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Eliminating Excess CVD Risk for Diabetic Type2 - Risk Factors, Mortality, and
Cardiovascular Outcomes in Patients with Type 2 Diabetes
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Aug 15 2018
important new study - Death & CVD Outcomes for type 2 diabetics Can be controlled to same risk as those without diabetes 2 by normalizing certain risk factors including LDL, blood pressure, A1C; physical activity important factor, no smoking....see figures & tables below for complete lists. Jules
"In conclusion, patients with type 2 diabetes who had five risk-factor variables within target ranges appeared to have little or no excess risks of death, myocardial infarction, and stroke as compared with the general population."
"Our analysis of Swedish nationwide registry data from 1998 through 2012 showed that patients with type 2 diabetes and five selected risk-factor variables within target range had, at most, marginally higher risks of death, stroke, and myocardial infarction than the general population. The study indicates that having all five risk-factor variables within the target ranges could theoretically eliminate the excess risk of acute myocardial infarction. However, there was a substantial excess risk of hospitalization for heart failure among patients who had all the variables within target ranges. We identified a monotonic relationship among younger age, increasing number of variables not within target ranges, and a higher relative risk of adverse cardiovascular outcomes. The results suggest that there may be greater potential gains from more aggressive treatment in younger patients with diabetes.
The following risk factors were considered to be the strongest predictors for cardiovascular outcomes and death: low physical activity, smoking, and glycated hemoglobin, systolic blood-pressure, and LDL cholesterol levels outside the target ranges. Using real-world data, we found that levels of glycated hemoglobin, systolic blood pressure, and LDL cholesterol that were lower than target levels were associated with lower risks of acute myocardial infarction and stroke.
In the overall cohort, patients with type 2 diabetes who had no risk-factor variables outside the target ranges had a marginally higher risk of death than the controls (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.12).....
Figure 2A shows the predictors with the apparent greatest importance with regard to death from any cause. The five strongest predictors regarding the risk of death among patients with type 2 diabetes were smoking, physical activity, marital status, glycated hemoglobin level, and use of statins (lipid-lowering medication). The data shown in Figure 3A suggest that lower glycated hemoglobin levels than are currently recommended in guidelines were associated with a lower risk of death.
In the present analyses, a glycated hemoglobin level outside the target range was a strong predictor for all outcomes, especially for atherothrombotic events, which shows the importance of dysglycemia with regard to these complications. Low physical activity was also a strong predictor of cardiovascular outcomes and death, but randomized trials have not shown long-lasting beneficial effects from increased physical activity in patients with diabetes.16-18
Patients with diabetes who were 80 years of age or older at baseline and had no risk factors outside target ranges had the lowest hazard ratio, as compared with controls, for acute myocardial infarction across all the groups (hazard ratio, 0.72; 95% CI, 0.49 to 1.07) (Figure 1B). Overall, patients with type 2 diabetes who had no risk-factor variables outside the target ranges had a lower risk of acute myocardial infarction than the matched controls (hazard ratio, 0.84; 95% CI, 0.75 to 0.93). Corresponding estimates for the excess risk of stroke are shown in Figure 1C. The overall hazard ratio for stroke among patients with no risk-factor variables outside the target ranges, as compared with controls, was 0.95 (95% CI, 0.84 to 1.07) (Table S2 in the Supplementary Appendix)."br clear="all" />
Our study shows, in accordance with previous studies, that lower systolic blood pressure is associated with lower risks of cardiovascular outcomes and death.19
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August 15, 2018
Risk Factor Control Can Mitigate Danger from Type 2 Diabetes
Harlan M. Krumholz, MD, SM reviewing Rawshani A et al. N Engl J Med 2018 Aug 16
People with diabetes and optimal values for five health variables had risks similar to those in people without diabetes.
Diabetes has been considered as dangerous as cardiovascular disease in its association with death and cardiovascular events, but to what extent can modifying patients' risk factors mitigate this association? Investigators made use of a Swedish national registry enrolling people with type 2 diabetes to determine whether the excess risk for death and cardiovascular events (stroke, acute myocardial infarction, and hospitalization for heart failure) could be reduced or eliminated with control of five risk factors - glycated hemoglobin, LDL cholesterol, albuminuria, smoking, and blood pressure.
