Abstract
Dysglycaemia (i.e. type 2 diabetes mellitus or impaired glucose tolerance) is not only common in patients with cardiovascular disease but increases the risk for future cardiovascular complications. Hyperglycaemia, the hallmark of diabetes, has since long been considered to be the link between diabetes and cardiovascular disease. Diabetes is, however, a complex, multifactorial disorder to which, for example, insulin resistance, endothelial dysfunction and factors such as increased thrombogenicity, hypertension and dyslipidaemia contribute. Thus, treatment needs to be multifactorial and to take cardiovascular aspects into account. Life-style adjustments are, together with blood pressure, lipid and glucose control, important parts of such management. Recent trial data reveal a beneficial effect on cardiovascular prognosis and mortality of blood glucose lowering agents belonging to the classes: sodium-glucose-transporter 2 inhibitors and glucagon-like peptide 1 agonists. The precise mechanisms by which certain sodium-glucose-transporter 2 inhibitors and glucagon-like peptide receptor agonists lead to these beneficial effects are only partly understood. An important impact of the benefits of sodium-glucose-transporter 2 inhibitors is a reduction in heart failure while glucagon-like peptide receptor agonists may retard the development of atherosclerotic vascular disease or stabilising plaques. Although there has been a considerable improvement in the prognosis for people with atherosclerotic diseases over the last decades there is still a gap between those with dysglycaemia, who are at higher risk, than those without dysglycaemia. This residual risk is reasonably related to two major factors: a demand for improved management and a need for new and improved therapeutic opportunities of type 2 diabetes, both routes to an improved prognosis that are at hands. This review is a comprehensive description of the possibilities to improve the prognosis for patients with dysglycaemia by a multifactorial management according to the most recent European guidelines issued in 2019 by the European Society of Cardiology in collaboration with the European Association for the Study of Diabetes.
Introduction
The different glycaemic categories defined by the World Health Organisation1 are outlined in Table 1. In the present context the term dysglycaemia is defined as the presence of either type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT), both common in patients with cardiovascular disease (CVD) and both increasing the risk for future cardiovascular complications.2 Impaired fasting glucose (IFG) is left aside due to less convincing evidence on its immediate impact on CVD. Still, IFG should be acknowledged since it entails a risk of progression towards IGT or T2DM as detailed in a separate article in this issue of the journal.3
Definitions of glycaemic categories according to the World Health Organisation.1
| Venous plasma glucose (mmol/l) | ||
|---|---|---|
| Fasting | Two-hour post-load | |
| Normoglycaemic | <6.1 | <7.8 |
| Impaired fasting glucose (IFG) | 6.1–6.9 | <7.8 |
| Impaired glucose tolerance (IGT) | <7.0 | 7.8–11.0 |
| Diabetes (DM) | ≥7.0 | >11.0 |
| Venous plasma glucose (mmol/l) | ||
|---|---|---|
| Fasting | Two-hour post-load | |
| Normoglycaemic | <6.1 | <7.8 |
| Impaired fasting glucose (IFG) | 6.1–6.9 | <7.8 |
| Impaired glucose tolerance (IGT) | <7.0 | 7.8–11.0 |
| Diabetes (DM) | ≥7.0 | >11.0 |
Definitions of glycaemic categories according to the World Health Organisation.1
| Venous plasma glucose (mmol/l) | ||
|---|---|---|
| Fasting | Two-hour post-load | |
| Normoglycaemic | <6.1 | <7.8 |
| Impaired fasting glucose (IFG) | 6.1–6.9 | <7.8 |
| Impaired glucose tolerance (IGT) | <7.0 | 7.8–11.0 |
| Diabetes (DM) | ≥7.0 | >11.0 |
| Venous plasma glucose (mmol/l) | ||
|---|---|---|
| Fasting | Two-hour post-load | |
| Normoglycaemic | <6.1 | <7.8 |
| Impaired fasting glucose (IFG) | 6.1–6.9 | <7.8 |
| Impaired glucose tolerance (IGT) | <7.0 | 7.8–11.0 |
| Diabetes (DM) | ≥7.0 | >11.0 |
The cardiovascular risk related to dysglycaemia is multifactorial, i.e. not only related to the hyperglycaemic state, but also to a number of other factors including an unhealthy lifestyle, hypertension and dyslipidaemia. Thus, efficient prevention of cardiovascular complications can only be accomplished by means of a multifactorial approach. The objective of this review is to present state of the art information on such risk factor management.
