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INTRODUCTION
Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia due to insufficient insulin action, and it leads to abnormalities in almost the entire metabolic system [1,2]. One of the most important goals of diabetes management is to prevent the development or progression of diabetic complications [3], but it is well known that glycemic control alone is not sufficient, and indeed, multifactorial intervention is widely recommended in order to prevent not only macrovascular but also microvascular complications [3-7].
Results began to be reported from the late 1970s onwards from clinical trials examining the efficacy of multifactorial intervention, which focused mainly on primary prevention of coronary heart disease through pharmacological or non-pharmacological approaches [8], but not in the field of diabetes. Notably, a meta-analysis of these trials found no significant effect on mortality, suggesting that the benefits of multifactorial intervention could be evident only in patients at high risk, such as those with hypertension [8]. To the best of our knowledge, the Risk Factor Intervention Study is the first trial to examine the effect of multifactorial intervention on diabetes, blood pressure, lipids, and smoking, in patients with treated hypertension and an additional risk factor including diabetes. It was reported in 1994 that multifactorial intervention was associated with no reduction in mortality but with a reduction in the risk of stroke [9].
Two years before this report, the Steno-2 study was launched, the first trial to examine the effects of multifactorial intervention in patients with type 2 diabetes mellitus [10], with microalbuminuria defined as the key inclusion criterion [11,12]. This was a landmark study in the field of diabetes, despite involving only 160 participants.
Two other trials are of major interest, in that they were conducted to elucidate the role of multifactorial intervention in patients with type 2 diabetes mellitus [13,14]: the Anglo-DanishDutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care (ADDITION)-Europe [15], and the Japan Diabetes Optimal Treatment study for 3 major risk factors of cardiovascular diseases (J-DOIT3) [16], both of which recruited more than 2,000 patients with less advanced microangiopathies.
Moreover, results of two other trials were recently reported: the Nephropathy In Diabetes-Type 2 (NID-2) study [17], and Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan) [18], both recruiting a smaller number of patients with advanced microangiopathies.
Fig. 1 gives an overview of these five trials examining the efficacy of multifactorial intervention, polypharmacotherapy for multiple risk factors in combination with lifestyle modification, on ‘hard outcomes,’ i.e., cardiovascular and renal events, in patients with type 2 diabetes mellitus.
STENO-2 STUDY
In the Steno-2 study, patients with microalbuminuria were registered and randomly assigned to either conventional therapy or intensive therapy aimed at stricter multifactorial treatment targets (e.g., glycosylated hemoglobin [HbA1c] <6.5%). The primary outcome for microangiopathies during 4 years of intervention was defined as progression to macroalbuminuria, and that for macroangiopathies during 8 years of intervention was defined as a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, amputation, and revascularization (Fig. 1) [11,12].
The baseline patient characteristics in the Steno-2 study are summarized in Table 1 [11,12]. In the microangiopathy study, during a mean follow-up of 3.8 years, intensive therapy was shown to be associated with a significant risk reduction in progression to macroalbuminuria (odds ratio, 0.27; 95% confidence interval [CI], 0.10 to 0.75) [11].
In the macroangiopathy study, during a mean follow-up of 7.8 years, and major risk factors were better with statistical significance in the intensive therapy group during the intervention period, such as HbA1c (7.9% in the intensive therapy group vs. 9.0% in the conventional therapy group, the same as below) (Table 1) [12].
Event rates in the Steno-2 study are summarized in Table 1. Intensive therapy was shown to be associated with a significant risk reduction in the primary outcome (hazard ratio [HR], 0.47; 95% CI, 0.24 to 0.73), even after adjustment for baseline risk factors (HR, 0.47; 95% CI, 0.22 to 0.74) (Fig. 1) [12], while it was later reported that this had not affected morality at this point [19].
Intensive therapy was associated with a significant risk reduction in nephropathy (HR, 0.39; 95% CI, 0.17 to 0.87), retinopathy (HR, 0.42; 95% CI, 0.21 to 0.86), and autonomic neuropathy (HR, 0.37; 95% CI, 0.18 to 0.79). End-stage renal failure was reported only in the conventional therapy group (3.8%), while estimated glomerular filtration rate (eGFR) was lower by around 30 mL/min/1.73 m2 in both groups compared to baseline (Table 1). Blindness was less frequent in the intensive therapy group (1.3% vs. 8.8%). Among major adverse events, severe hypoglycemia was shown to be also less frequent in the intensive therapy group (6.3% vs. 15.0%) [12].
