Anna Norhammar

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.

Periodontitis Increases the Risk of a First Myocardial Infarction: A Report From the PAROKRANK Study

Background— The relationship between periodontitis (PD) and cardiovascular disease is debated. PD is common in patients with cardiovascular disease. It has been postulated that PD could be causally related to the risk for cardiovascular disease, a hypothesis tested in the Periodontitis and Its Relation to Coronary Artery Disease (PAROKRANK) study. Methods and Results— Eight hundred five patients (<75 years of age) with a first myocardial infarction (MI) and 805 age- (mean 62±8), sex- (male 81%), and area-matched controls without MI underwent standardized dental examination including panoramic x-ray. The periodontal status was defined as healthy (≥80% remaining bone) or as mild-moderate (from 79% to 66%) or severe PD (<66%). Great efforts were made to collect information on possibly related confounders (≈100 variables). Statistical comparisons included the Student pairwise t test and the McNemar test in 2×2 contingency tables. Contingency tables exceeding 2×2 with ranked alternatives were tested by Wilcoxon signed rank test. Odds ratios (95% confidence intervals) were calculated by conditional logistic regression. PD was more common (43%) in patients than in controls (33%; P<0.001). There was an increased risk for MI among those with PD (odds ratio, 1.49; 95% confidence interval, 1.21–1.83), which remained significant (odds ratio, 1.28; 95% confidence interval, 1.03–1.60) after adjusting for variables that differed between patients and controls (smoking habits, diabetes mellitus, years of education, and marital status). Conclusions— In this large case–control study of PD, verified by radiographic bone loss and with a careful consideration of potential confounders, the risk of a first MI was significantly increased in patients with PD even after adjustment for confounding factors. These findings strengthen the possibility of an independent relationship between PD and MI.Background— The relationship between periodontitis (PD) and cardiovascular disease is debated. PD is common in patients with cardiovascular disease. It has been postulated that PD could be causally related to the risk for cardiovascular disease, a hypothesis tested in the Periodontitis and Its Relation to Coronary Artery Disease (PAROKRANK) study. Methods and Results— Eight hundred five patients (<75 years of age) with a first myocardial infarction (MI) and 805 age- (mean 62±8), sex- (male 81%), and area-matched controls without MI underwent standardized dental examination including panoramic x-ray. The periodontal status was defined as healthy (≥80% remaining bone) or as mild-moderate (from 79% to 66%) or severe PD (<66%). Great efforts were made to collect information on possibly related confounders (≈100 variables). Statistical comparisons included the Student pairwise t test and the McNemar test in 2×2 contingency tables. Contingency tables exceeding 2×2 with ranked alternatives were tested by Wilcoxon signed rank test. Odds ratios (95% confidence intervals) were calculated by conditional logistic regression. PD was more common (43%) in patients than in controls (33%; P <0.001). There was an increased risk for MI among those with PD (odds ratio, 1.49; 95% confidence interval, 1.21–1.83), which remained significant (odds ratio, 1.28; 95% confidence interval, 1.03–1.60) after adjusting for variables that differed between patients and controls (smoking habits, diabetes mellitus, years of education, and marital status). Conclusions— In this large case–control study of PD, verified by radiographic bone loss and with a careful consideration of potential confounders, the risk of a first MI was significantly increased in patients with PD even after adjustment for confounding factors. These findings strengthen the possibility of an independent relationship between PD and MI. # CLINICAL PERSPECTIVE {#article-title-44}

Improved but still high short- and long-term mortality rates after myocardial infarction in patients with diabetes mellitus : A time-trend report from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admission