Dysglycaemia and cardiovascular risk
The 2016 joint European guidelines on CVD prevention state that people with diabetes mellitus (DM) and at least one other CVD risk factor or target organ damage are at very high risk for future cardiovascular events, and that all other people with DM are at high risk.4 Accumulating information favours the conclusion that patients with established coronary artery disease and IGT are at an almost similarly increased risk.5–8 Factors contributing to the development of CVD among people with dysglycaemia are the same as for normo-glycaemic people. A report from the World Health Organisation states that hypertension, hyperglycaemia, physical inactivity and overweight/obesity are among the five most common factors attributed to the total global mortality and loss of disability adjusted life years (DALYs) and they are all common in dysglycaemic patients.9 The adjusted hazard ratio (HR) in people with compared with those without diabetes has been reported as 1.80 (95% confidence interval (CI), 1.71–1.90) for death by any cause and 2.32 (95% CI, 2.11–2.56) for death from vascular causes.10 Translated into life years lost, the differences in life expectancy range from almost seven years for women aged 40–50 years to 0.1 years for men aged 85–89 years. The observed life-expectancy deficits are greater in women than in men and more apparent in those below the age of 65–75 years at the onset of T2DM.10,11
Hyperglycaemia, the hallmark of diabetes, is associated with an atherogenic lipid profile, high blood pressure, low-grade inflammation, renal disorder and advanced glycation end products (AGEs), all of which increase the cardiovascular risk.12 However, 100% of the actual patient category have dysglycaemia, about 90% are obese or overweight, 70% dyslipidaemic and almost 70% hypertensive.13,14 The cardiovascular risk increases with increasing blood pressure or plasma cholesterol in patents with as well as those without T2DM. However, for each risk factor level the mortality risk in coronary artery disease is considerably higher in the presence of T2DM,15 underlining that prevention of CVD in people with dysglycaemia should be multifactorial and treatment targets stricter than for people without glucose perturbations.12
Multifactorial management
The principles for a target-driven multifactorial management of patients with diabetes and its pre-states are outlined in Figure 1 summarising the present treatment targets according to the 2019 European guidelines on diabetes, prediabetes and CVD.12
A summary of the most essential components and treatment targets of an evidence-based management of patients with diabetes and its pre-states (modified after reference12).
ASA: acetylsalicylic acid; CVD: cardiovascular disease; HbA1c: glycated haemoglobin A1c; LDL-C: low density lipoprotein cholesterol; SBP: systolic blood pressure.
Lifestyle
Lifestyle advice is a cornerstone when managing people with dysglycaemia with a focus on a diet rich in fruits, vegetables, wholegrain cereals and low-fat protein sources with a reasonable energy intake.16 Since weight reduction may be very hard to accomplish in overweight/obese patients, a first goal should be weight stabilisation. Physical activity of at least moderate intensity is recommended during at least 150 min a week. Ideally it should be composed of a combination of aerobic and resistance training.17 Smoking cessation is mandatory, and structured advice, including pharmacological support, should be provided.
Glucose control
The attitude to tight vs less tight glycaemic control has shifted during the recent decade. The evidence that strict glycaemic control would be more protective as regards macro- and microvascular complication has not been verified, for example, as reviewed by Rodriquez-Gutiérrez et al.18 Present recommendations12 advocate an individualised approach paying attention to age, diabetes duration and history of CVD in order to avoid untoward effects, not the least hypoglycaemia. The general glycated haemoglobin A1c (HbA1c) target is <53 mmol/mol (<7%). This should be more stringent in younger patients with a short duration of T2DM without evidence of CVD while somewhat less stringent targets, 64–75 mmol/mol (<8–9%), may be adequate for elderly patients with longstanding DM and limited life expectancy, and in frail patients with multiple comorbidities, including hypoglycaemic episodes.
There is a variety of glucose-lowering drugs available. Newer classes of drugs, originally launched as glucose-lowering, among them inhibitors of dipeptidyl peptidase 4 (DPP-4), sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like protein-1 (GLP-1) receptor agonists have been studied in cardiovascular outcome trials (CVOTs).
