Unexplained Residual Risk In Type 2 Diabetes: How Big Is The Problem?

Abstract

Purpose of Review

What is new? Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes (T2D) individuals. Of the major risk factors for CVD, less than 10% of T2D people meet the American Diabetes Association/American Heart Association recommended goals of therapy. The present review examines how much of the absolute cardiovascular (CV) risk in type 2 diabetes patients can be explained by major CV intervention trials.

Recent Findings

Multiple long-term cardiovascular (CV) intervention trials have examined the effect of specific target-directed therapies on the MACE endpoint. Only one prospective study, STENO-2, has employed a multifactorial intervention comparing intensified versus conventional treatment of modifiable risk factors in T2D patients, and demonstrated a 20% absolute CV risk reduction.

Summary

If the absolute CV risk reduction in these trials is added to that in the only prospective multifactorial intervention trial (STENO-2), the unexplained CV risk is 44.1%.

Introduction

Type 2 diabetes (T2D) is a major health care problem in the US, affecting approximately 37 million Americans or ~ 10% of the adult population, and for every person with T2D, there ~ 2 individuals with prediabetes [1]. Cardiovascular disease (CVD) is the leading cause of mortality in T2D individuals and in the US it accounts for approximately half of the deaths [2, 3]. The risk of myocardial infarction (MI), stroke, heart failure (HF), and peripheral vascular disease (PVD) is increased 2.5–fourfold in people with diabetes [4, 5] and diabetes is the leading cause of chronic kidney disease (CKD) [6, 7], which is an independent risk factor for CVD [8–10]. Of the major risk factors for macro- and microvascular disease, including hypertension, hypercholesterolemia, and HbA1c, less than 20% of adult T2D individuals meet all ADA/AHA recommended goals of therapy [11]. If obesity (BMI < 27.5 kg/m²) is included, this percentage drops to 6.8% [11]. Multiple large, long-term cardiovascular outcome trials have been carried to examine the effect of treatment of known cardiovascular risk factors on MACE (major adverse cardiovascular events) and other combined cardiovascular endpoints. Most of these studies report the headline results as the relative risk reduction. However, in all of these studies the absolute risk reduction can be determined from the published data. In the present review, we present a summary of the results for the absolute risk reduction in these major clinical trials in order to provide an estimate of the unexplained or residual cardiovascular risk, followed by a discussion of the limitations inherent in these studies and factors that may contribute to the residual absolute risk.

Multifactorial Intervention for CVD

Only one previous prospective study, STENO-2, has employed a multifactorial intervention comparing intensified versus conventional treatment of modifiable risk factors in T2D patients [12••, 13]. In STENO-2 microalbuminuria was included in the entry criteria because it is an independent risk factor for cardiovascular disease [14]. Optimal therapy for modifiable CV risk factors according to the AHA [15] and ADA [16] are shown in Table 1 and achievement of these goals in STENO-2 is shown in the juxtaposed column. In STENO-2 blood pressure was well controlled (132/73 mmHg) with antihypertensive therapy and was close to the goal observed in SPRINT, albeit SPRINT did not include diabetic patients [17]. Plasma triglyceride and HDL concentrations in STENO-2 were close to recommended goals and all participants were on aspirin therapy. LDL cholesterol, HbA1c and BMI (shaded boxes) were suboptimally controlled (Table 1). Insulin resistance (HOMA-IR) was not measured, but both the fasting plasma glucose and C-peptide concentrations declined significantly, indicating an improvement in insulin sensitivity. Microalbuminuria decreased significantly in the intensively treated group. hsCRP was not measured in STENO-2. The primary endpoint (nonfatal MI, nonfatal stroke, CV death, coronary bypass or PCI, amputation or surgery for PAD) decreased significantly in the intensive versus conventional treatment group (HR = 0.47; 95% CI = 0.24, 0.73; p = 0.008) (Fig. 1). Significant reductions in most microvascular endpoints also were observed (neuropathy, HR = 0.39; p = 0.003; retinopathy, HR = 0.42, p = 0.02; autonomic neuropathy, HR = 0.37, p = 0.002; peripheral neuropathy, HR = 1.09, p = 0.66).

Table 1.

Guideline recommended cardiovascular goals and values achieved in STENO-2. Shaded areas represent values achieved in STENO-2. Values in parentheses represent optimal goals beyond those recommended in guidelines. Shaded numbers represent guideline-direct goals that were not achieved in Steno-2.

