Abstract
Background
The effect of Intensified Multifactorial treatments on coronary atherosclerosis in PAtients with Coronary artery disease and Type 2 Diabetes Mellitus (IMPACT-DM) trial was designed to investigate the effects of intensified multifactorial treatments (IMT) on coronary plaque progression in patients with coronary artery disease (CAD) and diabetes.
Methods and Results
In this prospective, randomized, open-label, parallel assignment, multicenter study, eligible patients with diabetes who underwent successful percutaneous coronary intervention in culprit lesions are randomly assigned to receive either IMT or guideline-oriented standard treatments (Control) for 18 months. The IMT are managed according to strict target goals and step-by-step medical treatment protocols based on modern medical treatments. Target goals in IMT and Control groups are set to hemoglobin A1c <6.2% vs. <7.0%; low-density lipoprotein cholesterol <55 mg/dL for any type of CAD vs. <70 mg/dL for acute coronary syndrome, or <100 mg/dL for stable CAD; and blood pressure <120/80 mmHg vs. <130/80 mmHg, respectively. Non-culprit lesions are evaluated using intravascular ultrasound (IVUS) at post-procedure and 18 months follow up. The primary endpoint is absolute changes in percent plaque volumes in non-culprit lesions as assessed using IVUS from post-procedure to 18 months.
Conclusions
The IMPACT-DM trial will clarify the clinical benefits of IMT on non-culprit coronary plaques in patients with diabetes undergoing successful PCI in culprit lesions.
Key Words: Coronary plaque regression, Intensified multifactorial treatments, Secondary prevention
Diabetes is a well-established risk factor for coronary plaque progression and subsequent development of coronary artery disease (CAD).1 However, several issues associated with its management should be noted. While cardiovascular risk and coronary plaque instability can increase from the early diabetic stages,1,2 there are concerns about the risk of hypoglycemia with early intervention and intensified glucose-lowering therapy. Additionally, patients with diabetes often have comorbidities such as dyslipidemia and hypertension, but treatment effects of which are more difficult to obtain than in non-diabetic patients. Patients with diabetes have been reported to exhibit diminished responses to statin treatments regarding coronary plaque regression, even when low-density lipoprotein cholesterol (LDL-C) levels are similarly managed.3 Conversely, several studies have reported that intensified multifactorial treatments (IMT), which comprehensively manage diabetes alongside comorbid risk factors, can significantly improve cardiovascular outcomes than what would be expected from decreases in hemoglobin A1c (HbA1c) levels.4,5 The Steno-2 study has shown that IMT reduced cardiovascular and mortality risks in patients with diabetes and microalbuminuria.4 The Japan Diabetes Optimal Treatment study for 3 major risk factors of cardiovascular diseases (J-DOIT3) trial also suggested the potential benefit of IMT in reducing cerebrovascular events in patients with diabetes.5 Additionally, studies by the United Kingdom Prospective Diabetes Study have indicated that intensive glycemic control from early diabetic stages could lower the incidence of CAD.6 However, most of these previous studies have mainly focused on primary prevention, and evidence of IMT regarding secondary prevention remains insufficient. In particular, few studies have examined the impact of IMT that combines modern diabetes medications, such as glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter 2 inhibitors, on coronary plaque progression. Against this background, the IMPACT-DM (Intensified Multifactorial intervention on coronary atherosclerosis in PAtients with Coronary artery disease and Type 2 Diabetes Mellitus) trial was planned to evaluate clinical benefits of IMT on coronary artery plaques in patients with CAD and diabetes.
Methods
Study Design and Population
The IMPACT-DM trial is a prospective, randomized, open-label, parallel assignment, multicenter study conducted across 7 institutions in Japan to investigate the effects of goal-oriented IMT on coronary plaque progression compared with guideline-oriented standard treatments (Control) in patients with type 2 diabetes who have undergone percutaneous coronary intervention (PCI; Figure 1). Eligible patients include those with CAD and type 2 diabetes who have successfully undergone intravascular ultrasound (IVUS)-guided PCI in culprit lesions and who exhibit target coronary plaques in non-culprit lesions. Inclusion and exclusion criteria are detailed in Supplementary Table 1. Exclusion criteria were primarily defined according to contraindications listed in the drug package inserts relevant to the study. Due to safety concerns regarding increased risks of hypoglycemia associated with intensified therapy, patients currently using insulin or planning to initiate insulin therapy are excluded. A total of 156 patients who meet inclusion and exclusion criteria are randomly assigned in a 1 : 1 ratio to receive either IMT or guideline-based standard therapy (Control) using a web-based randomization system. Randomization is adjusted for the following factors: (1) institutions; (2) age (<65 years or ≥65 years); (3) acute coronary syndrome (ACS); and (4) HbA1c levels (<7.0% or ≥7.0%). The study protocol was first approved on December 17, 2020, and modifications in the protocol, including those on inclusion criteria, study duration, frequency of hospital visits, funding agency, and sample size, have been performed several times to date. Each revision of protocol was approved by the Yokohama City University Accredited Institutional Review Board and the Ethics Committees of all participating sites. The study was registered on the Japan Registry for Clinical Trials website (jRCTs031200359). Written informed consent is obtained from all participants before enrollment. The study protocol adheres to the principles of the Declaration of Helsinki. Definitions of terms and criteria used in the study are provided in Supplementary Table 2.