The DPP-4 inhibitors sitagliptin,19 alogliptin,20 saxagliptin21 and linagliptin22 have been studied in patients with T2DM at high cardiovascular risk. The impact on a composite of cardiovascular death, myocardial infarction or stroke was neutral in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) study, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study and Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (CARMELINA) and in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in which hospitalisation for unstable angina was included as well. Of note, is that these trials only had short periods of follow-up (1.5–3 years) and were designed to show non-inferiority to placebo. Another explanation may be that DPP-4 inhibitors are merely glucose lowering and without any direct cardiovascular effects. An unexpected finding in SAVOR21 was that hospitalisation for heart failure was significantly more common in patients randomised to saxagliptin than among in those allocated to placebo (3.5% vs 2.8%; HR 1.27; 95% CI, 1.07–1.51; p = 0.007). In EXAMINE20 the corresponding HR was 1.19 (95% CI, 0.90–1.58); p = 0.220). In contrast there was no increased risk in TECOS (HR 1.00 (95% CI, 0.83–1.20, p = 0.98).23 The reasons for the increased risk of heart failure related to some incretins are not known but this does not seem to be a class effect. Indeed, a population-based prescription study24 and a recent meta-analysis do not indicate that heart failure is increased by the use of saxagliptin.25 Anyhow, the US Food and Drug Administration (FDA) has issued a warning label in 2016 for the DPP-4 inhibitors saxagliptin and alogliptin regarding the risk of developing heart failure in patients with CVD.26
As can be seen in Table 2, the SGLT-2 inhibitors empagliflozin27 and canagliflozin,28 and the GLP-1 receptor agonists liraglutide,29 semaglutide,30,31 albiglutide32 and dulaglutide,33 added to pre-existing glucose-lowering therapy resulted in significant reductions in total and cardiovascular mortality and morbidity. The cardiovascular benefits, an absolute risk reduction of major cardiovascular events of 1.6–2.3% and a relative reduction between 13–26%, were obtained at HbA1c levels of 56.3–63.9 mmol/mol (7.3–8.0%). Similar, but non-significant, trends in cardiovascular benefits were seen with the SGLT-2 inhibitor dapagliflozin34 and the GLP-1 receptor agonist exenatide35 (Table 2).
An overview of pertinent characteristics of outcome trials with sodium-glucose-transporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists.
| Trial (ref no) | Compound vs placebo (patients no) | Patient characteristics with CV disease (%) | Median follow-up (years) | Primary endpoint | Risk reduction (%) absolute and relative | HbA1c (%) at baseline Reduction |
|---|---|---|---|---|---|---|
| SGLT-2 inhibitors | ||||||
| EMPA-REG27 | Empagliflozin 7020 | T2DM+CV disease 100 | 3.1 | CV death, nonfatal MI or stroke | 1.6 14 | 8.0 –0.2 |
| CANVAS28 | Canagliflozin 10,142 | T2DM+high CV risk 66 | 2.4 | CV death, nonfatal MI or stroke | – 14 | 8.1 –0.6 |
| DECLARE TIMI 5834 | Dapagliflozin 17,160 | T2DM+CV disease or high CV risk 41 | 4.2 | CV death, nonfatal MI or stroke | 0.6 7 | 8.3 –0.4 |
| GLP-1 receptor agonists | ||||||
| LEADER29 | Liraglutide 9340 | T2DM+high CV risk 81 | 3.8 | CV death, nonfatal MI or stroke | 1.9 13 | 7.7 –0.4 |
| SUSTAIN 630 | Semaglutide (sc) 3297 | T2DM+high CV risk 83 | 2.1 | CV death, nonfatal MI or stroke | 2.3 26 | 7.3 –0.8 |
