kelingwang/causation_strength_rating huggingface dataset:
Although the Action for Health in Diabetes (Look AHEAD) trial did not show that the intensive lifestyle intervention reduced cardiovascular events in adults with type 2 diabetes and overweight or obesity (41), it did confirm the feasibility of achieving and maintaining long-term weight loss in people with type 2 diabetes.
In the intensive lifestyle intervention group, mean weight loss was 4.7% at 8 years (42).
Approximately 50% of intensive lifestyle intervention participants lost and maintained =5% of their initial body weight, and 27% lost and maintained =10% of their initial body weight at 8 years (42).
Participants assigned to the intensive lifestyle group required fewer glucose-, blood pressure-, and lipid-lowering medications than those randomly assigned to standard care.
Secondary analyses of the Look AHEAD trial and other large cardiovascular outcome studies document additional weight loss benefits in people with type 2 diabetes, including improved mobility, physical and sexual function, and health-related quality of life (34).
Moreover, several subgroups had improved cardiovascular outcomes, including those who achieved >10% weight loss (43).
Clinical benefits typically begin upon achieving 5% weight loss (19,54), and the benefits of weight loss are progressive; more intensive weight loss goals (>7%, >10%, >15%, etc.) may be pursued to achieve further health improvements if the individual is motivated and more intensive goals can be feasibly and safely attained.
Significant weight loss can be attained with lifestyle programs that achieve a 500–750 kcal/day energy deficit, which in most cases is approximately 1,200–1,500 kcal/day for women and 1,500–1,800 kcal/day for men, adjusted for the individual�s baseline body weight (19,54).
Proven intensive behavioral interventions included =16 sessions during an initial 6 months and focus on nutritional changes, physical activity, and behavioral strategies to achieve an ~500–750 kcal/day energy deficit.
Such interventions should be provided by trained individuals and can be conducted in either individual or group sessions (54).
Assessing a person�s motivation level, life circumstances, and willingness to implement behavioral changes to achieve weight loss should be considered along with medical status when such interventions are recommended and initiated (38,60).
If such intensive behavioral interventions are not available or accessible, structured programs delivering behavioral counseling (face-to-face or remote) can be considered; however, their effectiveness varies (61,62).
Nutrition interventions may differ by macronutrient goals and food choices as long as they create the necessary energy deficit to promote weight loss (19,55–57).
Using meal replacement plans prescribed by trained practitioners, with close monitoring, can be beneficial.
Within the intensive lifestyle intervention group of the Look AHEAD trial, for example, the use of a partial meal replacement plan was associated with improvements in nutrition quality and weight loss (54), and improvement in cardiovascular risk factors (41).
In a systematic review and meta-analysis, efficacy and safety of meal replacements (partial or total meal replacement) as compared with conventional diets showed improvements in A1C, FBG, body weight, and BMI (58).
In the most recent ESC/EURObservational Research Programme (EORP) EUROASPIRE surveys, history of hypertension was present in 80% of men and 87% of women with known diabetes and in 74% of men and 81% of women with newly diagnosed diabetes with a history of coronary heart disease (CHD) (191).
Regular BP measurements under standardized conditions are mandatory in all patients with diabetes (Figure 9; Table 8).
Hypertension should be confirmed in both arms using multiple readings, including measurements on separate days (48,157).
In patients with CVD and values >180/110 mmHg, it could be reasonable to diagnose hypertension at a single visit (192).
Details on BP measurements are comprehensively summarized in the 2018 ESC/European Society of Hypertension (ESH) Guidelines for the management of arterial hypertension and in the Supplementary data online, Section 2.6.1 (193).
In general, the diagnosis and treatment of hypertension is comparable between sexes, except for women of child-bearing potential or during pregnancy, when some drugs, such as RAS blockers, can have adverse effects on the foetus, especially in early gestation (227).
The possible effect of oral contraceptives on BP should also be considered (48).
There is some evidence from RCTs that BP targets during pregnancy should range from 110 to 135 mmHg for SBP and 80 to 85 mmHg for DBP (228).
This is also supported by the recent CHAP (Chronic Hypertension and Pregnancy) study of mild chronic hypertension in pregnancy, where 16% of the pregnant women had diabetes (229).
The strategy targeting a BP of <140/90 mmHg was related with better pregancy outcomes without an increase in the number of Small for Gestational Age babies.