	Guideline
	Recommended	STENO-2
(1) Hypertension	< 130/80	132/73
(2) LDL Cholesterol (mg%)	< 70 (< 50)	86
(3) Triglycerides (mg%)	< 150	154
(4) HDL Cholesterol (mg%)	> 50	46
(5) HbA1c (%)	< 6.5 (5.7%)	7.9
(6) BMI (kg/m2)	< 27.5 (< 25)	28.6
(7) Insulin Resistance (HOMA-IR)	< 1.5	not measured
(8) Hyperinsulinemia (uU/ml)	< 10	13% ↓*
(9) hsCRP (mg/L)	< 1.0	not measured
(10) Prothrombotic state	dual antiplatelet	all on aspirin
(11) MAFLD (% liver fat)	< 5%	not measured
(12) Physical Activity (VO2max)	none	not measured
(13) Smoking	no smoking	not measured
(14) Other - SNS, VO2max	none	not stated

^*estimated from the decline in C-peptide in Steno-2

Fig. 1.

Kaplan–Meier plot of composite cardiovascular endpoint in STENO-2 [13]

The number/percentage of CV events in the control and intensive therapy groups in STENO-2 is shown in Fig. 2. 24% of diabetes patients in the intensive-treated group experienced a cardiovascular event compared to 44% in the conventional therapy group. This 47% relative risk reduction translates to an absolute risk reduction of 20%. The absolute 20% reduction in the risk of cardiovascular events is considerably higher than that observed when single-factor intervention strategies are employed. Nonetheless, even with intensive therapy addressing multiple risk factors simultaneously, there remains a large unexplained residual risk of 80% for cardiovascular disease (Fig. 3). In the subsequent sections, the major cardiovascular risk factor intervention trials will be reviewed in an attempt to explain how much of the unexplained residual CV risk can be accounted for beyond that explained by the multifactorial intervention strategy employed in STENO-2.

Fig. 2.

Relative and absolute cardiovascular risk reduction in STENO-2 [13]

Fig. 3.

Absolute cardiovascular risk reduction explained by known cardiovascular risk factors (see text for discussion)

Hypertension

Based upon multiple antihypertensive trials, the recommended level of blood pressure (BP) control in T2D individuals is 130/80 mmHg [18, 15, 19]. However, the results of SPRINT demonstrated that intensive systolic BP lowering to < 120 mm Hg in individuals at high CV risk produced a 25% risk reduction in cardiovascular events compared with standard blood pressure lowering to < 140 mmHg. However, diabetes patients were not included in SPRINT [17] and the ACCORD BP study [20] in T2D individuals failed to demonstrate any CV benefit of intensive (< 120 mmHg) versus standard (< 140 mmHg) systolic BP lowering. The relative CV risk reduction in 5 major antihypertensive trials is shown in Supplemental Fig. 1 and averaged 21.6%. This translates to a mean absolute risk reduction of 3.47%. In STENO-2 the intensively treated group achieved a BP of 133/73 mmHg which was within the goals recommended by the AHA and the ADA. Therefore, it is unlikely that further BP reduction would have reduced CV risk beyond that observed in STENO-2; consequently, nothing has been added to the unexplained CV risk depicted in Fig. 3.

Cholesterol and Non-Cholesterol Lipids

For most patients with diabetes who otherwise are healthy, the recommended LDL-cholesterol goal should be < 100 mg/dl. For T2D patients with CV risk factors the LDL goal should be < 75 mg/dl, and for T2D with established CV disease a goal of < 55 mg/dl is desirable [21–24, 19]. The relative risk reduction in 10 large LDL-cholesterol lowering trials is shown in Supplemental Fig. 2 and averaged 23.4% which translates to an absolute risk reduction of 2.5%. In STENO-2 the LDL-cholesterol in statin-treated patients with multiple CV risk factors was 86 mg/dl. Thus, these individuals could benefit from high intensity statin therapy which potentially could reduce the absolute risk by an additional 2.5%. Further, in the FOURIER trial, which included 27,564 statin-treated patients with ASCVD, multiple risk factors, and an LDL > 70 mg/dl, evolocumab caused a 15% relative risk reduction in CV events which translates to a 1.5% absolute risk reduction [25]. Thus, combined high intensity statin plus a PCSK9 inhibitor potentially could account for an additional 4% absolute risk reduction (Fig. 3).