| EXSCEL35 | Exenatide 14,752 | T2DM+high CV risk 73 | 3.2 | CV death, nonfatal MI or stroke | 9 0.8 | 8.1 0.5 |
| PIONEER 631 | Semaglutide (oral) 3183 | T2DM+high CV risk 85 | 1.3 | CV death, nonfatal MI or stroke | 1.0 21 | 8.7 –0.7 |
| HARMONY32 | Albiglutide 9463 | T2DM+CV disease 100 | 1.6 | CV death, nonfatal MI or stroke | 2.0 22 | 8.7 –0.5 |
| REWIND33 | Dulaglutide 9901 | T2DM+high CV risk 31 | 5.4 | CV death, nonfatal MI or stroke | 1.4 12 | 7.3 –0.6 |
| Trial (ref no) | Compound vs placebo (patients no) | Patient characteristics with CV disease (%) | Median follow-up (years) | Primary endpoint | Risk reduction (%) absolute and relative | HbA1c (%) at baseline Reduction |
|---|---|---|---|---|---|---|
| SGLT-2 inhibitors | ||||||
| EMPA-REG27 | Empagliflozin 7020 | T2DM+CV disease 100 | 3.1 | CV death, nonfatal MI or stroke | 1.6 14 | 8.0 –0.2 |
| CANVAS28 | Canagliflozin 10,142 | T2DM+high CV risk 66 | 2.4 | CV death, nonfatal MI or stroke | – 14 | 8.1 –0.6 |
| DECLARE TIMI 5834 | Dapagliflozin 17,160 | T2DM+CV disease or high CV risk 41 | 4.2 | CV death, nonfatal MI or stroke | 0.6 7 | 8.3 –0.4 |
| GLP-1 receptor agonists | ||||||
| LEADER29 | Liraglutide 9340 | T2DM+high CV risk 81 | 3.8 | CV death, nonfatal MI or stroke | 1.9 13 | 7.7 –0.4 |
| SUSTAIN 630 | Semaglutide (sc) 3297 | T2DM+high CV risk 83 | 2.1 | CV death, nonfatal MI or stroke | 2.3 26 | 7.3 –0.8 |
| EXSCEL35 | Exenatide 14,752 | T2DM+high CV risk 73 | 3.2 | CV death, nonfatal MI or stroke | 9 0.8 | 8.1 0.5 |
| PIONEER 631 | Semaglutide (oral) 3183 | T2DM+high CV risk 85 | 1.3 | CV death, nonfatal MI or stroke | 1.0 21 | 8.7 –0.7 |
| HARMONY32 | Albiglutide 9463 | T2DM+CV disease 100 | 1.6 | CV death, nonfatal MI or stroke | 2.0 22 | 8.7 –0.5 |
| REWIND33 | Dulaglutide 9901 | T2DM+high CV risk 31 | 5.4 | CV death, nonfatal MI or stroke | 1.4 12 | 7.3 –0.6 |
CV: cardiovascular; MI: myocardial infarction; T2DM: type 2 diabetes; sc: subcutaneous. An explanation of the study acronyms is given above.
An overview of pertinent characteristics of outcome trials with sodium-glucose-transporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists.
| Trial (ref no) | Compound vs placebo (patients no) | Patient characteristics with CV disease (%) | Median follow-up (years) | Primary endpoint | Risk reduction (%) absolute and relative | HbA1c (%) at baseline Reduction |
|---|---|---|---|---|---|---|
| SGLT-2 inhibitors | ||||||
| EMPA-REG27 | Empagliflozin 7020 | T2DM+CV disease 100 | 3.1 | CV death, nonfatal MI or stroke | 1.6 14 | 8.0 –0.2 |
| CANVAS28 | Canagliflozin 10,142 | T2DM+high CV risk 66 | 2.4 | CV death, nonfatal MI or stroke | – 14 | 8.1 –0.6 |
| DECLARE TIMI 5834 | Dapagliflozin 17,160 | T2DM+CV disease or high CV risk 41 | 4.2 | CV death, nonfatal MI or stroke | 0.6 7 | 8.3 –0.4 |
| GLP-1 receptor agonists | ||||||
| LEADER29 | Liraglutide 9340 | T2DM+high CV risk 81 | 3.8 | CV death, nonfatal MI or stroke | 1.9 13 | 7.7 –0.4 |
| SUSTAIN 630 | Semaglutide (sc) 3297 | T2DM+high CV risk 83 | 2.1 | CV death, nonfatal MI or stroke | 2.3 26 | 7.3 –0.8 |
| EXSCEL35 | Exenatide 14,752 | T2DM+high CV risk 73 | 3.2 | CV death, nonfatal MI or stroke | 9 0.8 | 8.1 0.5 |
| PIONEER 631 | Semaglutide (oral) 3183 | T2DM+high CV risk 85 | 1.3 | CV death, nonfatal MI or stroke | 1.0 21 | 8.7 –0.7 |
| HARMONY32 | Albiglutide 9463 | T2DM+CV disease 100 | 1.6 | CV death, nonfatal MI or stroke | 2.0 22 | 8.7 –0.5 |