Women usually show greater differences in BP and higher proportions of hypertension than men already at diagnosis of T2DM compared with women and men without T2DM, and worse BP control thereafter (191,230).
Moreover sex-specific, hypertension-mediated organ damage was evidenced with a very high risk of HFpEF in women, especially in the presence of diabetes (231).
Randomized controlled trials have shown the benefit (reduction of stroke, coronary events, and kidney disease) of lowering SBP to <140 mmHg and diastolic blood pressure (DBP) to <90 mmHg in patients with diabetes (Evidence in Table S10).
However, the optimal BP target in patients with diabetes is still a matter of debate.
The UKPDS post-trial, 10-year follow-up study reported no benefits persisting from the earlier period of tight BP control with respect to macrovascular events, death, and microvascular complications, while initial between-group BP differences were no longer maintained (132).
RCTs evaluating the benefits and risks of more intense compared with standard hypertension treatment strategies in patients with diabetes are summarized in Supplementary data online, Table S10.
In a meta-analysis of RCTs involving patients with diabetes or pre-diabetes, an SBP reduction to =135 mmHg compared with a less intensive control reduced the RR of all-cause mortality by 10% (odds ratio [OR] 0.90; 95% CI, 0.83–0.98), whereas more intensive BP control (=130 mmHg) was associated with a greater reduction in stroke but did not reduce other events (194,195).
Similarly, anti-hypertensive treatment significantly reduced mortality in people with T2DM, CAD, HF, and stroke, with an achieved mean SBP of 138 mmHg, whereas only stroke was reduced significantly, with a mean SBP of 122 mmHg compared with higher BP values (196).
Thus, reducing SBP to <130 mmHg may benefit patients with a particularly high risk of a cerebrovascular event, such as those with a history of stroke (193,194,196–200).
However, SBP >140 mmHg or <120 mmHg were related to higher risk of adverse renal outcomes in patients with diabetes when compared with those without diabetes and with high CV risk (199–202).
The 2018 ESC/ESH Guidelines for the management of arterial hypertension recommend that in all patients with diabetes, office BP should be targeted to an SBP of 130 mmHg, and lower if tolerated but not <120 mmHg; DBP should be lowered to <80 mmHg but not <70 mmHg (193).
In older patients (age =65 years), the SBP target range should be 130–140 mmHg if tolerated (193).
However, more recent data challenge these recommendations for all patients with diabetes, and highlight a potential need for more individualized target levels (157,203,204).
The 2021 ESC Prevention Guideline recommends office SBP treatment target ranges of 120–130 mmHg in patients with diabetes, with lower SBP acceptable if tolerated until the age of 69 years (48).
In patients aged =70 years, SBP values <140 mmHg, down to 130 mmHg if tolerated are recommended.
DBP treatment target <80 mmHg is recommended for all treated patients.
Diets rich in vegetables, fruits, and low-fat dairy products, such as the Mediterranean diets and Dietary Approaches to Stop Hypertension-style eating patterns (including reducing sodium to <100 mmol/day and increasing potassium intake), improve BP control (205–207).
Long-term exercise training intervention modestly but significantly reduces SBP (by -7 mmHg) and DBP (by -5 mmHg).
Ideally, an exercise prescription aimed at lowering BP in individuals with normal BP or hypertension would include a mix of predominantly aerobic exercise training supplemented with dynamic resistance exercise training (208).
A marked improvement in CV risk factors (hypertension, dyslipidaemia, diabetes), associated with marked weight loss, was observed after bariatric surgery (209).
In the Look AHEAD trial, those who lost 5 to <10% of body weight had increased odds of achieving a 5 mmHg decrease in SBP and DBP compared with those who lost >10% or <5% (210).
The frequency of CV complications appears to be modulated by ethnicity or racial identity (193,211,212).
Home BP self-monitoring should be considered in patients with diabetes on anti-hypertensive treatments to check that BP is appropriately controlled (242).
24 h ambulatory blood pressure monitoring should be considered to assess abnormal 24 h BP patterns, including nocturnal hypertension and reduced or reversed nocturnal BP dipping, and to adjust anti-hypertensive treatment (243).
Optimal risk factor and lifestyle management, as well as early identification and treatment of comorbidities, is a cornerstone of treatment for T2DM (357–359).
The Swedish National Diabetes Registry revealed a clear improvement of clinical outcomes by each risk factor within the target range (HbA1c, LDL-C, albuminuria, smoking, and SBP) (360).