In subsequent sub-analyses, intensive therapy was associated with a significant risk reduction in stroke [20]. The largest effect on the cardiovascular risk calculated on the basis of the UK Prospective Diabetes Study (UKPDS) [21] was accounted for by changes in lipids among those in major risk factors [20]. Besides, intensive therapy was shown to be more cost-effective than conventional therapy [22].
Moreover, the patients were followed up even after completion of intervention with death from any cause as the primary outcome. During a mean follow-up of 13.3 years, intensive therapy was shown to be associated with a significant risk reduction in mortality (HR, 0.54; 95% CI, 0.32 to 0.89). It was associated with a significant risk reduction in other events, and nearly half of deaths were shown to be due to cardiovascular disease in the conventional therapy group, which was significantly reduced in the intensive therapy group (Fig. 2) [19].
After a median follow-up of 21.2 years, intensive therapy was shown to be still associated with a significant risk reduction in mortality (HR, 0.55; 95% CI, 0.36 to 0.83), yielding an elongation of a median survival of at least 7.9 years, as well as a significant reduction in other events [23].
In sub-analyses, intensive therapy was associated with a significant reduction in stroke [24] and heart failure [25], as well as a significant reduction in the combined renal events including mortality, with the annual eGFR decline shown to be less rapid with intensive therapy (3.1 mL/min/1.73 m2/year vs. 4.0 mL/min/1.73 m2/year) [26]. Again, intensified multifactorial intervention was shown to be associated with no increase in total costs [27].
ADDITION-EUROPE
ADDITION-Europe examined the effects of multifactorial intervention on macrovascular complications and mortality in patients with screening-detected type 2 diabetes mellitus (Fig. 1) [15,28-31], who were randomly assigned to either routine care or intensive treatment following the Steno-2 study [12], with the primary outcome defined as a composite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation.
The baseline patient characteristics are summarized in Table 1 [15,32,33]. Major risk factors were slightly improved without statistical significance in the intensive treatment group during the intervention period, such as HbA1c (6.6% vs. 6.7%) (Table 1) [15], showing the feasibility of risk factor control in patients with screening-detected diabetes [34].
Event rates during the mean follow-up of 5.3 years are summarized in Table 1 [15]. Intensive treatment was shown to be associated with a non-significant risk reduction in the primary outcome (HR, 0.83; 95% CI, 0.65 to 1.05) (Fig. 1) and in morality (HR, 0.91; 95% CI, 0.69 to 1.21), with no increase reported in adverse events including hypoglycemia [15].
In subsequent sub-analyses, intensive treatment was associated with a non-significant reduction not only in the first event but also in any events of the primary outcome [35]. It was associated with no reduction in nephropathy, retinopathy, or neuropathy, with the eGFR value shown to be rather elevated compared to baseline in both groups compared to the baseline [32].
Intensive treatment was associated with an improvement in aortic stiffness [36], but not in peripheral neuropathy [37], cardiac autonomic neuropathy [38], peripheral arterial disease [37], or cognitive function [39]. It was not shown to be cost-effective [40], with only slight changes shown in psychological outcomes [41-43], although glycemic control was associated with diabetes-specific quality of life [44]. It was also reported that screening for diabetes per se was not associated with a reduction in mortality [45].
Moreover, the patients were followed up even after completion of intervention. During a mean follow-up of 9.61 years, intensive treatment was associated with a risk reduction, albeit non-significant, in the primary outcome (HR, 0.87; 95% CI, 0.73 to 1.04) and in morality (HR, 0.90; 95% CI, 0.76 to 1.07). Nearly half of deaths were due to malignant neoplasms in both groups (Fig. 2) [33]. A subsequent sub-analysis showed that intensive treatment did not affect psychological outcomes [46].
J-DOIT3
The J-DOIT3 examined the effects of multifactorial intervention on macrovascular complications and mortality in patients with type 2 diabetes mellitus (Fig. 1) [16,47], as one of the programs comprising the strategic research, Japan Diabetes Outcome Intervention Trial, launched by the Ministry of Health, Labor and Welfare (MHLW) [48]. The J-DOIT3 was aimed at a 30% reduction in diabetic complications, whereas the JDOIT1 was focused on conversion of impaired glucose tolerance to diabetes [49], and the J-DOIT2 was on dropout from diabetes treatment [50], respectively.
In the J-DOIT3 study, patients with type 2 diabetes mellitus with hypertension and/or dyslipidemia were registered and randomly assigned to either conventional therapy or intensive therapy for stricter multifactorial treatment targets (e.g., HbA1c <6.2%), with the primary outcome defined as a composite of myocardial infarction, stroke, revascularization, and all-cause mortality [16,47].