| REWIND33 | Dulaglutide 9901 | T2DM+high CV risk 31 | 5.4 | CV death, nonfatal MI or stroke | 1.4 12 | 7.3 –0.6 |
| Trial (ref no) | Compound vs placebo (patients no) | Patient characteristics with CV disease (%) | Median follow-up (years) | Primary endpoint | Risk reduction (%) absolute and relative | HbA1c (%) at baseline Reduction |
|---|---|---|---|---|---|---|
| SGLT-2 inhibitors | ||||||
| EMPA-REG27 | Empagliflozin 7020 | T2DM+CV disease 100 | 3.1 | CV death, nonfatal MI or stroke | 1.6 14 | 8.0 –0.2 |
| CANVAS28 | Canagliflozin 10,142 | T2DM+high CV risk 66 | 2.4 | CV death, nonfatal MI or stroke | – 14 | 8.1 –0.6 |
| DECLARE TIMI 5834 | Dapagliflozin 17,160 | T2DM+CV disease or high CV risk 41 | 4.2 | CV death, nonfatal MI or stroke | 0.6 7 | 8.3 –0.4 |
| GLP-1 receptor agonists | ||||||
| LEADER29 | Liraglutide 9340 | T2DM+high CV risk 81 | 3.8 | CV death, nonfatal MI or stroke | 1.9 13 | 7.7 –0.4 |
| SUSTAIN 630 | Semaglutide (sc) 3297 | T2DM+high CV risk 83 | 2.1 | CV death, nonfatal MI or stroke | 2.3 26 | 7.3 –0.8 |
| EXSCEL35 | Exenatide 14,752 | T2DM+high CV risk 73 | 3.2 | CV death, nonfatal MI or stroke | 9 0.8 | 8.1 0.5 |
| PIONEER 631 | Semaglutide (oral) 3183 | T2DM+high CV risk 85 | 1.3 | CV death, nonfatal MI or stroke | 1.0 21 | 8.7 –0.7 |
| HARMONY32 | Albiglutide 9463 | T2DM+CV disease 100 | 1.6 | CV death, nonfatal MI or stroke | 2.0 22 | 8.7 –0.5 |
| REWIND33 | Dulaglutide 9901 | T2DM+high CV risk 31 | 5.4 | CV death, nonfatal MI or stroke | 1.4 12 | 7.3 –0.6 |
CV: cardiovascular; MI: myocardial infarction; T2DM: type 2 diabetes; sc: subcutaneous. An explanation of the study acronyms is given above.
Although the mechanisms behind the effects are not fully understood, an important reason for the benefits of SGLT-2 inhibitors seems be a reduction in heart failure while GLP-1 receptor agonists may retard the development of atherosclerotic vascular disease or perhaps help in stabilising atherosclerotic plaques. An important task is to incorporate the findings of these outcome trials into clinical practice. In a recent consensus report by the American Diabetes Association and the European Association for the Study of Diabetes it is stated that, after first-line therapy with a comprehensive lifestyle and metformin, an SGLT-2 inhibitor is recommended in people with T2DM with or prone to develop heart failure, whereas a GLP-1 receptor agonist or a SGLT-2 inhibitor with proven cardiovascular benefit is recommended in those with progressive atherosclerotic CVD.36 In the 2019 ESC guidelines on diabetes, prediabetes and CVD, SGLT-2 inhibitors and GLP-1 receptor agonists are recommended as the first-line glucose-lowering options in drug-naïve patients and as second-line treatment after metformin in T2DM patients with established atherosclerotic CVD or in people at high or very high CV risk (target organ damage or multiple risk factors) regardless of HbA1c target.12 This represents a paradigm shift away from a glucocentric towards a cardioprotective management approach with the implication that SGLT-2 inhibitors and GLP-1 receptor agonists are seen primarily as cardiovascular-protective drugs with antihyperglycaemic effects. The latter can not, however, be the key to cardiovascular protection since many other glucose-lowering drugs have more profound antihyperglycaemic effects without exerting any cardiovascular protection.
