Metabolic syndrome, diabetes mellitus, or both and cardiovascular risk in outpatients with or at risk for atherothrombosis

Abstract

Background

The incidence of metabolic syndrome (MetS), diabetes mellitus (DM), and their coexistence is increasing but whether MetS increases cardiovascular risk beyond component risk factors is controversial.

Design

We compared the risk of cardiovascular death, myocardial infarction, or stroke among patients with MetS, newly detected DM, established DM, or coexistent MetS and DM in the global REduction of Atherothrombosis for Continued Health (REACH) registry.

Methods

Outpatients with or at risk for atherothrombosis were recruited between 1 December 2003 and 31 December 2004 and followed up to 4 years for cardiovascular events. Risk was compared in patients with or without MetS or DM after adjustment for age, sex, risk factors, vascular disease, fasting blood glucose, therapy, and region.

Results

Among 44,548 REACH participants, 17,887 (40%) were without MetS or DM; 6459 had MetS (15%); 12,059 had established DM (27%); 7503 had both (17%); and 640 had newly detected DM (1%). Presence of MetS was not associated with higher cardiovascular events (12.6%, adjusted HR 0.98, 95% CI 0.89–1.08). In addition, once DM was evident, patients with coexistent MetS had similar increased risk (16.1%, adjusted HR 1.33, 95% CI 1.21–1.47) as DM alone (16.7%, adjusted HR 1.36, 95% CI 1.24–1.48). Newly detected DM was associated with increased cardiovascular risk (18.5%, adjusted HR 1.26, 95% CI 1.02–1.57), similar to longstanding DM. MetS was associated with incident DM (adjusted OR 1.94).

Conclusions

In the REACH registry, presence of newly detected DM but not metabolic syndrome was associated with an increased risk of cardiovascular events.

Introduction

The incidence of insulin resistance manifest by diabetes mellitus (DM), metabolic syndrome (MetS), and their co-existence, is rapidly increasing worldwide.^1–4 DM is independently associated with an increased risk of developing atherothrombosis in multiple circulatory beds (coronary artery disease, CAD, cerebrovascular disease, CVD, or peripheral artery disease, PAD).^5,6 However, prior results are mixed as to whether the presence of MetS further aggravates cardiovascular risk beyond its component risk factors, above the risk of DM when coexistent, or when subclinical atherothrombosis is detected.^7–13 In addition, most studies suggest that DM of recent onset confers a lower risk than longstanding DM for long-term development of atherothrombosis.^14–16 Screening and detection of DM or MetS may offer the potential opportunity to intervene early with lifestyle modification and primary or secondary cardioprotective therapy to alter prognosis in these patients^17–21 if they are at sufficient long-term cardiovascular risk.²²

No prior report has comparatively studied the risk associated with MetS, DM, or both among an internationally diverse population of outpatients with varying cardiovascular risk factors. Therefore, we set out to determine in the global REduction of Atherothrombosis for Continued Health (REACH) Registry whether (a) MetS is independently associated with increased cardiovascular risk in patients with and without DM; and (b) whether newly detected DM is associated with similar cardiovascular risk as an established history of DM, across an international population of outpatients with or at risk for atherothrombosis.

Methods

Study population

The design of the REACH Registry has previously been described as detailed in the Supplemental Methods section.⁶ Briefly, REACH was an international cohort study of outpatients ≥45 years of age with established atherothrombosis (prior CAD, CVD, or PAD) or with ≥3 atherothrombotic risk factors between December 2003 and December 2004 and followed for up to 4 years (Supplementary Figure S1, available online). This study complied with the Declaration of Helsinki; an institutional review board approved the research protocol, and written informed consent was obtained from all subjects.

Patients were classified at baseline into five groups based on whether or not they met clinical or laboratory diagnostic criteria for MetS or DM using standardized case report forms as detailed in the Supplementary Methods. Metabolic syndrome was defined as the presence of any three of the following four criteria (Supplementary Table S1): hypertension, hypertriglyceridaemia or drug treatment for hypertriglyceridaemia or reduced high-density lipoprotein cholesterol (HDL-C), elevated fasting blood glucose (≥100 mg/dl, 5.6 mmol/l but <126 mg/dl, 7.0 mmol/l), and centripetal obesity (Supplementary Table S2). Diabetes was defined by history or use of antidiabetic drug treatment according to local standards. Patients without a history of DM and not previously on antidiabetic treatment but with a baseline fasting blood glucose ≥126 mg/dl, 7.0 mmol/l were classified as newly detected DM.³ Patients with coexistent MetS and new or established DM were categorized as having both. Patients that did not meet any of the above definitions were considered without MetS or DM.