Other lipid disturbances that could contribute to increased CV risk in T2D patients disease include hypertriglyceridemia, reduced HDL-cholesterol, increased Lp(a) and ApoB, elevated plasma free fatty acids (FFA), and postprandial lipemia. Treatment with fenofibrate in the FIELD study [26] and cholesterol ester transfer inhibitors [27] failed to show any CV benefit from reducing the plasma triglyceride concentration or raising the plasma HDL cholesterol. Ongoing studies may help to define the CV risk associated with elevated Lp (a) [28] and ApoB [29] levels. No studies have examined the CV risk benefit afforded by correction of postprandial lipemia. Icosapent ethyl (IPE) in statin-treated patients with CVD or diabetes with cardiovascular risk factors (CVRFs) and elevated fasting plasma triglycerides (135–499 mg/dl) produced a 21.8% relative and 4.8% absolute CV risk reduction [30]. Although the mechanism(s) via which IPE produces its CV benefit remain unclear, we have added 4.8% to the unexplained residual risk although this could be disputed (Fig. 3).

Glycemic Control: HbA1c

Multiple studies have shown that an increase in HbA1c throughout the nondiabetic (4.4 to 6.4%) and diabetic (≥ 6.5%) range progressively increases the risk of ASCVD [31–34]. Whether the increased CV risk associated with rising HbA1c is related to glucose per se or to its associated correlation with the metabolic syndrome and underlying insulin resistance can be debated [35•]. A metaanalysis of 7 observational cohorts with 19,630 subjects demonstrated that an increase in fasting plasma glucose concentration from 90 to ≥ 125 mg/dl was associated with a relative risk increase for CV events of 39.2% in men and 37.9% in women [32]; this translates to a 4.0% increase in absolute CV risk in men and 7.4% in women (mean = 5.7% for both sexes combined). Assuming that normoglycemia can be achieved with antidiabetic therapy, this could reduce CV risk by 5.7%.

Obesity

Obesity is a major risk factor for cardiovascular mortality [36–39]. It is estimated that 62% of the US population is obese (BMI ≥ 30 kg/m²) or overweight (BMI > 27) [40]. Obesity promotes CVD directly through cardiac adaptations and indirectly by causing diabetes, hypertension, dyslipidemia, inflammation, lipotoxicity, and endothelial dysfunction. The most pronounced weight loss is produced by bariatric surgery and two large studies [41, 42] have provided long term follow up of MACE in surgically-treated obese and diabetic patients (Supplemental Fig. 3). The mean relative risk reduction in CV events in these two studies was 41.0% with a mean absolute risk reduction of 9.8%, which can be added to the unexplained CV risk in T2D patients (Fig. 3). Which of the multiple CV components of obesity and their relative contribution to MACE that are corrected by bariatric surgery contribute to the reduction in CV events is impossible to segregate. It should be noted that plasma GLP-1 levels increase markedly following bariatric surgery and GLP-1 therapy has been shown to decrease CV events in T2D patients [42]. Most recently, obese nondiabetic patients with multiple CVRFs and/or established ASCVD who were treated with the GLP-1 receptor agonist semaglutide (SELECT trial) experienced a 8.0% relative risk reduction and 1.5% absolute risk reduction in CV events in association with a mean weight loss of 9.1 kg or 9.39% of their body weight [43•]. How much of the cardiovascular benefit in SELECT [43•] could be explained by the GLP-1 receptor agonist is discussed later.

Insulin Resistance and ASCVD

In a metaanalysis of 17 large prospective studies [44], HOMA-IR (product of fasting plasma insulin and glucose concentrations) was shown to be a strong predictor of adverse cardiovascular events (HR = 1.64; 95% CI = 1.35, 2.00; p < 0.001). Insulin resistance is the underlying molecular disturbance responsible for the metabolic syndrome [35•], which is characterized by obesity (especially visceral obesity), hypertension, and dyslipidemia [35•, 45] and each of these individual components is a CV risk factors. The only true insulin sensitizing drug is pioglitazone [46] which was used in the IRIS study to treat nondiabetic (HbA1c = 5.8 ± 0.4%), insulin resistant (HOMA-IR = 4.7; range = 3.8–6.2) individuals with a recent stroke or transient ischemic attack (TIA) [47]. In the IRIS study recurrent CV events were reduced by 24%, giving an absolute risk reduction of 3.0%, which we added to the unexplained CV risk in Fig. 3. Although pioglitazone exerts multiple pleotropic effects (including amelioration of lipotoxicity, decrease in blood pressure, correction of dyslipidemia, inhibition of inflammation, and others), it is the only intervention that reduces insulin resistance directly. Since the mean HbA1c was 5.8% in IRIS, reduction of glycemia cannot explain the cardiovascular benefit [47].