Blood pressure
It has been estimated that 60–80% of people with T2DM have an elevated blood pressure.37 Overweight/obesity and renal involvement may be at least partial reasons for this high prevalence. The combination is prognostically unfavourable by increasing the risk for CVD about four-fold.38 When a cohort of 34,000 Swedish patients aged 35 years or older with T2DM, but free of CVD, was followed between 1999–2008, 19% had a first cardiovascular event and 18% died.39 The association between annually updated systolic and diastolic blood pressure and risk of major events was U-shaped with the lowest cardiovascular risk at a systolic pressure of 135–139 mm Hg and a diastolic pressure of 74–76 mm Hg. The lowest mortality risk was seen with systolic pressures between 142–150 mm Hg and 78–79 mm Hg, respectively. According to a meta-analysis of randomised trials in patients with T2DM, impaired fasting glucose and or impaired glucose tolerance, a lowering of the systolic pressure to <135 mm Hg is not worthwhile.40 This finding gained support from another meta-analysis according to which cardiovascular mortality increased if the blood pressure was targeted where <140 mm Hg.41 The 2019 European guidelines for the management of diabetes, prediabetes and CVD provide the following recommendations for patients with T2DM:12 antihypertensive drug treatment is recommended when office blood pressure is >140/90 mm Hg. The systolic blood pressure target should be 130 mm Hg in patients with DM and <120–129 mm Hg if tolerated, but not <120 mm Hg. In older people (>65 years), the systolic blood pressure goal is in the range of 130–139 mm Hg. The diastolic BP target is <80 mm Hg but not <70 mm Hg.
All classes of blood pressure-lowering drugs can be used in patients with T2DM. Renin–angiotensin system blockers (angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs)) should be preferred, especially in the presence of proteinuria or microalbuminuria. It is recommended to initiate treatment with a combination of a renin-angiotensin-system blocker and a calcium channel blocker or thiazide/thiazide-like diuretic. The choices of drugs for individuals should take co-morbidities into account. Both ACEis or ARBs are effective antihypertensive drugs. In a pooled analysis of 20 morbidity-mortality trials, with at least two-thirds of 158,998 patients diagnosed with hypertension, renin-angiotensin blockers were associated with a 7% reduction in cardiovascular mortality.42 This effect was entirely confined to patients treated with ACEis (HR 0.90, 95% CI, 0.84–0.97) while no mortality difference was seen in patients on ARBs (HR 0.99, 95% CI, 0.94–1.04), a significant difference (p-value for heterogeneity 0.036). These findings gained support from a recent meta-analysis by Salvador et al.43 based on 17 prospective studies of which 12 were assigned to ARB therapy (n = 24,697) and five to ACEi therapy (n = 12,170). ACEis and ARBs were similar in the prevention of acute myocardial infarction, stroke and heart failure hospitalisation while the use ACEis was more effective than ARBs in reducing total and cardiovascular mortality. These findings favour initiation of renin–angiotensin system blockade with an ACEi and the use of ARB if the former compound causes side effects e.g. cough.