The baseline patient characteristics are summarized in Table 1 [16,51]. Major risk factors were significantly improved in the intensive therapy group during the intervention period, such as HbA1c (6.79% vs. 7.20%) (Table 1) [16,51].
Event rates during the median follow-up of 8.5 years are summarized in Table 1 [16]. Intensive therapy was shown to be associated with a non-significant risk reduction in the primary outcome (HR, 0.81; 95% CI, 0.63 to 1.04), which was statistically significant after adjustment for baseline risk factors (HR, 0.76; 95% CI, 0.59 to 0.99) (Fig. 1). It was associated with a significant risk reduction in cerebrovascular events in a post hoc breakdown (HR, 0.42; 95% CI, 0.24 to 0.74) [16], and also with a significant risk reduction in the secondary outcomes, i.e., nephropathy events (HR, 0.68; 95% CI, 0.56 to 0.82) [16,51], and retinopathy events (HR, 0.86; 95% CI, 0.74 to 1.00) [16], with end-stage renal failure reported only in the conventional therapy group (0.4%) and no blindness reported in either group [16].
Although the incidence of any hypoglycemia was higher in the intensive therapy group (41% vs. 22%), the incidence of severe hypoglycemia was quite low in both groups (0.6% and 0.3%) during the intervention period. More than half of deaths were due to malignant neoplasms in both groups (Fig. 2) [16].
In subsequent sub-analyses, glycemic control was associated with onset of nephropathy, and blood pressure control was associated with progression of eGFR decline, with the annual eGFR decline less than 2 mL/min/1.73 m2/year in both groups during the first 3 years [51]. Intensive therapy did not lead to an elevate risk in fractures [52].
NID-2
In the NID-2 study, patients with type 2 diabetes mellitus with micro- or macroalbuminuria and severe retinopathy were registered and randomly assigned to either standard of care or multifactorial intensive therapy involving the same treatment targets (e.g., HbA1c <7%), with a history of myocardial infarction or stroke as one of the exclusion criteria. The primary outcome was defined as a composite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, amputation, and revascularization [17,53].
The baseline patient characteristics are summarized in Table 1. Major risk factors were significantly improved in the multifactorial intensive therapy group during the intervention period, e.g., HbA1c (6.9% vs. 7.4%) (Table 1) [17].
Mortality rates during intervention for a median of 3.40 and 3.84 years in the standard of care group and the multifactorial intensive therapy group, respectively, are shown in Table 1. Multifactorial intensive therapy was shown to be associated with a significant risk reduction in the primary outcome during the intervention period (HR, 0.28; 95% CI, 0.13 to 0.63) (Fig. 1), although it was just an additional secondary outcome because the follow-up for the primary analysis was continued even after intervention was terminated until a sufficient number of events were reported [17].
eGFR was shown to be mildly declined in both groups (Table 1). Among adverse events, hyperkalemia and eGFR decline by 30% were shown to be more frequent, albeit non-significantly, in the multifactorial intensive therapy group (10% vs. 5% and 16% vs. 9%, respectively), possibly due to more frequent concurrent use of renin-angiotensin system blockers, while end-stage renal failure was reported in both groups (3.4% vs. 2.7%) [17].
After almost an additional decade of follow-up after the end of intervention, during the median follow-up of 13.0 years in total, multifactorial intensive therapy was shown to be associated with a significant risk reduction in the primary outcome (HR, 0.49; 95% CI, 0.35 to 0.69), and in mortality (HR, 0.58; 95% CI, 0.34 to 0.98), as well as in myocardial infarction and stroke [17].
Some other analyses were performed before the end of follow-up, and albuminuria and eGFR at baseline were shown to be associated with the risk of cardiovascular events [54], and HbA1c was also shown to be positively associated with the risk after adjustment for aspirin or statin use and other risk factors [55,56].
DNETT-JAPAN
In the DNETT-Japan, patients with type 2 diabetes mellitus with macroalbuminuria and elevated serum creatinine were registered and randomly assigned to either conventional treatment or multifactorial intensive treatment for stricter multifactorial treatment targets (e.g., HbA1c <6.2%), with a history of recent myocardial infarction or stroke as one of the exclusion criteria. The primary outcome was defined as a composite of end-stage renal failure, doubling of serum creatinine or death [18,57].
The baseline patient characteristics are summarized in Table 1. Major risk factors showed no significant between-group differences during the intervention period, e.g., HbA1c (6.86% vs. 6.94%) (Table 1) [18].