Inflammation

Type 2 diabetes is characterized by a state of chronic inflammation as evidenced by an elevation in the hsCRP [48, 49]. Multiple inflammatory peptides and pathways have been shown to be increased in T2D including Ikβ/NFκB, TLR-4, TNFα, IL-1β, IL-6, MAP kinase, NLRP3 inflammasome, and others [48, 49]. In the CANTOS [50] and COLCOT [51] studies canakinumab and colchicine, respectively, reduced the relative risk of MACE in post-MI patients by 14% and 23%, and this translates to absolute risk reductions of 0.64% and 1.6%, respectively. Although modest, these two studies provide support for an important contribution of inflammation in the atherosclerotic process.

The JUPITER study [52], which examined the impact of rosuvastatin in 17,802 healthy subjects with LDL cholesterol < 130 mg/dl and hsCRP > 2.0 mg/dl is of particular note. Over a mean follow up of 1.9 years, rosuvastatin reduced the LDL from 108 to 55 mg/dl and hsCRP from 2.2 to 3.8 mg/dl, resulting in a relative risk reduction of 44% which translates to an absolute risk reduction of 12.3%. If we attribute 2.5% of the absolute risk reduction to the decline in LDL cholesterol (see Supplemental Fig. 2), this leaves 9.8% possibly related to a decrease in inflammation as implicated by the decline in hsCRP. If we take the average of the CANTOS, COLCOT, and JUPITER trials, approximately 4% of the absolute risk reduction in CV events in T2D can be attributed to inflammation (Fig. 3).

Prothrombotic State

Diabetes is a generalized prothrombotic state [53] and antithrombotic therapy has been examined in multiple studies [19]. With aspirin (Supplemental Fig. 4) the relative and absolute CV risk reductions were 8.0% and 1.6%, respectively. Similar risk reductions were observed with dual antiplatelet therapy with ticagrelor in THEMIS [54] and PEGASUS [55] and with rivaroxaban in COMPASS [56]. Thus, the prothrombotic state can account for ~ 1.6% of the unexplained CV risk in T2D patents, and this has been added to Fig. 3.

GLP-1 RAs and SGLT2i

Multiple large, double-blind prospective cardiovascular outcome trials have examined glucagon-like peptide-1 receptor agonists (GLP-1 RAs) (Supplemental Fig. 5) and sodium glucose cotransporter-2 inhibitors (SGLT2i) (Supplemental Fig. 6) in T2D patients. The mechanisms via which these antihyperglycemic drugs exert their cardioprotective effect are multiple in origin and have been reviewed in depth [57, 58]. For the GLP-1 RAs, their mean relative and absolute risk reduction are 19.9% and 1.5%, respectively (Supplemental Fig. 5). For the SGLT2i their mean and absolute CV reductions are 15.2% and 1.1% reduction, respectively. Although highly significant, the absolute CV risk reduction with these two classes of antidiabetic agents combined is modest, 2.6% (Fig. 3).

Physical Activity

Physical activity is an important determinant of cardiovascular risk [59]. In the EPIC study [60] 5,859 diabetic patients were followed for a period of 9.4 years. In this study individuals who were categorized as having poor physical fitness compared to those with good physical fitness had a 56% increase in the relative risk of experiencing a cardiovascular event, but in absolute terms the risk was only 0.35%. If the individual with low physical fitness could increase their exercise capacity to match that of the high physical fitness group, this could explain only a small amount of the unaccounted residual CV risk in T2D patients.

MASH/MAFLD

Metabolic dysfunction-associated steatohepatitis (MASH) and metabolic dysfunction associated steatotic liver disease (MAFLD) are associated with an increased incidence of cardiovascular disease [61]. However, there are no approved therapies for MASH/MAFLD other than weight loss, and it would be difficult to demonstrate a cardiovascular benefit from reversal of MASH/MAFLD above and beyond that afforded by weight loss. Whether MASH/MAFLD represents an independent CV risk factor will await the development of drugs that reverse hepatic steatosis and fibrosis with altering body weight.