Simultaneous administration of two blockers of the renin–angiotensin system should be avoided in patients with DM according to the results of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) in which such combination was associated with more adverse events.44
Blood lipids
T2DM is frequently associated with dyslipidaemia. It may be overlooked if total serum cholesterol alone is measured since low-density lipoprotein cholesterol (LDL-C) may remain in the normal range. The typical pattern of dyslipidaemia in patients with T2DM is a combination of high serum triglycerides, low high-density lipoprotein cholesterol (HDL-C), with an accumulation of small, dense highly atherogenic LDL-C particles.45 A meta-analysis of the association between LDL-C and cardiovascular risk in people with T2DM reported that LDL-C is an independent risk factor for incident CVD and mortality.46 Statin therapy is very effective in the prevention of CVD in T2DM.47 In a meta-analysis including 18,686 people with T2DM a 1 mmol/l reduction of LDL-C caused a 9% reduction of all-cause mortality and a 21% reduction in major vascular events. The benefit was similar to that seen in people without DM, and was seen at LDL-C levels as low as 2.6 mmol/l. Concerns have been raised due to reports that statins may increase the risk of T2DM by 9%.47 Although such risk exists it is by far outweighed by the beneficial effects of statin therapy.48
The lowering of LDL-C with newer classes of drugs is also beneficial for patients with T2DM. Ezetimibe, a selective cholesterol absorption inhibitor, results in incremental lowering of LDL-C as well as improved cardiovascular prognosis when added to simvastatin.49 Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors induce a very efficient LDL-C lowering (up to 60%) and have shown cardiovascular benefit in large clinical trials including patients with T2DM.50,51
The 2019 European guidelines for the management of diabetes, pre-diabetes and CVD12 provide the following recommendations: an LDL-C target of <2.5 mmol/l (<100 mg/dl) in patients at moderate cardiovascular risk, an LDL-C target of <1.8 mmol/l (<70 mg/dl) or an LDL-C reduction of at least 50% in patients at high cardiovascular risk and an LDL-C target of <1.4 mmol/l (<55 mg/dl) or an LDL-C reduction of at least 50% in patients at very high risk. The use of drugs that increase HDL-C to prevent CVD is discouraged.
Platelet stabilisation
The general principles for platelet stabilisation are similar for patients with and without DM. Thus, primary prevention with aspirin is not recommended in patients at moderate cardiovascular risk while it may be considered in patients at high or very high risk without contraindications. In secondary prevention, i.e. in patients with CVD, aspirin at a low-dose (75–160 mg) should be used.12 The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial revealed that the combination of aspirin (100 mg once daily) and rivaroxaban (2.5 mg twice daily) reduced the primary endpoint, a composite of cardiovascular death, stroke or myocardial infarction, compared with aspirin only (HR 0.76; 95% CI, 0.66–0.86; p < 0.001) in patients with stable atherosclerotic vascular disease of whom 38% had diabetes.52 The impact of the combined platelet stabilisation was similar in this group to the total study population and the combination of low-dose aspirin with low-dose rivaroxaban can therefore be considered in patients with T2DM and atherosclerotic vascular disease, without known bleeding risk. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) recruited patients with T2DM above the age of 50 years with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of coronary angioplasty or coronary artery bypass grafting, or an angiographic stenosis ≥50% in at least one coronary artery with a composite of cardiovascular death, myocardial infarction or stroke as the primary endpoint. The main outcome of this trial was that the benefits of adding ticagrelor to aspirin in terms of reduced ischaemic events did not outweigh the bleeding risk. There did, however, appear to be a net clinical benefit of ticagrelor in the subgroup with a previous percutaneous coronary intervention.53
The impact of multifactorial management
Multifactorial treatment, defined as a simultaneous management of all trackable risk factors i.e. lifestyle adaptation together with glycaemic, blood pressure and lipid control and, if indicated, platelet stabilisation by the use of evidence-based combinations of pharmacological agents, is mandatory for successful cardiovascular prevention of complications in patients with dysglycaemia. One of the first observations on the efficacy of a multifactorial risk factor management was reported from the Euro Heart Survey on diabetes and the heart.54 The impact of evidence-based medication on mortality and cardiovascular events was examined in 3488 patients, 2063 (59%) without and 1425 (41%) with T2DM. Evidence-based medication consisted of the combined use of renin-angiotensin-aldosterone system inhibitors, beta-blockers, antiplatelets and statins that were administered to 44% of the patients with T2DM. In these patients, evidence-based treatment had an independent protective effect on one-year mortality (HR 0.37, 95% CI, 0.20–0.67; p = 0.001) and on cardiovascular events (0.61, 95% CI, 0.40–0.91; p = 0.015). In a recent Swedish cohort study, 271,174 patients with T2DM registered in the Swedish National Diabetes Register were matched with 1,355,870 controls on the basis of age, sex and county.55 Patients and controls were assessed according to age categories and the presence of five risk factors (elevated HbA1c, elevated low-density lipoprotein cholesterol level, albuminuria, smoking and elevated blood pressure). During a median follow-up of 5.7 years the excess risk of outcomes decreased stepwise for each risk-factor variable within the target range. The HR for death from any cause, as compared with controls, was 1.06 (95% CI, 1.00–1.12). The corresponding HR for acute myocardial infarction was 0.84 (95% CI, 0.75–0.93) and for stroke 0.95 (95% CI, 0.84–1.07). The risk of hospitalisation for heart failure was consistently higher among patients with T2DM than among controls (HR 1.45; 95% CI, 1.34–1.57). A HbA1c outside the target range was the strongest predictor of stroke and acute myocardial infarction while smoking was the strongest predictor of death (Figure 2).