Outcomes

At annual follow up, physicians reported subjects’ clinical outcomes determined from available clinical or hospitalization data according to local clinical practice. The primary endpoint was the four-year composite occurrence of cardiovascular death, nonfatal MI, and nonfatal stroke. Secondary endpoints included cardiovascular death, all-cause mortality, and incident DM. Cardiovascular death was defined as fatal stroke, MI, or other cardiovascular cause. Any MI or stroke followed by death in the subsequent 28 days was considered fatal. Individual components of the primary endpoint were also evaluated. Although outcomes were not adjudicated, baseline and outcome data quality was randomly and data-driven audited in person in 10% of sites to confirm source documentation accuracy.

Statistical analysis

Clinical characteristics and therapy were compared between groups using the chi-squared test for categorical variables, and F-test or Kruskal–Wallis one-way analysis of variance tests for continuous variables. Kaplan–Meier event rate curves were constructed for each group of participants. Survival time was calculated according to the date of the outcome as collected by the enrolling physicians. For patients who did not experience the event of interest, data were censored at the time of the last visit with available information. The risk of cardiovascular endpoints was estimated using Cox proportional hazard regression models to derive hazard ratios (HR) and 95% confidence interval (CI) for each patient group. Risk of incident DM was estimated using logistic regression models to derive odds ratios (OR) since exact dates of this outcome were unknown. The models were adjusted for age, sex, geographic region, history of smoking, atrial fibrillation/flutter, heart failure, vascular disease status at baseline (any prior ischaemic event, stable atherothrombosis, or risk factors only), fasting blood glucose, and baseline statin and aspirin use. To determine whether there was heterogeneity for the association of MetS or newly detected DM at baseline and cardiovascular risk by sex, race/ethnicity, or the presence of vascular disease status, we explored differential effect modification with introduction of interaction terms in the models. A test for interaction with p < 0.10 was considered statistically significant. Two-sided p-values for all other tests were calculated with p < 0.05 considered significant. Statistical analyses were performed with SAS version 9 (SAS Institute, Cary, NC, USA).

Results

Baseline characteristics

Among the 44,548 participants within the REACH registry eligible for inclusion, 13,962 (31%) patients met criteria for MetS with or without DM. Specifically, 6459 (15%) patients had MetS alone, 12,059 (27%) patients had established DM alone, 640 (1%) patients had newly detected DM, 7503 (17%) patients had both MetS and DM, and 17,887 (40%) were free of either MetS or DM at baseline. Clinical history and medication use differed significantly between baseline metabolic risk groups (Table 1). Presence of MetS tended to be more frequent in Asian countries, while established DM with or without MetS was more frequent in North America. Higher rates of newly detected DM were evident in Latin America, the Middle East, Japan, and other Asian countries.

Cardiovascular events

The 4-year cumulative event rates of patients according to baseline metabolic risk group are presented in Table 2 and Figure 1. Compared with patients free of either MetS or DM at baseline, presence of MetS was not associated with higher risk of the primary endpoint after adjustment for clinical risk factors, preexisting cardiovascular disease, fasting blood glucose, therapy, and region of dwelling (12.6 vs. 12.8%, adjusted HR 0.98, 95% CI 0.89–1.08, p = 0.67). Similarly, MetS was not associated with an increased risk of mortality or individual cardiovascular events comprising the primary endpoint (Table 2). In contrast, coexistent MetS and DM was associated with an increased risk of the primary endpoint (16.1%, adjusted HR 1.33, 95% CI 1.21–1.47, p < 0.0001), which was similar to the risk associated with the presence of DM alone (16.7%, adjusted HR 1.36, 95% CI 1.24–1.48, p < 0.0001). Specifically, there was no significant difference between the adjusted risk of the primary endpoint for patients with coexistent MetS and DM compared with established DM alone (adjusted HR 0.98, 95% CI 0.90–1.07, p = 0.72).

The presence of newly detected DM was also associated with high risk of the primary endpoint (18.5%, adjusted HR 1.26, 95% CI 1.02–1.57, p = 0.03), similar to patients with established DM (adjusted HR 0.93, 95% CI 0.75–1.15, p = 0.52 for newly detected vs. established DM). Risk adjustment for age and sex suggested that no sex-based differences in outcomes were observed (Table 2; p-interaction between metabolic risk groups and sex p = 0.11).

When the event rates and hazard associated with each group were compared according to baseline atherothrombotic risk, we observed no significant effect modification of MetS or newly detected DM among participants with a history of risk factors only or prior ischaemic atherothrombotic event, after multivariable adjustment (p-interaction = 0.94). Similarly, no significant interaction of risk was seen by race/ethnicity (p-interaction = 0.87). In further parsimonious models excluding fasting blood glucose, risk estimates were similar for MetS (adjusted HR 1.00, 95% CI 0.91–1.09) and newly detected DM (adjusted HR 1.39, 95% CI 1.13–1.72). In analyses restricted to patients without baseline use of lipid-lowering or antihypertensive medication, the risk estimate for MetS (adjusted HR 0.74, 95% CI 0.47–1.18, p = 0.21) remained consistent.

