Results from randomized trials will be important to elucidate causal relationships.

Low-Dose Aspirin Discontinuation and Risk of Cardiovascular Events : A Swedish Nationwide, Population-Based Cohort Study

Background: There are increasing concerns about risks associated with aspirin discontinuation in the absence of major surgery or bleeding. We investigated whether long-term low-dose aspirin discontinuation and treatment gaps increase the risk of cardiovascular events. Methods: We performed a cohort study of 601 527 users of low-dose aspirin for primary or secondary prevention in the Swedish prescription register between 2005 and 2009 who were >40 years of age, were free from previous cancer, and had ≥80% adherence during the first observed year of treatment. Cardiovascular events were identified with the Swedish inpatient and cause-of-death registers. The first 3 months after a major bleeding or surgical procedure were excluded from the time at risk. Results: During a median of 3.0 years of follow-up, 62 690 cardiovascular events occurred. Patients who discontinued aspirin had a higher rate of cardiovascular events than those who continued (multivariable-adjusted hazard ratio, 1.37; 95% confidence interval, 1.34–1.41), corresponding to an additional cardiovascular event observed per year in 1 of every 74 patients who discontinue aspirin. The risk increased shortly after discontinuation and did not appear to diminish over time. Conclusions: In long-term users, discontinuation of low-dose aspirin in the absence of major surgery or bleeding was associated with a >30% increased risk of cardiovascular events. Adherence to low-dose aspirin treatment in the absence of major surgery or bleeding is likely an important treatment goal.

Treatment pattern of contemporary dual antiplatelet therapies after acute coronary syndrome: a Swedish nationwide population-based cohort study

Abstract Objectives New dual antiplatelet therapies (DAPTs) have been introduced in clinical practice for patients with acute coronary syndrome (ACS). This nationwide study investigated DAPT patterns over time and patient characteristics associated with the various treatments in a population with ACS. Design This observational cohort study linked morbidity, mortality and medication data from Swedish national registries. Results Overall, 91% (104 012 patients) of all patients admitted to the hospital with an ACS (2009–2013) were alive after discharge and included in this study. Compared with 2009, in 2013 patients investigated with angiography increased by 10%, patients revascularized with percutaneous coronary intervention (PCI) increased by 11% and patients prescribed DAPT increased by 8%. Mean DAPT duration increased from 225 to 298 days in patients investigated with angiography, and from 155 to 208 days in patients who were not investigated with angiography. Furthermore, in patients undergoing angiography a treatment switch from clopidogrel to ticagrelor was observed. DAPT with prasugrel was used to a low extent. Approximately 10% of patients initiated on prasugrel or ticagrelor switched to clopidogrel during the first year of treatment. Conclusion During the study more patients underwent angiography and PCI. There was an increase in the proportion of ACS patients receiving DAPT, as well as longer duration of DAPT in line with ESC guidelines. Among DAPT-treated patients, ticagrelor has emerged as the preferred P2Y12 antagonist in patients undergoing angiography, whereas clopidogrel tended to be prescribed to patients treated non-invasively.