During a median follow-up of 5.7 years, the investigators compared 271,174 people with diabetes to 1,355,870 controls without diabetes and matched by age, sex, and county. The excess diabetes-associated risk decreased with each variable that fell within the target range. People with diabetes and optimal values for all five risk factors had a similar risk for death as controls - and a significantly lower risk for acute myocardial infarction. However, their risk for hospitalization for heart failure remained consistently higher. The effect of having risk factors within target ranges seemed most prominent in younger individuals. Smoking was the strongest predictor of death.
Comment
This study heralds great news: The risk associated with type 2 diabetes can be eliminated with risk factor control. A remaining question is which treatment strategies, if any, can produce what was found in this observational study, particularly with regard to glucose, LDL cholesterol, and blood pressure control. Although we cannot answer that question today, the findings are promising that type 2 diabetes need not be considered a risk that cannot be eliminated.
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"In conclusion, patients with type 2 diabetes who had five risk-factor variables within target ranges appeared to have little or no excess risks of death, myocardial infarction, and stroke as compared with the general population."
"Our analysis of Swedish nationwide registry data from 1998 through 2012 showed that patients with type 2 diabetes and five selected risk-factor variables within target range had, at most, marginally higher risks of death, stroke, and myocardial infarction than the general population. The study indicates that having all five risk-factor variables within the target ranges could theoretically eliminate the excess risk of acute myocardial infarction. However, there was a substantial excess risk of hospitalization for heart failure among patients who had all the variables within target ranges. We identified a monotonic relationship among younger age, increasing number of variables not within target ranges, and a higher relative risk of adverse cardiovascular outcomes. The results suggest that there may be greater potential gains from more aggressive treatment in younger patients with diabetes.
The following risk factors were considered to be the strongest predictors for cardiovascular outcomes and death: low physical activity, smoking, and glycated hemoglobin, systolic blood-pressure, and LDL cholesterol levels outside the target ranges. Using real-world data, we found that levels of glycated hemoglobin, systolic blood pressure, and LDL cholesterol that were lower than target levels were associated with lower risks of acute myocardial infarction and stroke.
In the overall cohort, patients with type 2 diabetes who had no risk-factor variables outside the target ranges had a marginally higher risk of death than the controls (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.12).....
Figure 2A shows the predictors with the apparent greatest importance with regard to death from any cause. The five strongest predictors regarding the risk of death among patients with type 2 diabetes were smoking, physical activity, marital status, glycated hemoglobin level, and use of statins (lipid-lowering medication). The data shown in Figure 3A suggest that lower glycated hemoglobin levels than are currently recommended in guidelines were associated with a lower risk of death.
In the present analyses, a glycated hemoglobin level outside the target range was a strong predictor for all outcomes, especially for atherothrombotic events, which shows the importance of dysglycemia with regard to these complications. Low physical activity was also a strong predictor of cardiovascular outcomes and death, but randomized trials have not shown long-lasting beneficial effects from increased physical activity in patients with diabetes.16-18
Patients with diabetes who were 80 years of age or older at baseline and had no risk factors outside target ranges had the lowest hazard ratio, as compared with controls, for acute myocardial infarction across all the groups (hazard ratio, 0.72; 95% CI, 0.49 to 1.07) (Figure 1B). Overall, patients with type 2 diabetes who had no risk-factor variables outside the target ranges had a lower risk of acute myocardial infarction than the matched controls (hazard ratio, 0.84; 95% CI, 0.75 to 0.93). Corresponding estimates for the excess risk of stroke are shown in Figure 1C. The overall hazard ratio for stroke among patients with no risk-factor variables outside the target ranges, as compared with controls, was 0.95 (95% CI, 0.84 to 1.07) (Table S2 in the Supplementary Appendix)."
Our study shows, in accordance with previous studies, that lower systolic blood pressure is associated with lower risks of cardiovascular outcomes and death.19
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Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes
NEJM - Aug 16 2018 - Aidin Rawshani, M.D., Araz Rawshani, M.D., Ph.D., Stefan Franzén, Ph.D., Naveed Sattar, M.D., Ph.D., Björn Eliasson, M.D., Ph.D., Ann‑Marie Svensson, Ph.D., Björn Zethelius, M.D., Ph.D., Mervete Miftaraj, M.Sc., Darren K. McGuire, M.D., M.H.Sc., Annika Rosengren, M.D., Ph.D., and Soffia Gudbjörnsdottir, M.D., Ph.D.
Abstract
Background
Patients with diabetes are at higher risk for death and cardiovascular outcomes than the general population. We investigated whether the excess risk of death and cardiovascular events among patients with type 2 diabetes could be reduced or eliminated.