Objective: The aim of the study was to compare time-trends in mortality rates and treatment patterns between patients with and without diabetes based on the Swedish register of coronary care (Register of Information and Knowledge about Swedish Heart Intensive Care Admission [RIKS-HIA]). Methods: Post myocardial infarction mortality rate is high in diabetic patients, who seem to receive less evidence-based treatment. Mortality rates and treatment in 1995–1998 and 1999–2002 were studied in 70 882 patients (age <80 years), 14 873 of whom had diabetes (the first registry recorded acute myocardial infarction), following adjustments for differences in clinical and other parameters. Results: One-year mortality rates decreased from 1995 to 2002 from 16.6% to 12.1% in patients without diabetes and from 29.7% to 19.7%, respectively, in those with diabetes. Patients with diabetes had an adjusted relative 1-year mortality risk of 1.44 (95% CI 1.36 to 1.52) in 1995–1998 and 1.31 (95% CI 1.24 to 1.38) in 1999–2002. Despite improved pre-admission and in-hospital treatment, diabetic patients were less often offered acute reperfusion therapy (adjusted OR 0.85, 95% CI 0.80 to 0.90), acute revascularisation (adjusted OR 0.78, 95% CI 0.69 to 0.87) or revascularisation within 14 days (OR 0.80, 95% CI 0.75 to 0.85), aspirin (OR 0.90, 95% CI 0.84 to 0.98) and lipid-lowering treatment at discharge (OR 0.81, 95% CI 0.77 to 0.86). Conclusion: Despite a clear improvement in the treatment and myocardial infarction survival rate in patients with diabetes, mortality rate remains higher than in patients without diabetes. Part of the excess mortality may be explained by co-morbidities and diabetes itself, but a lack of application of evidence-based treatment also contributes, underlining the importance of the improved management of diabetic patients.

Abnormal glucose tolerance - a common risk factor in patients with acute myocardial infarction in comparison with population-based controls

Background.  A high prevalence of newly detected diabetes and impaired glucose tolerance (abnormal glucose tolerance) was recently reported in patients with acute myocardial infarction. It is important to verify whether this finding is specific for the patients or attributable to the population, from which they were recruited.

Oral Glucose Tolerance Test: A Reliable Tool for Early Detection of Glucose Abnormalities in Patients With Acute Myocardial Infarction in Clinical Practice : A report on repeated oral glucose tolerance tests from the GAMI Study

OBJECTIVE—Previously undetected glucose abnormalities are common in patients with acute myocardial infarction (AMI). We evaluated long-term reliability of early glucometabolic classification of patients with AMI by repeated oral glucose tolerance tests (OGTTs). RESEARCH DESIGN AND METHODS—A glucometabolic OGTT-based classification was obtained in 122 patients by measuring capillary whole-blood glucose. The classification was performed on three occasions, before hospital discharge and 3 and 12 months thereafter. RESULTS—At discharge, 34, 31, and 34% were classified as having normal glucose tolerance, impaired glucose tolerance (IGT), or type 2 diabetes, respectively, and 93% of all patients with type 2 diabetes were still classified with type 2 diabetes (n = 27) or IGT (n = 12) after 12 months. The agreements between the OGTTs at discharge and 3 and 12 months were κ = 0.35, P < 0.001, and κ = 0.43, P < 0.001, respectively. CONCLUSIONS—The outcome of an OGTT performed in AMI patients at hospital discharge reliably informs on long-term glucometabolic state.

Type 2 diabetes and cardiovascular disease in women

Cardiovascular disease is the leading cause of death in both men and women. This is also true for patients with diabetes. In general, differences between the sexes are present in several areas, such as epidemiology, pathophysiology, diagnostics, treatment response and prognosis, as well as the way in which disease is experienced and expressed. Cardiovascular disease presents later in life in women, who are therefore more likely to suffer from comorbidities. However, this age-related difference is attenuated in women with diabetes, who suffer their first myocardial infarction at about the same age as men with diabetes. Diabetes mellitus increases the risk of cardiovascular disease by three to four times in women and two to three times in men, after adjusting for other risk factors. This paper describes the differences in cardiovascular disease in men and women and the special situation of women with type 2 diabetes when it comes to risk factors, symptoms and the setting of acute coronary syndromes. Furthermore, it highlights the importance of sex-specific analyses in clinical research to improve our knowledge of cardiovascular disease in women in general and in women with diabetes in particular. The importance of taking sex into account when treating women and men at risk of cardiovascular disease is discussed.

