A few weeks ago, the 82nd Annual Meeting of the American Diabetes Association announced the "Expert Consensus on the Management of Hyperglycemia in ADA/EASD Type 2 Diabetes Mellitus (Draft)". The introduction of this internationally authoritative guideline document has attracted widespread attention in the industry, and has also made everyone focus on the transformation of the concept of clinical treatment of diabetes again.
In recent years, with the continuous deepening of epidemiological research and interventional clinical research at home and abroad, people's understanding of the pathophysiological process and harm of type 2 diabetes has been deepening, and its prevention and control concepts and strategies have also undergone substantial changes.
Complications of type 2 diabetes include acute hyperglycemia events, microvascular complications, neuropathy, and macrovascular complications, among which macrovascular complications are the main causes of death and disability in patients with type 2 diabetes. Therefore, effective prevention and treatment of macrovascular complications should be the core strategy of integrated management of type 2 diabetes. Although hyperglycemia is the most characteristic manifestation of type 2 diabetes, numerous studies have found that simply lowering blood glucose levels makes it difficult to reduce the risk of cardiovascular complications. Reasonable glucose control, intensive lifestyle intervention, comprehensive prevention and control of multiple risk factors, and selection of effective hypoglycemic drugs should become the four cornerstones of type 2 diabetes treatment.
Improving prognosis is not enough to lower glucose alone
Before the advent of insulin, acute metabolic disorders were the leading cause of death in people with diabetes. After the advent of insulin, the survival of diabetics has improved significantly. Since then, with the wide application of various hypoglycemic drugs such as biguanides and sulfonylureas, the number of diabetic patients who die due to acute metabolic disorders has gradually decreased. The survival time of diabetic patients is significantly prolonged, and atherosclerotic cardiovascular disease has gradually become the main factor endangering the life and health of patients.
The Flemingham study, published in 1979, confirmed with conclusive epidemiological data that there is a strong link between diabetes and cardiovascular disease, and considered diabetes as one of the important risk factors for cardiovascular disease. Since then, scholars at home and abroad have been working to improve the macrovascular prognosis of type 2 diabetes patients by strictly controlling blood glucose levels. However, the landmark UKPDS study, published in 1998, found that intensive control of blood glucose levels did not reduce the incidence of cardiovascular events such as myocardial infarction. Subsequently, studies that ended in 2008 and 2009 have shown that attempts to improve cardiovascular prognosis through stricter hypoglycemic therapy may be futile.
Not only that, but the study suggests that controlling blood glucose levels too tightly may also pose an additional risk to patients due to hypoglycemic events. Based on the above research conclusions, scholars at home and abroad have gradually realized that active and effective hypoglycemic therapy can significantly reduce the occurrence of acute hyperglycemia events and microvascular complications, but it is difficult to effectively improve cardiovascular prognosis.
Prevention and treatment of macrovascular complications is central
The risk of cardiovascular complications in patients with type 2 diabetes is significantly higher than that of non-diabetic patients, and some scholars once believed that diabetes was a critical condition of coronary heart disease. That being the case, in addition to rational glucose control, active control of various reversible cardiovascular risk factors in patients with type 2 diabetes should help minimize the risk of cardiovascular events in such patients.
The results of the Danish Steno-2 study, published in 2008, confirmed this hypothesis. Since then, domestic and foreign guidelines have made important adjustments, recommending stricter blood pressure management, cholesterol management, weight management, diet control, smoking cessation, and increased exercise for patients with type 2 diabetes. The advancement of these measures has played a positive role in effectively reducing the risk of cardiovascular events in patients with type 2 diabetes.
At the same time, many scholars believe that the relationship between type 2 diabetes and cardiovascular complications may be different from hypertension and hypercholesterolemia. The latter two are not only independent risk factors for atherosclerotic cardiovascular disease, but also direct causative factors, so strict control of blood pressure and cholesterol levels can effectively reduce the risk of cardiovascular events. However, type 2 diabetes and cardiovascular disease may be a "common soil" relationship rather than a causative factor, so lowering blood glucose is difficult to have a fundamental effect on the pathophysiological process of cardiovascular disease. Intensive lifestyle interventions (especially weight management) not only help to reduce blood glucose levels, but also have a beneficial effect on blood pressure and blood lipids, and may fundamentally trigger the common pathophysiology of type 2 diabetes and atherosclerotic cardiovascular disease (such as insulin resistance, oxidative stress, subclinical inflammatory response, etc.), thereby reducing the incidence of cardiovascular disease.