Methods
In a cohort study, we included 271,174 patients with type 2 diabetes who were registered in the Swedish National Diabetes Register and matched them with 1,355,870 controls on the basis of age, sex, and county. We assessed patients with diabetes according to age categories and according to the presence of five risk factors (elevated glycated hemoglobin level, elevated low-density lipoprotein cholesterol level, albuminuria, smoking, and elevated blood pressure). Cox regression was used to study the excess risk of outcomes (death, acute myocardial infarction, stroke, and hospitalization for heart failure) associated with smoking and the number of variables outside target ranges. We also examined the relationship between various risk factors and cardiovascular outcomes.
Results
The median follow-up among all the study participants was 5.7 years, during which 175,345 deaths occurred. Among patients with type 2 diabetes, the excess risk of outcomes decreased stepwise for each risk-factor variable within the target range. Among patients with diabetes who had all five variables within target ranges, the hazard ratio for death from any cause, as compared with controls, was 1.06 (95% confidence interval [CI], 1.00 to 1.12), the hazard ratio for acute myocardial infarction was 0.84 (95% CI, 0.75 to 0.93), and the hazard ratio for stroke was 0.95 (95% CI, 0.84 to 1.07). The risk of hospitalization for heart failure was consistently higher among patients with diabetes than among controls (hazard ratio, 1.45; 95% CI, 1.34 to 1.57). In patients with type 2 diabetes, a glycated hemoglobin level outside the target range was the strongest predictor of stroke and acute myocardial infarction; smoking was the strongest predictor of death.
Conclusions
Patients with type 2 diabetes who had five risk-factor variables within the target ranges appeared to have little or no excess risk of death, myocardial infarction, or stroke, as compared with the general population. (Funded by the Swedish Association of Local Authorities and Regions and others.)
Type 2 diabetes is a complex disease that leads to continuous medical care with comprehensive, multifactorial strategies for reducing cardiovascular risk. Patients with type 2 diabetes have risks of death and cardiovascular events that are 2 to 4 times as great as the risks in the general population.1 Results from randomized trials support a range of interventions that target isolated risk factors such as elevated levels of glycated hemoglobin, blood pressure, and cholesterol to prevent or postpone complications of type 2 diabetes. The Steno-2 Study investigated the effects of multifactorial risk-factor control by means of behavior modification and pharmacologic therapy and showed long-lasting reductions in the risks of death and cardiovascular events among patients in whom these risks were reduced, as compared with patients who had been randomly assigned to usual care.2,3
The extent to which the excess risk associated with type 2 diabetes may be mitigated, or potentially eliminated, by contemporary evidence-based treatment and multifactorial risk-factor modification is unclear. In a nationwide cohort, we evaluated the association between the excess risks of death and cardiovascular outcomes among patients with type 2 diabetes, according to the number of risk-factor variables within therapeutic guideline levels, as compared with controls who were matched for age, sex, and county in Sweden. Risk-factor data were not available for controls.
In ancillary analyses, we estimated the strength of the associations between various risk factors and the incremental risks of death and cardiovascular outcomes associated with diabetes. Moreover, we examined the association between selected risk-factor variables such as levels of glycated hemoglobin, systolic blood pressure, and low-density lipoprotein (LDL) cholesterol within evidence-based target ranges and these outcomes.
Discussion
Our analysis of Swedish nationwide registry data from 1998 through 2012 showed that patients with type 2 diabetes and five selected risk-factor variables within target range had, at most, marginally higher risks of death, stroke, and myocardial infarction than the general population. The study indicates that having all five risk-factor variables within the target ranges could theoretically eliminate the excess risk of acute myocardial infarction. However, there was a substantial excess risk of hospitalization for heart failure among patients who had all the variables within target ranges. We identified a monotonic relationship among younger age, increasing number of variables not within target ranges, and a higher relative risk of adverse cardiovascular outcomes. The results suggest that there may be greater potential gains from more aggressive treatment in younger patients with diabetes.
The following risk factors were considered to be the strongest predictors for cardiovascular outcomes and death: low physical activity, smoking, and glycated hemoglobin, systolic blood-pressure, and LDL cholesterol levels outside the target ranges. Using real-world data, we found that levels of glycated hemoglobin, systolic blood pressure, and LDL cholesterol that were lower than target levels were associated with lower risks of acute myocardial infarction and stroke.