Mortality rates during the median follow-up of 3.11 years are shown in Table 1. Multifactorial intensive treatment was shown to be associated with a non-significant risk reduction in the primary outcome (HR, 0.69; 95% CI, 0.43 to 1.11) (Fig. 1). It was not associated with a reduction in cardiovascular events (HR, 0.56; 95% CI, 0.19 to 1.64), end-stage renal failure (HR, 0.77; 95% CI, 0.31 to 1.86), or mortality (HR, 0.54; 95% CI, 0.10 to 2.97) [18].
eGFR was shown to have declined by around 10 mL/min/1.73 m2 in both groups (Table 1). Severe adverse events were not increased in the multifactorial intensive treatment group [18]. It was also shown that, low-density lipoprotein cholesterol (LDL-C) during the intervention was associated with the risk of the primary outcome after adjustment with baseline characteristics [18].
OTHER TRIALS
Intensive multifactorial therapy was shown to be feasible with less frequent hypoglycemia [58], with the improved risk factor profile shown to be sustained even after the end of intervention [59]. It suppressed progression of the intima-media thickness of the carotid artery in patients with short-duration type 2 diabetes mellitus [60-62], and those with type 2 diabetes mellitus and at least two insufficient risk factors [63]. It also delayed onset of microalbuminuria in patients with short-duration type 2 diabetes mellitus [64]. Moreover, intensive multifactorial therapy by structured care including administration of a renin-angiotensin system blocker showed no effect on renal outcomes in patients with elevated serum creatinine, but addressing multiple targets led to a risk reduction in the renal outcome [65]. Intensive multifactorial therapy for stricter targets in the elderly with a mean age over 70 years did not affect fatal or nonfatal events without inter-group difference in risk factors [66].
PERSPECTIVE
Overall, intensified multifactorial intervention is shown to be associated with risk reductions in micro- and macrovascular complications, which are shown to be significant in some trials and non-significant in others.
As summarized in Table 1, the background patient characteristics are shown to vary among the trials, with HbA1c and eGFR, for instance, shown to be higher in the Steno-2 study than in the other four trials (Table 1). Thus, the study results might not apply to patients with microalbuminuria, but with better glycemic control and without glomerular hyperfiltration, in a ‘straight forward’ manner, although they could possibly be ‘extrapolated’ to these patients as well.
Although risk factor targets were not fully achieved in the Steno-2 study, as was pointed out previously [67], those are shown to have been generally well controlled in the trials launched after 2000, with the mean HbA1c shown to be less than 7% in the intervention groups in all trials, as well as in the control groups in the ADDTION-Europe and the DNETT-Japan. The mean systolic blood pressure was less than 130 mm Hg even in the conventional therapy group in the J-DOIT3, and the mean LDL-C was less than 100 mg/dL even in the routine care group in the ADDITION-Europe (Table 1). This could be due to recent advances in diabetes care resulting in low event rates during intervention [68]. The incidence of the primary outcome in the ADDITION-Europe was lower than expected on the basis of the preceding UKPDS, which was initiated in the late 1970s [69]. The incidences of myocardial infarction and stroke in the J-DOIT3 were almost half or less of those observed in the Japan Diabetes Complications Study [70], a preceding clinical trial initiated in the mid 1990s [16]. The mortality rate in the J-DOIT3 is also deemed to be much lower than those in recent surveys in the general population [71].
Still there remain several issues to be addressed, and first, the long-term effects of multifactorial intervention on vascular complications and mortality should be further evaluated [68,72], given that the potential benefits of intensive multifactorial therapy may become more evident during a long-term follow-up, as in the UKPDS, the Steno-2 study, and the 10-year follow-up of the Veterans Affairs Diabetes Trial (VADT) [19,73,74], while any observed benefits could be seen to fade, as in the 15-year follow-up of the VADT [75].
Given the mean patient age of around 60 years in these trials, it is also important to examine the effects of intensive multifactorial intervention in younger patients [71], as well as in elderly patients, as they were not included in many of the clinical trials conducted to date, with some exceptions [66], possibly due to low event rates in younger patients and susceptibility to adverse events in elderly patients. Retrospective real-world data may complement prospective clinical trials and provide us with insight into the effects of intensified multifactorial intervention in these patients, although it should also be noted that adverse events are carefully monitored in clinical trials but are not necessarily analyzed in retrospective cohort studies [76,77]. Especially in elderly patients with diabetes, the treatment would be better to be individualized rather than uniformly intensified on the basis of their prognosis and preferences [78].