Hyperglycaemia and cardiovascular disease

Coronary artery disease and type 2 diabetes are chronic diseases of substantial and growing prevalence. Their coincidence is common, markedly enhancing mortality and morbidity. The risk for cardiovascular disease increases along a spectrum of blood glucose concentrations already apparent at levels regarded as normal. Accordingly, strategies for the early detection of glucometabolic disturbances are needed to find ways to prevent the occurrence of cardiovascular complications or to treat them already at an early stage. More specifically, abnormal glucose tolerance is almost twice as common amongst patients with a myocardial infarction as in population‐based controls and a normal glucose regulation is indeed less common than abnormal glucose metabolism also amongst patients with stable coronary artery disease. Already an abnormal glucose tolerance is a strong risk factor for future cardiovascular events after an acute myocardial infarction. An oral glucose tolerance test should, therefore, be a part of the evaluation of total risk in all patients with coronary artery disease. As glucose disturbances are common and easy to detect, they may be suitable targets for novel secondary preventive efforts.

Women younger than 65 years with diabetes mellitus are a high-risk group after myocardial infarction: a report from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA)

Objective: To analyse gender differences in prognosis, risk factors and evidence-based treatment in patients with diabetes and myocardial infarction. Methods: Mortality in 1995–2002 was analysed in 70 882 Swedish patients (age <80) with a first registry-recorded acute myocardial infarction stratified by gender and age. Owing to gender differences in mortality, specifically characterising patients below the age of 65 years, a more detailed analysis was performed within this cohort of 25 555 patients. In this group, 5786 (23%) were women and 4473 (18%) had diabetes. Differences in clinical and other parameters were adjusted for using a propensity score model. Results: Long-term mortality in diabetic patients aged <65 years was significantly higher in women than men (RR 1.34; 95% CI 1.16 to 1.55). Compared with diabetic men, women had an increased risk factor burden (hypertension 49 vs 43%; RR 1.12; 95% CI 1.05 to 1.20; heart failure 10 vs 8%; RR 1.25; 95% CI 1.03 to 1.53). Diabetic women aged <65 years were less frequently treated with intravenous β-blockade during the acute hospital phase and with angiotensin-converting enzyme inhibitors at hospital discharge. However, this under-use was not associated with the mortality differences, nor was female gender by itself. Conclusion: Women below 65 years of age with diabetes have a poorer outcome than men after a myocardial infarction. This relates to an increased risk factor burden. It is suggested that greater awareness of this situation and improved prevention have the potential to improve what is an unfavourable situation for these women.

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.

Effects of improved metabolic control on platelet reactivity in patients with type 2 diabetes mellitus following coronary angioplasty

The aim of this study was to investigate the impact of improved metabolic control on platelet reactivity in patients with type 2 diabetes undergoing percutaneous coronary intervention (PCI). Twenty-two patients were randomised to intensive insulin or conventional treatment for diabetes. Platelet P-selectin expression was analysed before and three months after PCI. Metabolic control, as measured by level of glycosylated haemoglobin (HbA1C) and platelet P-selectin expression, was similar in the two treatment groups after three months. However, six of the 12 patients in the intensive group had increased levels of HbA1C after three months and three patients of the 10 in the conventionally treated group showed improved metabolic control. A re-analysis was performed, based on metabolic control. It showed that patients with improved control at three months (HbA1C 6.1% ± 0.7 at baseline; 5.7% ± 0.5 at three months; p<0.01; n=9) had lower ADP-induced P-selectin expression (p<0.05) than patients with worsened glycaemic control (HbA1C 5.9% ± 1.0 at baseline; 6.5% ± 1.4 at three months; p<0.01; n=13). Levels of HbA1C and fasting glucose were correlated to P-selectin expression (R=0.34 and R=0.31; p<0.05). We conclude from this study that improved glycaemic control reduces platelet reactivity in type 2 diabetes patients following PCI.