Randomized trials investigating the effect of multifactorial cardiovascular risk-factor intervention in patients with type 2 diabetes are scarce, and contemporary studies were designed to measure the cumulative incidence of cardiovascular events among patients with various risk factors (e.g., hyperglycemia, hypertension, dyslipidemia, and microalbuminuria) who received intensive therapy, as compared with those who received conventional therapy.2,3,8,9 Observational studies and randomized trials have shown inconsistent evidence of effects of glycated hemoglobin levels below contemporary guideline levels (<7.0%) with regard to cardiovascular events and death.10-15
In the present analyses, a glycated hemoglobin level outside the target range was a strong predictor for all outcomes, especially for atherothrombotic events, which shows the importance of dysglycemia with regard to these complications. Low physical activity was also a strong predictor of cardiovascular outcomes and death, but randomized trials have not shown long-lasting beneficial effects from increased physical activity in patients with diabetes.16-18
With regard to hospitalization for heart failure, the present analyses showed that the presence of atrial fibrillation, a high body-mass index, and a glycated hemoglobin level and renal function outside the target ranges were the strongest predictors. These findings indicate that cardiorenal mechanisms may contribute to the development of heart failure in patients with type 2 diabetes. A high body-mass index was a stronger risk factor for heart failure than for other outcomes, which may explain why the risks associated with this outcome may continue to be higher among patients with type 2 diabetes than among controls, since patients with diabetes are, on average, heavier than compared controls.
Our study shows, in accordance with previous studies, that lower systolic blood pressure is associated with lower risks of cardiovascular outcomes and death.19 The Systolic Blood Pressure Intervention Trial (SPRINT) showed that systolic blood-pressure targets below guideline levels in patients without diabetes were associated with a lower risk of cardiovascular outcomes and death.20 However, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial examined the same systolic blood-pressure targets in patients with type 2 diabetes (<120 mm Hg vs. <140 mm Hg) and did not show a significant effect on cardiovascular mortality.15,21 Our analysis implies that systolic blood pressure is a central factor for virtually all outcomes in patients with diabetes, and lower levels of systolic blood pressure are associated with significantly lower risks of acute myocardial infarction and stroke among patients with diabetes. The assessment of systolic blood pressure and its relation to death and heart failure is more difficult, owing to potential reverse causality. More-specific trials of blood-pressure reduction to differential targets in patients with type 2 diabetes may be warranted.20,22
Our observational study has several strengths but also some notable limitations. Almost all the patients with type 2 diabetes in Sweden were included. The epidemiologic definitions of type 2 diabetes and the outcomes are well validated. We did not consider changes in the risk-factor variables during follow-up, and although this would have some advantages, the approach we used minimizes the risk of reverse causation in the interpretation of the results. In addition, we did not distinguish between patients with all or some variables within target range without any specific intervention and patients who had been medically treated to attain the observed risk-factor levels. We also acknowledge that residual confounding and reverse causation are impossible to overcome fully. Finally, given the observational nature of this work, this cannot be a complete comparison of the effects of treating risk factors; rather, because some patients may have had risk-factor variables in the target ranges without treatment, the findings represent the prognostic importance of such risk factors for persons with diabetes.
In conclusion, patients with type 2 diabetes who had five risk-factor variables within target ranges appeared to have little or no excess risks of death, myocardial infarction, and stroke as compared with the general population.
Results
Study Population
A total of 433,619 patients with type 2 diabetes and 2,168,095 controls were identified, and 271,174 patients with type 2 diabetes and 1,355,870 matched controls were included in the study (Fig. S1 in the Supplementary Appendix). The median follow-up among all the study participants was 5.7 years, during which 175,345 deaths occurred. The baseline characteristics of the patients with complete data on all five risk factors (96,673 patients with diabetes [35.6%]) and their matched controls are presented in Table 1. The number of patients in each risk-factor group in the imputed data sets is also shown in Table 1. The complete data regarding the characteristics of the participants at baseline are presented in Table S4 in the Supplementary Appendix.
The mean age of the patients was 60.60 years, and 47,777 of 96,673 patients (49.4%) were women. Table S5 in the Supplementary Appendix shows the baseline characteristics of the patients for whom data were missing for at least one risk factor. Figure S6 in the Supplementary Appendix shows the trends in risk factors over the period from 1998 through 2012, and Figure S7 in the Supplementary Appendix shows how causes of death varied among the groups according to the number of risk-factor variables in the target ranges.
