Blood pressure, blood glucose, lipids, blood clots, body weight and lifestyle are the five basic targets for risk interventions in patients with cardiovascular disease. type 2 diabetes is referred to in ATP III as an equivocal risk for coronary heart disease, meaning that patients with diabetes have the same rate of future cardiovascular events as patients with coronary heart disease. The series is a clinical registry study funded by the NIH, which stands for “Action to Control Cardiovascular Disease Risk in Patients with Diabetes.
The clinical trials focus on three important modifiable risk factors for cardiovascular disease: intensive glucose reduction, intensive blood pressure reduction, and combined lipid regulation to determine whether cardiovascular event rates can be reduced in patients with type 2 diabetes. The ACCORD series was a prospective, multicenter, randomized, controlled trial using a 2×2 double-analysis design that enrolled approximately 10,251 middle-aged and older patients with type 2 diabetes at high risk for cardiovascular disease at approximately 77 clinical centers in the United States and Canada, with a mean follow-up of approximately 5.6 years.
It can be said that this study is another landmark clinical study after the UKPDS and ADVANCE studies on the overall intervention of cardiovascular risk factors in patients with abnormal glucose metabolism, which not only focused on hypertension and hyperglycemia as previous studies, but also highlighted the clinical intervention of hyperlipidemia. Therefore, it is of great significance to carefully analyze and carefully discuss the results of this study to guide the choice of strategies for the control of major risk factors of cardiovascular diseases.
About blood glucose
The UKPDS epidemiological study, known as the “landmark study in diabetes”, showed that a 1% reduction in glycosylated hemoglobin (GHbA1) was associated with a 21% reduction in overall complications in diabetic patients: GHbA1 levels were strongly associated with the incidence of cardiovascular events in patients with type 2 diabetes, and intensive glycemic control was effective in reduce microvascular complications.
The ACCORD Study Group sought to answer the question of whether intensive glycemic control in such patients to achieve normal GHbA1 as soon as possible could reduce the incidence of cardiovascular events back in 2008. The study enrolled 10,251 middle-aged and elderly patients with type 2 diabetes with a mean age of 62.2 ± 6.8 years and a mean GHbA1 concentration of 8.1%. GHbA1 levels were reduced to 7.5% in the standard treatment group and 6.4% in the intensive treatment group at one year of follow-up. The results at 3.5 years of follow-up showed that the intensive glycemic control did not reduce the incidence of cardiovascular events as predicted, but instead resulted in more mortality (257 vs. 203, P=0.04), which ultimately led to early termination of the study.
Why higher mortality occurred in the intensive glycemic control group compared to the standard treatment group could not be conclusively determined by the researchers, and it was speculated that the possible reasons were inappropriate glucose-lowering treatments or (and) the target value of the intensive treatment in the intensive treatment group. Although the incidence of hypoglycemia and weight gain greater than 10 kg requiring treatment was significantly higher in the intensive glycemic control group than in the standard treatment group (P<0.001), subsequent analysis of the data did not support either of these indicators as independent risk factors for the higher mortality in the intensive glycemic control target group. Quite to the contrary, a mild, nonsignificant trend in glycemic control relative to that in the standard treatment group was associated with an increased risk of death.
The purpose of the ADVACE study was essentially the same as the ACCORD blood glucose study, but the results were very different. The former study had a significantly lower incidence of hypoglycemia or severe hypoglycemia to deal with than the ACCORD study because its glucose target values were set lower than the latter. However, the ACCORD study had a significantly lower incidence of the primary endpoint event than the ADVACE study due to its greater focus on aspirin, statin, and ACEI applications along with strict glycemic control. Once again, this is eloquent evidence that overall risk factor control, rather than interventions focused on glycemia or a single risk factor, can reduce the incidence of cardiovascular events in patients with type 2 diabetes.
At the same time, two studies have shown that controlling GHbA1 at an optimal level of 7% reduces microvascular complications such as new microproteinuria and nephropathy and also serves to prevent the risk of macrovascular complications without increasing the incidence of serious adverse events such as death. Although a recent Meta-analysis did not confirm the existence of an increased risk of lethality associated with intensive glucose lowering, and subsequent published series of ACCORD blood pressure and lipid studies failed to reach a consistent conclusion on this issue, the safety and feasibility of intensive glycemic control strategies remain unresolved clinical issues and must still await more convincing studies to become available.
About blood pressure
The results of the UKPDS study suggest that tight blood pressure control may provide a clinical benefit in terms of reduced cardiovascular events in patients with type 2 diabetes. In the ACCORD Blood Pressure Study, investigators evaluated the potential risks and benefits of a strict systolic blood pressure control target and a loose systolic blood pressure control target of 140 mmHg and 120 mmHg, respectively.
After enrolling 4733 diabetic hypertensive patients with a mean follow-up of 4.7 years, there was no significant difference in the incidence of primary composite endpoint events (nonfatal myocardial infarction, nonfatal stroke, and death due to cardiovascular disease) between the two groups, while the incidence of serious adverse reactions to antihypertensive medications was higher with intensive blood pressure control (0.33% vs. 0.13%, P<0.001).
Secondary endpoints showed that tighter blood pressure control may result in a lower overall stroke rate (0.32% vs 0.53%, P=0.01) but a higher rate of serious coronary events (253 vs 270, P<0.001). Apparently, the target value for blood pressure control in type 2 diabetic patients at ≤120 mmHg is not supported by evidence-based medical evidence. This is the biggest regret of the study, namely that no consistent conclusions were drawn regarding the optimal target blood pressure control value for diabetic patients.