In patients with advanced disease, e.g. T2DM and established microalbuminuria, an intensive, target-driven, multifactorial therapy (Steno-2 study; targets: HbA1c <6.5%, total cholesterol <4.5 mmol/L [175 mg/dL], and BP <130/80 mmHg) resulted in 50% fewer microvascular and macrovascular events after 7.8 years of follow-up (361).
Long-term follow-up (21 years from baseline) showed significantly reduced end-stage renal disease combined with death (HR 0.53; 95% CI, 0.35–0.80), and risk of HF hospitalization reduced by 70% (362).
Overall, this resulted in a 7.9 year gain of life expectancy (363).
These positive effects were not observed in the clinical intervention trials of intensified, multifactorial treatment for T2DM in primary care and early in the disease trajectory.
The ADDITION (Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care) trial showed that microvascular or macrovascular events were not significantly reduced after 5 or 10 years (17% and 13% reduction, respectively), while intervention only slightly improved HbA1c (364,365).
In accordance, the J-DOIT3 (Japan Diabetes Optimal Integrated Treatment Study for 3 Major Risk Factors of Cardiovascular Diseases) trial in patients with T2DM aged 45–69 years revealed a non-significant trend towards a reduced primary composite outcome (non-fatal MI, stroke, revascularization, or all-cause death; HR 0.81; 95% CI, 0.63–1.04; P = 0.094) with intensive vs. conventional therapy (366).
Post-hoc analyses showed that only cerebrovascular events were reduced (HR 0.42; 95% CI, 0.24–0.74; P = 0.002), while no differences were seen for all-cause death and coronary events.
In addition, the Look AHEAD trial, introducing lifestyle intervention in patients with obesity and T2DM with 10 years� follow-up, did not demonstrate a reduction in the composite CV outcome (56).
Key problems in optimally treating patients with T2DM and CVD are the low rate of detection of T2DM in patients with CVD, the low referral rate to diabetes specialists, and the difficulty of prolonged adherence to medication or lifestyle interventions in this patient group.
The EUROASPIRE V survey reported that many patients with CVD (29.7%) had known diabetes, while 41.1% of those with unknown T2DM were dysglycaemic (367).
Of patients with known diabetes, 31% had been advised to attend a diabetes clinic, though only 24% attended.
Only 58% of dysglycaemic patients were prescribed all cardio-protective drugs, and use of SGLT2 inhibitors or GLP-1 RAs was limited (3% and 1%, respectively) (367).
A BP target <140/90 mmHg was achieved in only 61% of patients with newly detected T2DM, and in 54% of patients with previously known T2DM (34).
An LDL-C target <1.8 mmol/L was only achieved in 18% and 28% of patients, respectively.
This was explained by low prescription rates of the combination of all cardio-protective drugs (antiplatelet therapy, beta-blockers, RAS inhibitors, and statins) in only 55% of patients with newly detected T2DM, and in 60% of patients with previously known T2DM (34).
The concept of a polypill, e.g. containing aspirin, ramipril, and atorvastatin, may even improve clinical events in secondary cardiovascular prevention (368).
Furthermore, adherence to lifestyle intervention fades over time, with continuously increasing body weight after 1 year (56).
To overcome adherence failures, the 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice outlines a stepwise approach to treating risk factors and intensifying treatment to help physicians and patients pursue risk-factor targets, taking into account patient profiles and preferences, ensuring targets are a part of a shared decision-making process involving healthcare professionals and patients (48).
This stepwise approach starts with assessing CVD risk in all patients with diabetes, including glycaemic state and lifestyle risk-factor profile (Figure 13).
CVD risk stratification should be individually adapted according to comorbidities, e.g. CAD, HF, AF, or PAD, as well as age, frailty, and sex.
This includes discussing individual preferences with the patient, particularly regarding lifestyle strategies and potential treatment benefits.
Particularly in the field of T2DM, studies have shown benefits of a stepwise approach to intensify treatment, and it appears that attaining treatment goals is similar, side effects are fewer, and patient satisfaction is significantly higher with such an approach (369,370).
Supporting evidence comes from the Italian Diabetes and Exercise Study 2, which showed that a behavioural intervention strategy compared with standard care resulted in a sustained increase in physical activity and decrease in sedentary time among patients with T2DM (371).