Adjusted hazard ratios for outcomes, according to age category and number of risk-factor variables outside target ranges, among patients with type 2 diabetes, as compared with matched controls (reproduced from reference55 by permission).
CI: confidence interval; MI: myocardial infarction; yr: years (of age).
The importance of a multifactorial management of people with T2DM has not only been demonstrated in observational studies. The Steno-2 trial, which randomised 160 patients with T2DM and microalbuminuria to intensive, target-driven multifactorial therapy at a specialised clinic or to conventional care has, in a series of publications, shown the value of a comprehensive multifactorial, target-driven approach combining lifestyle counselling with strict HbA1c, blood lipid and blood pressure control. The patients in the intensive group were prescribed a combination of renin–angiotensin system inhibitors and aspirin. Even if all treatment targets were not fully met, intensively treated patients had a considerably better outcome than those offered standard care. After 7.8 years of follow-up there was a 50% reduction in micro- and macrovascular events in the intensively treated group.56 Follow-up continued for a total of 13 years. By that time, patients originally allocated to the intensively managed group had an absolute mortality reduction of 20%, and an absolute reduction of cardiovascular events of 29%57 and diabetes-related nephropathy and progression of retinopathy was substantially less prevalent. After 21 years the mortality reduction had resulted in 7.9 years of gained life in the intensively treated group due to a reduction of cardiovascular mortality, as shown in Figure 3. In a recent publication,58 the trialists looked at the risk for heart failure during long-term follow-up. They concluded that intensified, multifactorial intervention during 7.8 years in patients with T2DM and microalbuminuria reduced the risk of hospitalisation for heart failure by 70% during a total of 21 years of observation (Figure 3).
Transition frequencies from entry to myocardial infarction (MI), heart failure (HF) and/or death. To the left: intensive-therapy group and to the right conventional-therapy (reproduced from reference58 by permission).
Residual risk
Although there has been a considerable improvement of the prognosis for people with atherosclerotic diseases over recent decades there is still a gap between those with T2DM, who are at higher risk, than those without dysglycaemia. This may be exemplified with data from Sweden comparing patients with T2DM with controls from the general population matched for age, sex and geographical area of living. As illustrated in Figure 4 the standardised incidence rate per 10,000 person-years decreased during the period 1998–2014 but it remains higher for those with T2DM for several measures of CVD.59
Major cardiovascular outcomes for people with type 2 diabetes mellitus (T2DM) and controls from the general population during the period 1998–2014 (reproduced from reference59 by permission). (a) Death from any cause. (b) Death from cardiovascular disease. (c) Death from coronary heart disease. (d) Hospitalization for cardiovascular disease.
This residual risk is reasonably related to two major factors. The first is a demand for improved management and the second a need for new and improved therapeutic opportunities of T2DM. Promising progress has been made as regards the second option. New glucose-lowering drugs with cardiovascular protective capacity has been launched since 2015 when the first results of major clinical trials were presented. A better understanding of their mechanisms of action and further refinement of such drugs is to be expected in the years to come. Meanwhile practising physicians and nurses with responsibility for T2DM patients have the possibility to improve their management. Experiences from the cross-sectional European EUROHEART survey60 revealed that of 2183 T2DM patients with known coronary artery disease only 60% were prescribed a combination of all four cardioprotective drugs. A blood pressure target of <140/90 mm Hg was only achieved in 54 %, a LDL-cholesterol target of >1.8 mmol/l in 28% and only 53% reached an HbA1c of 53 mmol/mol (7.0%). Thus, a considerable proportion of the patients were far from evidence-based treatment targets. The results presented in the section on the impact of multifactorial treatment should encourage increased efforts to offer patients a form of management that is already within reach while waiting for further therapeutic possibilities.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Funding
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