Limitations

The present review has a number of limitations. First, the treatment goals for many of the cardiovascular outcome trials have changed significantly over the last 10–20 years, i.e. LDL- cholesterol and blood pressure. Second, some therapies were tested in primary prevention, while others were examined in secondary prevention. Third, the trials included different populations with different patient characteristics, varying study designs, and different endpoints. Fourth, each therapy was tested individually, excluding synergistic interactions between therapies which were directed at different targets. Five, results from structured clinical trials may not have the same impact as real world trials carried out in the community setting. Six, trials designed to treat a specific CV risk factors often impact other associated risk factors. Thus, bariatric surgery for weight loss also reduces blood pressure, corrects diabetic dyslipidemia, and increases the plasma GLP-1 concentration, while high intensity statin therapy lowers the LDL cholesterol, reduces inflammation, and decreases the plasma triglyceride level. Seven, in most studies the duration of follow-up was relatively short and continued follow-up assuredly would have increased the absolute risk reduction.

Speculation

If one simply sums up the absolute risk reduction observed in clinical trials designed to target established cardiovascular risk factors (Fig. 3), it is clear that there remains a large unexplained absolute residual risk for cardiovascular disease which approximates 36%. What can explain this gap?

Most of the cardiovascular intervention trials reviewed herein are on the order of 2–4 years in duration, and it may take much longer for the therapeutic interventions to exert their full therapeutic impact and that continued benefits will continue to accrue over time with persistent therapy. It also is possible that there remains a number of yet-to-be-discovered cardiovascular risk factors, especially at the molecular/genomic level, that exert an influence on the development of atherosclerotic cardiovascular disease. The interaction between genes and the environment remains a largely unexplored area of fertile research.

The molecular basis of atherogenesis and its relationship to cardiometabolic disease remains largely unexplored. In order for insulin to act on skeletal and vasculature smooth muscle, it must first bind to specific cell surface receptors, leading to activation of ‘second messengers’, activating a phosphorylation–dephosphorylation cascade which results in stimulation of glucose transport/phosphorylation. Importantly, a defect in the insulin signal transduction cascade, not only impairs glucose utilization, but also causes hypertension and accelerated atherosclerosis [35•]. Insulin is a potent growth factor [62, 63], whose growth-promoting effects are mediated via the mitogen-activated protein (MAP) kinase pathway [62, 63] with activation of SHC and extracellular regulated kinase (ERK) [64]. This pathway promotes cell growth, cell proliferation and cell differentiation [64], and thus plays an important role in atherogenesis. MAP kinase blockade inhibits insulin’s growth-promoting effects, but has no effect on the metabolic actions of insulin [65]. Insulin resistance in the IRS-1/PI-3 kinase/Akt (metabolic) pathway with intact MAP kinase signalling activates multiple inflammatory pathways, exacerbating the insulin resistance. Sustained physiological hyperinsulinaemia, as occurs in the prediabetic and early diabetic state, activates multiple genes involved in inflammation [66]. In type 2 diabetes individuals, inhibition of insulin signalling at the IRS-1 level leads to decreased glucose transport/phosphorylation/metabolism and, most importantly, impairs activation of nitric oxide synthase and causes endothelial dysfunction [35•]. Because the MAP kinase pathway retains its sensitivity to insulin [35•], the compensatory hyperinsulinaemia (due to insulin resistance in the IRS-1/PI-3 kinase/Akt pathway) causes excessive stimulation of this pathway, which is involved in inflammation, cell proliferation and atherogenesis. Since nitric oxide synthase also is activated by the same PI-3 kinase pathway, nitric oxide production is impaired [67], resulting in endothelial dysfunction [68] and accelerated atherosclerosis [35•, 67, 68]. Thus, at the molecular level, insulin resistance, inflammation and accelerated atherosclerosis in people are tightly linked with type 2 diabetes mellitus and may account for a significant portion of the missing CV risk that cannot be explained by previously studied cardiovascular risk factors (Fig. 4). This pathogenic sequence also explains why insulin resistance is a strong predictor of CV disease [35•, 44, 69–71].

Fig. 4.