Theoretically, in the early stage of hypertensive disease, the remodeling of major target organs is not significant, and excessive blood pressure will only aggravate the abnormal hemodynamic effects such as acute congestion of tissues and organs and the pathophysiological processes such as chronic remodeling in the long term. In contrast, in the middle and late stages of most cardiovascular diseases, the tissue remodeling and autoregulatory dysfunction of important target organs such as the heart, brain and kidney have become more significant, at this time, maintaining a certain level of basal blood pressure is conducive to safeguarding the blood perfusion pressure of major organs and ensuring the basic blood supply and metabolic demand of target organs.
The only benefit from strict blood pressure control is a reduced incidence of stroke, but a greater incidence of cardiovascular events. Therefore, in patients with or without diabetes, the risk of cardiovascular events needs to be closely monitored when choosing whether to implement a strict blood pressure control strategy, especially in elderly patients with multiple chronic systemic cardiovascular diseases such as diabetes, coronary artery disease, or (and) severe target organ damage, the J curve effect and blood pressure variablilty (BPV) associated with excessive antihypertensive therapy. Blood pressure variablilty (BPV) is particularly pronounced in elderly patients with systemic cardiovascular disease and/or with more severe target organ damage. Therefore, the expert committee of JNC7, following the publication of the ACCORD blood pressure study, recommended that the target blood pressure in diabetic patients be controlled at around 130/80 mmHg, rather than as low as possible.
Although the 2009 re-evaluation of the European hypertension guidelines flagged setting the target blood pressure below 140/90 mmHg and considering dropping to lower levels if tolerated by the patient, the target systolic blood pressure in patients with diabetes and high cardiovascular risk can be lowered to 130 mmHg, with a more reasonable blood pressure control range of 130 to 139/80 to 85 mmHg. However, it is worth noting that However, it is worth noting that there is a lack of trustworthy clinical studies to support the benefit of lowering blood pressure targets below 130 mmHg systolic in elderly diabetic patients, and excessive blood pressure lowering may lead to reduced cardiovascular benefit.
In any case, even though controversy and confusion persist, the truth that it varies from person to person and from disease to disease will not change, and the ideal blood pressure control model is necessarily based on multiple factors such as patient demographic characteristics, risk factors, clinical status, major tissue and organ perfusion characteristics and autoregulatory mechanisms, blood pressure variability, antihypertensive pharmacological characteristics, and patient compliance.
Regarding blood lipids
Even intensive lipid regulation strategies with statins alone are difficult to achieve fully optimal lipid control goals. Moreover, compared with low-dose statin therapy, intensive lipid regulation strategies with high-dose statins have many limitations, such as lower patient compliance, increased incidence of diabetes, and more hepatotoxicity and muscle toxicity, which make their clinical application more limited.
Meanwhile, several major clinical studies in recent years, including PROVE IT-TIMIT22, A-Z, TNT, IDEAL, and SEARCH, have not yet reached a final and consistent conclusion on the clinical benefit or otherwise of intensive statin therapy. To address residual cardiovascular risk and achieve desired lipid control goals, it is natural for clinical research workers to think of a combination lipid modulation strategy with fibrates based on statin therapy alone, as the former has the advantage of robust LDL-C control and the latter has the advantage of well-corrected atherogenic lipid profiles, i.e., high LDL cholesterol, high triglycerides, low HDL-C lipid profiles (TG ≥ 204 mg/dl, HDL-C ≤ 34 mg/dl).
Studies have shown that this atherogenic lipid profile alteration is most common in patients with metabolic syndrome and diabetes mellitus. The ACCORD series is highlighted by the ACCORD Lipid Study, which compared the effects of statins alone and statins in combination with beta in patients with type 2 diabetes on cardiovascular risk.
Even when the number of patients with this lipid profile in the enrolled population was only about less than 17% of the total enrolled population (941 vs. 5518), the prospective subgroup analysis yielded statistically significant results: the incidence of the primary endpoint was 12.4% and 17.3% in the statin combined with fibrate treatment group and the statin combined with placebo control group, respectively, and statin-based combined with fibrate treatment resulted in a higher risk of cardiovascular events in type 2 The results of this study are consistent with the results of the series of clinical studies related to betablockers such as HHS, VAHIT, BIP, and FIELD. In the remaining population of approximately 4,548 patients without an atherogenic lipid profile enrolled in the ACCORD Lipid Study, the reduction in risk ratio was only 10.1%.
The investigators’ final conclusion was that a non-selective combination lipid-regulation strategy in the type 2 diabetic population did not reduce the overall rate of cardiovascular events compared with statin use alone. Therefore, this study does not support the routine administration of a combined lipid-modifying strategy of statin and fibrate to patients with type 2 diabetes.
Clearly, the number of people enrolled with or without an atherogenic lipid profile as a significant confounder confounded the final results of the study, because the number of people with an atherogenic lipid profile enrolled in the ACCORD study was significantly inconsistent with the epidemiological characteristics of real-world patients with type 2 diabetes or the metabolic syndrome, but subgroup analysis did not ultimately change the consistency with multiple studies. Conclusion: The combination of appropriate statins on top of fibrate or fibrate therapy alone is not only relatively safe but can benefit patients with atherogenic lipid profile such as diabetes or (and) metabolic syndrome, but patients without this lipid profile have no significant benefit from this treatment strategy.
In any case, until more convincing studies are available, it may be prudent to focus on the full range of modulatory strategies for glycemia, blood pressure, lipids, thrombosis, weight, and therapeutic lifestyle changes.