Incident diabetes mellitus

Among patients without DM at baseline that were followed for 4 years, 680 patients (4.17%) developed newly recognized DM. The risk of incident DM among patients with MetS at baseline was nearly two-fold higher as compared with patients without MetS after multivariable adjustment (7.46 vs. 2.94%, adjusted OR 1.94, 95% CI 1.58–2.38, p < 0.0001). The increased risk of incident DM among MetS patients was evident within the first year of follow up (2.14 vs. 1.12%, adjusted OR 1.69, 95% CI 1.25–2.30).

Discussion

Among this large international cohort of outpatients with varying degree of atherothrombotic risk, MetS was common but not associated with an increased risk of cardiovascular events in patients with or without DM at baseline. Newly detected DM was less common in this population but a marker of high risk for future cardiovascular events, similar to patients with longstanding DM.

Metabolic syndrome and cardiovascular risk

The alarming increase incidence of obesity and associated insulin resistance has been declared a pandemic for the 21st century as a result of sedentary lifestyle and high-caloric diet becoming more common across the globe.^1,4,23,24 Metabolic syndrome represents a tendency of concomitant cardiovascular risk factors to cluster, such as central obesity, hypertriglyceridaemia, low HDL-C, hyperglycaemia, and hypertension.²⁵. Recently, a harmonized definition of MetS applicable worldwide was proposed.²⁶ According to the harmonized definition, MetS is diagnosed when three or more of these risk factors are present. Both MetS and DM are thought to be associated with an increased risk for incident cardiovascular events due to development of atherogenic dyslipidaemia (lipid and lipoprotein abnormalities),^2,5 mounting insulin resistance typically mediated through visceral adipose deposits,²⁷ and dysglycaemia-mediated oxidative stress.⁵

We did not observe an association between MetS alone and near-term cardiovascular events independent of its component risk factors. Varied cardiovascular risk estimates have been associated with MetS, in part as a result of several different proposed definitions of its diagnosis since its recognition,²⁶ and in part due to difficulty discerning its risk independent of concomitant DM or impaired fasting glucose.⁹ Systematic reviews and meta-analyses have concluded that MetS is associated with an increased risk of future cardiovascular events, cardiovascular mortality, and all-cause mortality; however, these analyses included many patients with concomitant DM.^8–10 In the few studies that identified patients with MetS without DM, there was an attenuated association with mortality and cardiovascular events; however, most studies could not determine whether MetS represented an independent risk beyond its component factors or subclinical atherothrombosis.^28–31 The large sample size in REACH afforded risk estimates with relatively narrow confidence intervals such that the adjusted hazard ratios could exclude more than a 10% increase in the risk of cardiovascular events or 1% in the risk of all cause mortality associated with MetS. Nevertheless, a substantial overlap between coexistent MetS and DM was seen in our patient population. The risk associated with this severe insulin resistance phenotype was markedly elevated, although not distinctly more so than in patients with DM alone, consistent with prior reports.³²

Newly detected diabetes and cardiovascular risk

In contrast to conflicting estimates for MetS, DM has been considered an independent risk factor for incident cardiovascular disease for nearly 50 years.^33,34 In REACH, newly detected DM at baseline was associated with as high risk of future cardiovascular events as patients with longstanding DM. Longitudinal studies comparing the risk of incident to prevalent DM suggest that every 10-year increase in the duration of DM is associated with an approximate 38% increase risk of CAD and 86% increase risk in CAD mortality.¹⁴ Similarly, patients with a recent diagnosis of DM have a lower, but significant, risk for coronary and cardiovascular events compared with patients with longstanding DM.^15,16 Although the exact date of onset of DM in patients is typically unknown, our observation of an equivalent risk among patients with newly detected DM in REACH suggests these patients likely had undiagnosed DM for some time and were not patients with new-onset DM.

A relevant issue for physicians to address in patients with newly detected DM is whether early aggressive risk factor modification with lifestyle, drug therapy, or both may reduce subsequent risk for cardiovascular disease. These patients, who commonly presented with unrecognized concomitant subclinical or overt atherothrombosis in REACH, are likely candidates for primary or secondary cardioprotective therapy with angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker,¹⁸ statin,¹⁹ or aspirin,²⁰ which was of suboptimal use among them despite a high frequency of prior ischaemic events.

Finally, it is unclear whether improvement in glycaemic control and other risk factors among patients with newly detected DM, or concomitant MetS, results in improvement in cardiovascular risk,²¹ but remains a priority of currently tested novel antidiabetic interventions.^35,36 It will be important to determine if results are beneficial in patients with newly detected DM with or without MetS, given these patients appeared to be as high risk for future cardiovascular events as patients with longstanding DM in the REACH registry.