Figure 1.
Flowchart. ACS, acute coronary syndrome; BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; DM, diabetes; IVUS, intravascular ultrasound; PCI, percutaneous coronary intervention; other abbreviations as in Table.
Management Goals and Investigational Treatment
The IMT group is a goal-oriented IMT approach characterized by ‘strict target goals’ and ‘clear treatment steps’ for managing hyperglycemia, dyslipidemia, hypertension, and lifestyle modifications (Table). The IMT group aims at achieving treatment goals as early as possible, thereby promoting coronary plaque regression through preferential and aggressive uses of medications with proven effectiveness in reducing coronary plaque volumes and cardiovascular events. If target goals are not achieved within 3 months, treatments will advance to the next step. If a patient has already received treatments for the target step or cannot tolerate therapeutic agents, that step will be skipped, and the patient will move on to the next step as well. Treatments including choices of therapeutic agents in the Control group are determined at the discretion of attending physicians, based on the target goals established by guidelines. Patients are required to visit the study site at least once per month for the first 4 months; thereafter, the visit interval may be extended to up to 2 months, depending on the achievement of the control targets. The treatment goals and their rationale are outlined below.
Table.
Step-by-Step Treatment of Intensified Multifactorial Treatments
| Glycemic control | Lipid control | Blood pressure control | |||
|---|---|---|---|---|---|
| HbA1c | LDL-C | HDL-C, TG | LVEF <40% | LVEF ≥40% | |
| Step 1 | SGLT-2 inhibitors* | Strong statins** | Highly purified EPA | ACEI, ARB, ARNI | Amlodipine |
| Step 2 | GLP-1 receptor agonists* | Ezetimibe | Pemafibrate | Amlodipine | ACEI, ARB, ARNI |
| Step 3 | Metformin (or pioglitazone) | PCSK9 inhibitor | Fenofibrate† | Diuretic, β-blocker, the other CCBs, or their combination |
|
| Step 4 | α-glucosidase inhibitors | – | – | – | – |
| Step 5 | DPP-4 inhibitors†† | – | – | – | – |
*In patients without heart failure symptoms and with preserved LVEF, it is permitted to use STEP 2 drugs in preference to STEP 1 drugs. **Atorvastatin 20 mg/day at maximum tolerated dose, rosuvastatin 10 mg/day at maximum tolerated dose, pitavastatin 4 mg/day at maximum tolerated dose. †Consider fenofibrate if unable to administer pemafibrate. ††DPP-4 inhibitors are contraindicated in combination with GLP-1 receptor agonists. If the target goal is not achieved within 3 months, the treatment will advance to the next step. If a patient has already received treatment for the target step or cannot tolerate the therapeutic agents, that step will be skipped, and the patient will move on to the next step as well. ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; CCB, calcium channel blocker; DPP-4, dipeptidyl peptidase-4; EPA, eicosapentaenoic acid; GLP-1, glucagon-like peptide-1; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; PCSK9, protein convertase subtilisin/kexin type 9; SGLT-2, sodium-glucose cotransporter 2; TG, triglyceride.
Glycemic Control
Since CAD can develop from pre-diabetic stages, strict glycemic control aimed at normalizing blood glucose levels is necessary for prevention of CAD.2 Therefore, similar to the J-DOIT3 study,5 the target for blood glucose control in the IMT group is set as <6.2% for HbA1c. The protocol of IMT prioritizes agents with low risks of hypoglycemia and body weight gain that demonstrate efficacy in reducing cardiovascular events. Target HbA1c level for the Control group is set as <7.0%.7
Lipid Control
Regarding LDL-C levels, numerous clinical studies have demonstrated ‘the lower, the better’. Therefore, target LDL-C levels are set as <55 mg/dL in the IMT group,8 and <70 mg/dL for ACS (<100 mg/dL for stable CAD) in the Control group.9,10 Target triglycerides levels are set as <135 mg/dL in the IMT group and <150 mg/dL in the Control group, and target levels of high-density lipoprotein cholesterol are set as ≥40 mg/dL in both groups.9,10
Blood Pressure Control
Previous studies have shown that reduction of systolic blood pressure (SBP) to <120 mmHg has been observed to reduce cardiovascular events and regression of coronary artery plaques.11,12 Therefore, target SBP is set as <120 mmHg for the IMT group. Conversely, since there has been no evidence of coronary plaque regression by diastolic blood pressure intervention, a target value of diastolic blood pressure is set as <80 mmHg.9,10 Target blood pressure in the Control group is set as <130/80 mmHg.9,10
Lifestyle Interventions
All patients will be instructed to quit smoking.9,10 Target goals of body mass index (BMI) are set as <23 kg/m2 for the IMT group and <25 kg/m2 for the Control group. Total daily calorie intake should be recommended to be <25 kcal/kg for patients with a BMI of ≥25 kg/m2, and <27 kcal/kg for those with a BMI of <25 kg/m2. Salt intake should be limited to <6 g/day.5 For exercise recommendations, individuals should be advised to walk for 15–30 min at least twice a day.10
Study Endpoints and Safety Monitoring
The primary endpoint of this study is absolute changes in percentage of plaque volumes of non-culprit lesions as assessed using IVUS from post-procedure to 18 months, which are well-established surrogate markers for cardiovascular events.13 After achieving successful PCI in culprit lesions, target coronary plaques will be identified in non-culprit lesions of PCI or non-PCI vessels and recorded using IVUS, and will be quantitatively evaluated again using IVUS 18 months later. Target plaques in non-culprit lesions are defined as a continuous plaque (up to a maximum of 10 mm), with a maximum plaque area of 40% or more, and with a plaque thickness of ≥500μm or a % plaque area of 20% or more within 5 mm before and after the maximum plaque area site (Figure 2).1 Safety monitoring is also performed at each visit throughout the study. The details of secondary endpoints and safety profiles are shown in Supplementary Table 3.