New drugs bring a twist
In December 2008, the U.S. Food and Drug Administration (FDA) issued a code for diabetic drug companies, which requires cardiovascular disease risk assessment before new hypoglycemic drugs are marketed, and requires that the endpoints of such studies should be a composite endpoint of cardiovascular event death, myocardial infarction and stroke. The duration of the study should be 3 to 5 years, participants should be diabetics with cardiovascular risk factors, and an adequate number of endpoint events should be ensured.
Since then, foreign scholars have carried out dozens of randomized clinical controlled trials on the cardiovascular effects of hypoglycemic drugs. The EMPA-REG OUTCOME trial, which ended in 2015, was an epoch-making clinical study. The study looked at patients with type 2 diabetes who had been diagnosed with cardiovascular disease. The results showed that the addition of the SGLT-2 inhibitor empagliflozin to conventional treatment reduced all-cause mortality by 32% and cardiovascular mortality by 38%. This is the first trial of a hypoglycemic drug demonstrated to reduce the risk of cardiovascular events.
The results of the LEADER study, which ended in 2016, showed that the addition of liraglutide to conventional treatment significantly reduced the incidence of primary composite endpoint events in patients with type 2 diabetes. This study makes liraglutide the second hypoglycemic drug after empagliflozin to be randomized in clinical trials to produce cardiovascular benefits. The completion of these two blockbuster studies marks a new era in the drug treatment of type 2 diabetes.
In the years since, a number of studies have confirmed from different aspects that the use of novel hypoglycemic drugs can significantly improve cardiovascular and renal outcomes in patients with type 2 diabetes mellitus who have cardiovascular disease, chronic kidney disease and their risk factors. It should be noted that in the above studies, the benefits of various new hypoglycemic drugs were not achieved by lowering blood glucose levels, but from effects other than hypoglycemic.
New evidence gives rise to new guidelines
Since 2019, based on the above new research evidence, a number of international guidelines have been significantly revised. For example, the European Guidelines on Diabetes, Prediabetes and Cardiovascular Diseases, issued in 2019, and the European Guidelines for the Prevention of Cardiovascular Diseases, issued in 2021, both recommend GLP-1 receptor agonists or/and SGLT-2 inhibitors as the preferred hypoglycemic lowering agents for patients with type 2 diabetes with cardiovascular disease, chronic nephropathy and their high risk factors. The traditional front-line status of metformin has been strongly impacted.
The 2022 Edition of the American Diabetes Diagnostic and Therapeutic Standards, issued at the end of 2021, makes similar recommendations. A few weeks ago, the 82nd Annual Meeting of the American Diabetes Society announced the "Expert Consensus on the Management of Hyperglycemia in ADA/EASD Type 2 Diabetes Mellitus (Draft)". This internationally authoritative guideline document further affirms the clinical status of SGLT-2 inhibitors and GLP-1 receptor agonists. Even in patients with type 2 diabetes who do not have cardiovascular and kidney disease and its risk factors, these two classes of drugs have been given a very important position. Metformin, which has long been in the first line, is only recommended as a "moderate to highly effective" hypoglycemic drug to lower blood sugar, and is not regarded as a drug with cardioprotective effects. The evidence for these adjustments is based on a number of large randomized clinical trial studies published in recent years.
In summary, after a century of exploration, the management strategy of type 2 diabetes has changed from lowering blood glucose to reducing target organ damage and improving clinical prognosis of patients, which has truly achieved a historic turn. The formation of these new treatment concepts will play a positive role in minimizing the occurrence of clinical complications in patients with type 2 diabetes and improving long-term prognosis and quality of life.
Text: Professor Guo Yifang of Hebei Provincial People's Hospital
Source: Health Newspaper