Limitations

The definition of MetS we applied was an efficient choice because it takes into consideration international standards for elevated waist and also treatment for certain risk factors, such as low HDL-C; however, we did not directly measure HDL-C. The components of the exposure of interest, MetS, were dichotomized based on the harmonized definition as present or not at baseline. As a result, we did not determine whether a threshold effect in elevation of the cluster of risk factors results in significant risk. In addition, we elected to proceed with a conservative definition of concomitant MetS and DM requiring three further metabolic risk factors beyond hyperglycaemia. As a result, prevalence of MetS in REACH may be an underestimate, compared with simply screening for hypertriglyceridaemia and elevated waist circumference,⁷ though our results were not substantially different with this broader definition (data not shown).

Our observation of an approximate 1.4% rate of newly detected DM is similar to other contemporary international estimates.²¹ However, given the duration of DM at baseline was unknown, we cannot ascertain incident DM at baseline. In addition, we included patients with both type 1 and type 2 DM at baseline and cannot differentiate risk between these patients. Finally, our findings cannot necessarily be extended to untreated MetS patients. Outpatients in REACH with MetS were compared with patients with at least three other cardiovascular risk factors as per the registry’s eligibility criteria. Therefore, although these patients were not considered at a relative increased cardiovascular risk compared with patients without MetS or DM, they were estimated to have an absolute 10-year event rate over 30%, which prediction scores would consider high risk.³⁴

Conclusion

Within the global REACH registry of high-risk outpatients, presence of metabolic syndrome with or without concomitant diabetes mellitus was not independently associated with an increased relative risk of cardiovascular events after 4 years of observation. By contrast, patients with newly detected diabetes were a high-risk, yet undertreated, group for future cardiovascular disease. Future research to determine whether new detection of diabetes is a modifiable risk remains warranted given this group may be as high risk as patients with longstanding diabetes mellitus.

Funding

The REACH Registry was supported by Sanofi-Aventis (Bridgewater, NJ, USA), Bristol-Myers Squibb (New York, NY, USA), and the Waksman Foundation (Tokyo, Japan).

Conflict of interest

GS has received honoraria for advisory board attendance and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, GlaxoSmithKline, Merck, Nycomed, Sanofi-Aventis, Servier, Astellas, and The Medicines Company and payment for speakers' bureau from Boehringer Ingelheim, Bristol Myers-Squibb, GlaxoSmithKline, Medtronic, Nycomed, Sanofi-Aventis, and Servier. BMS is an investigator and receives salary from the TIMI Study Group, which has received research grant support from Abbott, Amgen, AstraZeneca, Beckman Coulter, BG Medicine, BRAHMS, Bristol-Myers Squibb, Buhlmann, Critical Diagnostics, CV Therapeutics, Daiichi Sankyo Co, Eisai, Eli Lilly, GlaxoSmithKline, Merck, Nanosphere, Novartis Pharmaceuticals, Ortho-Clinical Diagnostics, Pfizer, Randox, Roche Diagnostics, Sanofi-Aventis, Siemens, and Singulex and has received remuneration for consulting from Arena, Gilead, Lexicon, and St Jude Medical. KAE has received consulting fees or served on paid advisory boards from the National Heart, Lung, and Blood Institute and the RW Johnson Foundation and has received grant support from Sanofi-Aventis. EMO has received grant support from Bristol-Myers Squibb, The Medicines Company, Eli Lilly, Sanofi-Aventis, and Schering-Plough, consultancy fees from Abiomed, Datascope, Inovise, Liposcience, Response Biomedical, Savacor, and The Medicines Company, payment for speaker's bureau from CV Therapeutics and Schering-Plough within the past 3 years, and is a shareholder of Inovise, Medtronic, and Savacor. SG has received honoraria and consulting fees from Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Otsuka, and Sanofi-Aventis and has received research grants from Eisai, Sanofi-Aventis, AstraZeneca, Daiichi-Sankyo, and Pfizer within the past 3 years. AAA-A has received honoraria for CME steering committee, advisory board, and speakers' bureau attendance from Bayer, Boehringer Ingelheim, Merck, Pfizer, and St Jude Medical and has received research grants from Medtronic. DLB serves on the advisory board of Medscape Cardiology and the board of directors of Boston VA Research Institute and Society of Chest Pain Centers, is chair of the American Heart Association Get With The Guidelines science subcommittee, has received honoraria from American College of Cardiology (Editor, Clinical Trials, Cardiosource), Duke Clinical Research Institute (clinical trial steering committees), Slack Publications (Chief Medical Editor, Cardiology Today Intervention), and WebMD (CME steering committees) and research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-Aventis, and The Medicines Company, and has undertaken unfunded research for FlowCo, PLx Pharma, and Takeda. The other authors declare no conflict of interest.

References

Author notes