Insulin signal transduction system is impaired in T2DM [35•]. See text for a detailed discussion

Because the adverse impact of CV risk factors starts early in life, it logically follows that any therapeutic intervention to prevent cardiovascular events should be started early in the natural history of atherosclerosis. This is well exemplified by the CARDIA study [72]. Over a 15 year period (age 25 to 40 years) 1,238 healthy subjects were evaluated every 1–2 years and plasma LDL cholesterol was measured (OBSERVATION WINDOW). At age 40 years subjects participated in a 16 year PREDICTION WINDOW during which 275 first cardiovascular events occurred. The single plasma LDL cholesterol concentration measured at age 40 was a predictor of subsequent CV events, but it was markedly outperformed by area under the LDL cholesterol curve from age 25 to 40 years. Further, when divided into quartiles, the LDL cholesterol AUC correlated strongly and linearly with the number of CV events during the PREDICTION WINDOW. These results are consistent with the hypothesis that the longer it takes to initiate the therapeutic intervention and the more established is the atherosclerotic process, the more difficult will it be to reverse or halt its progression. Thus, time can be a major contributor to the unexplained residual CV risk. A similar conclusion can be reached from the PESA study [31] in which 3,973 healthy nondiabetic subjects without clinical evidence of ASCVD were assessed by 2D IVUS and coronary artery calcium score (CACS). Over the range of HbA1c from 4.4 to 6.4%, the absence of atherosclerotic disease decreased from 53.9% to 18.0%, while the presence of intermediate/generalized atherosclerosis increased from 20.3% to 63.2%. These results suggest that severity of disease before initiation of therapy is an important determinant of the unexplained CV risk in T2D patients and why the therapeutic intervention must be started early and carried out for an extended period of time to get its full beneficial impact. Consistent with this, in the STENO-2 study, there was a continued time-related divergence in the rate of primary CV outcome between the intensive and conventional therapy groups. A provocative nationwide Swedish cohort study [73] with 20 years of follow up for guideline–based achievement of 5 major CV risk factors (HbA1c, systolic BP, LDL cholesterol, eGFR, BMI), found no excess cardiovascular risk (acute MI, coronary artery disease, cerebrovascular disease) in 679,072 diabetic individuals compared to nondiabetic controls. These results suggest that long-term maintenance with recommended goals can markedly reduce, even normalize, CV risk in T2D patients. Unfortunately, cardiometabolic risk markers were not available for control subjects, and this might explain why, for some risk factors, cardiovascular risk was less than in controls. Somewhat in contradiction to the Swedish study are the results of the Global Cardiovascular Risk Consortium [74], which evaluated individual-level data from 112 cohort studies in 34 countries including 1,518,028 participants. When five major CV risk factors (BMI, systolic BP, non-HDL cholesterol, current smoking, diabetes) were controlled, only 57.2% of the global population-attributable fraction of the 10-year incidence of cardiovascular disease could be accounted for.

Lastly, it is likely that atherogenic cardiovascular risk factors do not act in isolation with regard to their ability to promote atherogenesis and to cause clinically significant CV disease. Rather, they act additively or, more importantly synergistically, to cause heart attacks, stroke and peripheral vascular disease. Thus, correcting one specific CV risk factor without simultaneously treating all of the other associated CV risk factors compromises the impact of the therapeutic intervention. The nationwide Swedish cohort study [73] supports this concept, demonstrating that stepwise addition of five normalized major CV risk factors (HbA1c, systolic BP, LDL cholesterol, eGFR, BMI) reduces CV risk in type 2 diabetes patients to a level observed in nondiabetic control subjects. Using ultrasound to quantitate carotid intimalmedial thickness, a surrogate measure of atherosclerosis, a synergistic interaction between risk factors (systolic BP, hyperinsulinemia, increased triglycerides, decreased HDL-cholesterol, hyperglycemia, obesity) and excess carotid IMT has been demonstrated [75].

Conclusion

Despite multiple prospective long-term cardiovascular intervention trials designed to treat the known major cardiovascular risk factors (hypertension, dyslipidemia, hyperglycemia, obesity, insulin resistance, inflammation, prothrombotic state, physical inactivity), there remains a large unexplained absolute cardiovascular risk, 44.1%. It is likely that failure to take into account synergistic interactions between these major cardiovascular risk factors is responsible for the unexplained cardiovascular risk in type 2 diabetes patients. A multifactorial cardiovascular intervention trial in high CV risk diabetic individuals will be required to define the absolute residual risk after all know CV risk factors are optimally treated.

Supplementary Material

Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s11886-024-02055-0.

What are the clinical implications?

• Potential explanations for the unaccounted-for reduction in absolute CV risk in type 2 diabetes (T2D) patients are discussed.

• Hypothesis: failure to take into account synergistic interactions between major cardiovascular risk factors is responsible for the unexplained CV risk in T2D patients.

• Simultaneous treatment of all major CV risk factors to recommended AHA/ADA guideline goals is required to achieve the maximum reduction in CV risk.

Data Availability

No datasets were generated or analysed during the current study.