Multidisciplinary behavioural approaches that combine the knowledge and skills of different caregivers are recommended (104).
Adding exercise intervention combined with psychological support to diet recommendations is more effective than diet education alone (375).
Assessing depression and depressive symptoms is important in patients with CVD and T2DM, as adequate treatment improves adherence (376,377).
To achieve a high adherence and optimization of target goals, clinician�patient communication is crucial and should include a personalized approach explaining background and targets to improve understanding and encourage lifestyle changes and drug-therapy adherence.
Aside from the disease entity, including symptoms, the patient�s ability to adopt a healthy lifestyle depends on individual cognitive and emotional factors, educational level, socioeconomic factors, and mental health.
Perceived susceptibility to illness and the anticipated severity of the consequences are also prominent components of patients� motivation (372).
Patients can be motivated by motivational interviewing including the Open-ended questions, Affirmation, Reflective listening, and Summarizing (OARS) and Specific, Measurable, Achievable, Realistic, Timely (SMART) principles (372–374).
Mobile phone applications may improve adherence to both medication and behavioural changes, but more evidence, particularly in patients with CVD and T2DM, is needed (378).
Regarding the education method, individual education is more effective than face-to-face or web and mobile phone education (375).
Whether a tailored and automated text message (SMS) support programme may improve glycaemic control in adults with poorly controlled diabetes is equivocal (379).
Lifestyle changes are recommended as the basic measure for preventing and managing T2DM (48).
Advice should be addressed by a multifactorial approach with patient-centred communication adapted to the health status and health literacy of the patient (Section 5.7).
In T2DM, as investigated in the Action for Health in Diabetes trial (Look AHEAD; 5145 T2DM patients, 59% female, mean age 58 years, mean body mass index [BMI] 36 kg/m2), lifestyle intervention by nutritional counselling, meal replacement, and exercise induced an average of 8.6% weight loss, which was associated with a significant reduction in HbA1c and BP (56).
Effects on weight and risk-factor control diminished after 5 years in those with low adherence to the lifestyle programme (56).
After 10 years, CV events (i.e. a composite endpoint of CV death, non-fatal MI, non-fatal stroke, and hospitalization for angina) were not different to usual care (56).
However, microvascular disease complications (i.e. development of CKD) were significantly reduced (hazard ratio [HR] 0.69; 95% confidence interval [CI], 0.55–0.87; P = 0.002) by lifestyle intervention, an effect associated with improvements in CV risk factors (57).
Additional analyses 16.7 years after the start of the study (9.6 years of intervention and then observation) revealed that participants who lost =10% of weight at 1 year of intervention had a 21% reduced risk of mortality (HR 0.79; 95% CI, 0.67–0.94; P = 0.007) (58).
The decline in body fat mass was significantly associated with a lower risk of HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), while a decline in waist circumference was only significantly associated with a lower risk of HFpEF (59).
In addition, baseline cardio-pulmonary fitness was associated with reduced risks of mortality and CV events during follow-up of 9.2 years (60).
The DiRECT (Diabetes Remission Clinical Trial)�an open-label, cluster-randomized trial in patients with T2DM�assigned practices to provide either a weight-management programme including exercise (intervention group) or best-practice care by guidelines (control group).
At 12 months, almost half of the participants in the intervention group achieved remission to a non-diabetic state and were off glucose-lowering drugs (61).
Home-based exercise intervention in patients with CAD and T2DM (ARTEMIS study; Finnish randomized controlled trial [RCT]; n = 127; 2-year controlled, home-based exercise training vs. usual care), however, did not significantly improve CV risk factors despite significant improvements in exercise capacity (P = 0.030) (62).
In patients with obesity and T2DM, reducing weight is one of the cornerstones of treatment (63).
Weight loss of >5% improves glycaemic control, lipid levels, and BP in overweight and obese adults with T2DM (64,65).
These effects can be achieved by improving energy balance and/or introducing obesity medications.
Orlistat, naltrexone/bupropion, and phentermine/topiramate are each associated with achieving >5% weight loss at 52 weeks compared with placebo (66).
However, glucose-lowering agents such as GLP-1 RAs, the dual agonist tirzepatide, and SGLT2 inhibitors also significantly reduce body weight (67,68).
Adding exercise to a GLP-1 RA (liraglutide) had a greater effect on weight reduction and maintenance (69).
Comparing the effects on weight reduction between GLP-1 RAs and SGLT2 inhibitors, the former seems to be superior.