Figure 2.
Non-culprit target plaques.
Blood and Urine Samples
Whole blood and urine samples are collected at each visit up to 18 months to assess the control status of risk factors, secondary endpoints and safety profile. In some patients, expression profiling analysis of novel receptor binding factor (angiotensin II type-I receptor-associated protein), endothelial adhesion factor, oxidative stress and inflammatory genes in human blood and urine samples are also evaluated.14
Sample Size Calculation
Previous studies have shown that −1.0% differences in HbA1c, −10 mg/dL differences in LDL-C and −10-mmHg differences in SBP correlate with changes of −5.25%,1 −0.5 to −1.0%,15 and −0.17%11 in percentage of plaque volumes. Based on the protocol, expected differences in HbA1c, LDL-C, and SBP between the 2 groups are 0.3%, 15 mg/dL, and 10 mmHg, which translates into expected differences in percentage of plaque volume changes of 1.58%, 1.1%, and 0.17% for HbA1c, LDL-C, and SBP. Although the interventional effects were presumed to be additive to the effect of each factor (HbA1c, LDL-C, SBP), no study has examined the combined effects of IMT on coronary plaque to date. Thus, sample size calculation conservatively decided to use the effect of a single-factor intervention, and the largest difference in percentage of plaque volume changes, 1.58% with a standard deviation of 3.6% (2.8% to 3.6%)1 as expected from HbA1c, was adopted as the difference between the groups. Accordingly, calculation of sample size was performed, utilizing an effect size of 0.44, a 2-sided significance level of α of 10%, and a power of 80%, and designed to include 65 cases per group. Assuming a maximum of 20% loss to follow up,1 the final sample size was determined to be 78 per group, totaling 156 participants.
Analysis Plan
The full analysis set will be all study patients who are enrolled in the study, have received at least one dose of study drug after randomization, and have efficacy data. Study patients for whom both the baseline and follow-up analyzable IVUS data necessary to evaluate the primary endpoint of the study cannot be obtained, study patients with serious violations of study protocol (e.g., failure to obtain consent), and discontinued cases will be excluded. Differences in absolute changes in percentage of coronary plaque volumes between the groups will be analyzed using multiple regression analysis with the adjustment factors used for randomization (age, ACS, and HbA1c level) as covariates. In this study, since it is anticipated that institutions with extremely small numbers of enrolled patients may occur, institutions used as an adjusted factor will be removed from the multiple regression analysis. If there are baseline differences that might influence percentage of plaque volume changes, a multivariate analysis incorporating these factors will also be performed. Because this is the first study to examine the effects of IMT on coronary plaques, and given the exploratory nature of the study, a 2-tailed test of P<0.10 was adopted to determine a statistically significant difference.
Discussion
The IMPACT-DM study is a randomized control study to test the hypothesis that the goal-oriented IMT approach, characterized by ‘strict target goals’ and ‘clear treatment steps’, could be effective for coronary plaque regression in patients with CAD and type 2 diabetes in the Japanese population. Because diabetes-related atherosclerosis results from various factors, comprehensive management of these factors may contribute to an improved prognosis in diabetic patients with CAD. However, the effectiveness of IMT in secondary prevention is yet to be proven. If the IMPACT-DM study demonstrates the beneficial effect of IMT over standard therapy on coronary plaque regression, it will lead to the establishment of optimal management goals and treatment protocols to improve patient prognosis.
Disclosures
None.
IRB Information
The present study was approved by Yokohama City University Accredited Institutional Review Board (reference no. CRB20-018).
Supplementary Files
Supplementary Table 1. Supplementary Table 2. Supplementary Table 3.
Acknowledgments
None.
Funding Statement
Sources of Funding: This work was partially supported by JSPS KAKENHI (Grant no. 21K08132).
Data Availability
The datasets will not be publicly available because patient consent in each institute does not allow for such publication.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Table 1. Supplementary Table 2. Supplementary Table 3.
Data Availability Statement
The datasets will not be publicly available because patient consent in each institute does not allow for such publication.