Moreover, intensive multifactorial intervention using the so-called new classes of antidiabetic drugs, e.g., dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, may contribute to better and safer glycemic control [68]. In the J-DOIT3, in which intervention was continued until as recently as March, 2016, DPP-4 inhibitors were administered in over half of its participants at the end of intervention, but the use of GLP-1 receptor agonists or SGLT2 inhibitors remained still less common [16], while the latter two drugs are expected to show beneficial effects on cardiovascular and renal events [79,80].
Furthermore, while the mortality rate was lower in the J-DOIT3 study than in the others [16,71], it is deemed important to assess the effects of intensive therapy on all-cause mortality. In the Steno-2 study, almost half of deaths were due to cardiovascular disease in the conventional therapy group, but in the ADDITION-Europe, nearly half of deaths were due to malignant neoplasm and less than a quarter of them were due to cardiovascular disease in both groups. Again, in the JDOIT3 study, over half of deaths in both groups were due to malignant neoplasm, whereas 15% of deaths in the conventional therapy group and only 4% of deaths in the intensive therapy group were due to cardiovascular disease, although direct comparisons are difficult between these three trials, due to differences in baseline characteristics, e.g., age, race, sex, and duration of diabetes, and course of treatment (Table 1, Fig. 2). Cardiovascular deaths have also been relatively decreased in the general population with diabetes, accounting for over onethird, around a quarter, and just 15% of all deaths in the United States [81], the United Kingdom [82], and Japan [83], respectively. Indeed, deaths from malignant neoplasm are almost equivalent to those from cardiovascular deaths in the United Kingdom [82], and over twice as frequent as those from cardiovascular deaths in Japan [83]. Thus, it is increasingly important to focus on how best to achieve further risk reductions not only in micro- and macrovascular complications but also in diseases whose risks are increased by diabetes, such as malignant neoplasm, frailty and dementia, thereby decreasing all-cause mortality in patients with type 2 diabetes mellitus.
Lastly, it is essential to clarify the contribution of each risk factor targeted in multifactorial intervention to events and to what extent it should be controlled. Classically, it was assumed based on epidemiological findings that the contribution of risk factors to events, especially macroangiopathies, vary from one risk factor to the next, e.g., lipids largely affect coronary heart disease, blood pressure affects stroke, and hyperglycemia affects amputation [10,84].
Although the Steno-2 study suggested the importance of lipid control over glycemic control [20], recently, growing attention has been focused on the impact of glycemic control on cardiovascular events. A meta-analysis of classical five trials showed that intensive glycemic control was associated with a significant reduction in nonfatal myocardial infarction and coronary heart disease, but not in stroke and morality [85]. More patients receiving intensive glycemic control were shown to experience hypoglycemia in these trials [85], thus raising their risk of cardiovascular events and mortality [86]. An analysis of these five and more than 10 additional trials showed that differential glycemic exposure (% HbA1c×years) was negatively correlated with reductions in cardiovascular risk [87], suggesting that it could be effective to maintain good glycemic control for a longer duration to prevent cardiovascular events. Similarly, an analysis of more recent 15 trials treating patients with type 2 diabetes mellitus with DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors, all of which are considered to be associated with a low risk of hypoglycemia, showed that differential glycemic control was significantly correlated with a risk reduction in cardiovascular events and nonfatal stroke, irrespective of the class of drugs, but not in nonfatal myocardial infarction [88]. The 8-year data of the NID-2 study stated above also seem to suggest the importance of glycemic control in the prevention of cardiovascular events [55,56].
Further analyses are expected to clarify how intensive glycemic control without involving an increase in hypoglycemia, which might have been difficult to achieve and analyze, in combination with multifactorial intervention for other risk factors, could contribute to reductions in risk of cardiovascular events and mortality. The treatment target for HbA1c as well as those for other risk factors should be also explored, as they could differ depending on the event of interest.
CONCLUSIONS
Intensified multifactorial intervention for major risk factors, e.g., HbA1c, blood pressure, and lipids, is expected to reduce the risk of not only macroangiopathies but also microangiopathies in patients with type 2 diabetes mellitus. Multifactorial intervention needs to be examined for its effects over a longer duration and in younger or elderly patients, and new classes of antidiabetic drugs are expected to augment the treatment benefits. Given the recent relative decrease in cardiovascular deaths, it remains to be addressed whether intensified multifactorial intervention could reduce the risk of all-cause mortality over the long-term. Moreover, multifactorial intervention should be further optimized by clarifying how the risk of individual events may be affected by control of HbA1c and other individual risk factors.
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