Given the additional beneficial effects of GLP-1 RAs and SGLT2 inhibitors on CV outcomes in T2DM (Section 5.3), these agents should be the preferred glucose-lowering medication in overweight and obese patients with CVD and T2DM, as obesity medications have, to date, not shown to reduce CV events (70–72).
If weight is not managed effectively by lifestyle interventions and medication, bariatric surgery should be considered in patients with T2DM and a BMI =35 kg/m2 (=Class II; WHO classification) to achieve long-term weight loss, reduce blood glucose, and improve CV risk factors.
Data from the Swedish Obesity Subjects (SOS) study revealed that after 24-year follow-up, bariatric surgery was associated with a prolonged life expectancy compared with lifestyle and intensive medical management alone (73,74).
The corresponding HR was 0.70 (95% CI, 0.57–0.85) for CV death and 0.77 (95% CI, 0.61–0.96) for death from cancer (75,76).
This evidence has been extended to patients with CVD and obesity, as a large case-control study (n = 2638) revealed that bariatric surgery was also associated with a lower incidence of major adverse cardiovascular events (MACE) in those patients (77).
Still, potential adverse events after bariatric surgery should also be considered (78).
In general, patients with T2DM should follow nutritional recommendations that reduce body weight and improve metabolic control and outcomes (48).
A Mediterranean-style eating pattern improves glycaemic control, lipids, and BP (80,81).
If this diet is supplemented with olive oil or nuts, as in the non-randomized PREvencion con Dieta MEDiterranea (PREDIMED) study in individuals at high CV risk (49% T2DM), the risk of ASCVD was reduced by 28–31% (82).
Recent data from the Coronary Diet Intervention With Olive Oil and Cardiovascular Prevention (CORDIOPREV) study confirmed the benefit of a Mediterranean diet by showing that male patients with established CAD benefitted more from a Mediterranean diet than from a low-fat diet intervention after 7 years of follow-up.
A shift from a more animal-based to a plant-based food pattern may also reduce ASCVD risk (83–85).
Data from studies on supplementation with n�3 fatty acids do not support recommending n�3 fatty acid supplements for secondary prevention of CVD in T2DM (86,87).
The consumption of sugars, sugar-sweetened soft drinks, and fruit juices should be avoided (88,89).
Moreover, alcohol intake should generally be moderate, as any amount of alcohol uniformly increases BP and BMI (90–92).
A high-protein diet (30% protein, 40% carbohydrates, and 30% fat) seems to be superior to a standard-protein diet (15% protein, 55% carbohydrates, and 30% fat) in overweight and obese (mean weight 107.8 � 20.8 kg) patients with HF; both diets were equal in reducing body weight (3.6 vs. 2.9 kg, respectively) and waist circumference (1.9 vs. 1.3 cm, respectively), but the high-protein diet resulted in greater reductions in CV risk factors, e.g. HbA1c, cholesterol, triglycerides, and BP (93).
People with CVD and T2DM are encouraged to reduce sodium intake, as this may reduce systolic BP by, on average, 5.8 mmHg in hypertensive patients and 1.9 mmHg in normotensive patients (94,95).
In a meta-analysis, in hypertensive and normotensive people, reducing salt intake by 2.5 g/day resulted in a 20% relative reduction of ASCVD events (95).
In addition, salt substitution with reduced sodium levels and increased potassium levels has been shown to reduce stroke, CVD, and overall mortality in patients with high CV risk (96).
Regular moderate to vigorous PA has favourable effects on metabolic control and CV risk factors in T2DM (97–100).
Intervention programmes reduce HbA1c by 0.6% in patients with T2DM, with the combination of endurance and resistance exercise having the most beneficial effects (101).
Moreover, compared with low total PA, high total PA is associated with a lower CV mortality risk, as well as a reduction in all-cause mortality (all-cause mortality: HR 0.60 [95% CI, 0.49–0.73], comparing high vs. low total PA) (97).
Interventions are based on encouraging an increase in any PA, as even small amounts were shown to have beneficial effects; even an extra 1000 steps of walking per day is advantageous and may be a good starting point for many patients (98,100).
Moreover, a gradual increase in activity level is recommended.
Structured exercise should be additionally introduced at the start or after first achievements to increase activity.
Patients should perform =2 sessions per week of endurance exercise and/or resistance exercise training.