Risk of Cardiovascular Events
A total of 37,825 patients with diabetes (13.9%) and 137,520 controls (10.1%) died during the study period. The numbers of events, incidence rates, and hazard ratios for all the outcomes among patients with diabetes, as compared with controls, at increasing numbers of risk-factor variables, as well as the risks of death among men and women, are presented in Table S2 in the Supplementary Appendix.
Figure 1 shows the adjusted hazard ratios for the outcomes, according to age category and the number of risk-factor variables within target ranges, among patients with diabetes as compared with matched controls. The results show a stepwise increase in the hazard ratios for each additional variable that was not within the target range among patients with diabetes, and the incremental risks of cardiovascular events and death that were associated with diabetes decreased in a stepwise fashion from younger to older age groups. Patients with diabetes who were 80 years of age or older at baseline had the lowest incremental risk of cardiovascular events and death, as compared with controls. In the overall cohort, patients with type 2 diabetes who had no risk-factor variables outside the target ranges had a marginally higher risk of death than the controls (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.12).
Patients with diabetes who were 80 years of age or older at baseline and had no risk factors outside target ranges had the lowest hazard ratio, as compared with controls, for acute myocardial infarction across all the groups (hazard ratio, 0.72; 95% CI, 0.49 to 1.07) (Figure 1B). Overall, patients with type 2 diabetes who had no risk-factor variables outside the target ranges had a lower risk of acute myocardial infarction than the matched controls (hazard ratio, 0.84; 95% CI, 0.75 to 0.93). Corresponding estimates for the excess risk of stroke are shown in Figure 1C. The overall hazard ratio for stroke among patients with no risk-factor variables outside the target ranges, as compared with controls, was 0.95 (95% CI, 0.84 to 1.07) (Table S2 in the Supplementary Appendix). Similar to the findings with acute myocardial infarction, there was a higher incremental risk of stroke in the younger age categories and for each variable that was not within the target range. Estimates regarding hospitalization for heart failure are shown in Figure 1D. Patients with type 2 diabetes who were younger than 55 years of age and had all five risk-factor variables outside the target ranges had the highest excess risk of hospitalization for heart failure of all the outcomes assessed (hazard ratio vs. control, 11.35; 95% CI, 7.16 to 18.01). The overall hazard ratio for hospitalization for heart failure among patients with no risk-factor variables outside the target ranges, as compared with controls, was 1.45 (95% CI, 1.34 to 1.57) (Table S2 in the Supplementary Appendix).
Risk-Factor Strength and Levels in Patients with Type 2 Diabetes
Figure 2A shows the predictors with the apparent greatest importance with regard to death from any cause. The five strongest predictors regarding the risk of death among patients with type 2 diabetes were smoking, physical activity, marital status, glycated hemoglobin level, and use of statins (lipid-lowering medication). The data shown in Figure 3A suggest that lower glycated hemoglobin levels than are currently recommended in guidelines were associated with a lower risk of death.
The strongest predictors regarding the risk of acute myocardial infarction were the glycated hemoglobin level, systolic blood pressure, LDL cholesterol level, physical activity, and smoking (Figure 2B). These risk factors showed a linear association with the risk of acute myocardial infarction (Figure 3B).
The strongest predictors regarding the risk of stroke were the glycated hemoglobin level, systolic blood pressure, duration of diabetes, physical activity, and atrial fibrillation (Figure 2C). Levels below the guideline target levels for glycated hemoglobin and systolic blood pressure were associated with lower risks of stroke (Figure 3C).
Hospitalization for heart failure was predicted primarily by atrial fibrillation and a body-mass index outside the target range; a low estimated glomerular filtration rate and high glycated hemoglobin level were also strong predictors of this outcome (Figure 2D). The risk of hospitalization for heart failure was marginally lower at glycated hemoglobin levels of less than 53 mmol per mole (Figure 3D).
The glycated hemoglobin level was the strongest or the second strongest predictor regarding the risk of the outcomes in five of the eight models (Figure 2). Smoking was the strongest predictor of death.
Relative Risk-Factor Strength and Explained Log Likelihood
Figures S2 and S3 in the Supplementary Appendix show the relative strength of the associations for predictors of cardiovascular outcomes in patients with type 2 diabetes, with or without preexisting conditions, with the use of explained log-likelihood. The results were broadly consistent with the results obtained with the use of explained relative risk (R2) models.
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