The primary goal of diabetes treatment is to alleviate wasting symptoms by regulating blood glucose levels and to prevent diabetes-specific chronic complications, such as microvascular complications, thereby maintaining a normal life expectancy [1]. Blood glucose levels should be kept below 180 mg/dL to prevent wasting symptoms, and medications should be administered promptly with diet and exercise therapy, to stave off chronic complications. Despite these efforts, most diabetes patients do not achieve a normal lifespan due to associated conditions such as cardiovascular diseases (CVDs) and diabetic kidney disease (DKD) [2]. Therefore, an ideal antidiabetic drug should not only provide hypoglycemic effects but also fundamentally reduce mortality associated with diabetes. This article explores the "paradigm shift in diabetes management," moving from the traditional "glucocentric" approach in managing type 2 diabetes to the recently emphasized concept of "organ protection," and examines how this shift has evolved over time.

The UK Prospective Diabetes Study (UKPDS) [3], a landmark study that established the importance of blood glucose regulation in managing type 2 diabetes, was designed based on a clear link between hyperglycemia and microvascular complications identified in earlier observational studies [4,5]. The UKPDS found that type 2 diabetes patients who maintained strict blood glucose control (fasting blood glucose, <106 mg/dL) using sulfonylureas or insulin from the time of their diagnosis had better composite outcomes, including both vascular and nonvascular indices, than those who did not (fasting blood glucose, <270 mg/dL). However, it did not significantly reduce macrovascular complications or diabetes-related mortality [3]. Two decades ago, the only antidiabetic drugs available in clinical practice were sulfonylureas, insulin, metformin, and thiazolidinediones (TZDs). At that time, glycated hemoglobin A1c (A1c), now a common indicator of blood glucose regulation, was not yet used [6], and major adverse cardiovascular events (MACEs), a primary outcome of recent CVD research, had not been introduced. Additionally, neither statins nor angiotensin receptor blockers were in use [7]. Nonetheless, it was discovered that early and strict blood glucose control could have a "legacy effect" in preventing myocardial infarction [8]. While the benefits of strict blood glucose control in preventing CVDs in patients with diabetes have not been established, the results of interventional studies focusing on controlling risk factors other than hyperglycemia during the 1990s have been in the spotlight. UKPDS 75 demonstrated that blood pressure management is more effective than blood glucose control in preventing CVDs in diabetic patients [9]. Furthermore, the secondary and primary prevention of CVDs by low-density lipoprotein cholesterol reduction with statins was also demonstrated [10]. Therefore, the importance of comprehensive management of CVD risk factors through blood pressure control, management of dyslipidemia, and antiplatelet medications rather than strict glycemic control alone has been recognized [11]. Reflecting these insights, the emphasis in managing type 2 diabetes has shifted towards "blood glucose lowering" as a component of broader regulatory strategies. The Korean Diabetes Association’s guidelines recommend selecting antidiabetic drugs based on the level of hyperglycemia, categorized by A1c levels: 8.0%, 8.0%–10.0%, and 10% [12].

Subsequent observations revealed that A1c values have a linear relationship with CVD events or death in patients with type 2 diabetes [2]. This led to the planning of studies to prevent CVDs by actively lowering A1c levels. ACCORD (Action to Control Cardiovascular Risk in Diabetes) [13], ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) [14], and VADT (Veterans Affairs Diabetes Trial) [15] assessed whether CVDs could be prevented by strictly controlling blood glucose through combination therapy using TZDs or alpha-glucosidase inhibitors. These drugs, known for their low risk of hypoglycemia, have been in use since the 1990s. However, these studies showed that strict blood glucose control led to increased side effects such as weight gain, hypoglycemia, and arrhythmia, and that the risks outweighed the benefits concerning CVDs. Additionally, rosiglitazone, a TZD drug, was found to increase the risk of CVDs, sparking debates [16]. In response, the US Food and Drug Administration required new antidiabetic drugs to demonstrate CVD safety [17]. In addition, it became essential to establish individualized goals when selecting antidiabetic drugs for patients with type 2 diabetes [18].

Dipeptidyl peptidase-4 (DPP-4) inhibitors were the first subject of CVD safety evaluation guidelines for antidiabetic drugs. Introduced into clinical practice after 2006, DPP-4 inhibitors have a modest hypoglycemic effect, reducing A1c by about 0.8%. However, their low risks of hypoglycemia or weight gain make them the most commonly used drug in combination therapy with metformin in Korea [19]. Compared to placebos and other antidiabetic drugs, DPP-4 inhibitors have shown a slight tendency to reduce MACEs, although this reduction was not statistically significant. Generally, they are considered neutral regarding CVD safety (Table 1) [20]. In the SAVOR-TIMI 53 (Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53) study, the saxagliptin group exhibited a significant increase in hospitalizations due to heart failure compared to the placebo group (3.5% vs. 2.8%, P=0.007) [21]. A mechanism has been suggested in which DPP-4 inhibition leads to heart failure due to a “class effect” of increased substance P and neuropeptide Y, which stimulates the sympathetic nervous system [22]. In contrast, some reports have suggested that certain DPP-4 inhibitors do not increase the risk of heart failure, as they offset the increase in blood pressure by increased natriuresis [23]. Consequently, the association between DPP-4 inhibitors and heart failure has not been clearly established, but these studies have led to a renewed recognition of diabetic cardiomyopathy (DCM) as one of the chronic complications of type 2 diabetes. Although the UKPDS study predicted a 16% increase in heart failure for every 1% increase in A1c [4], intensive glycemic control alone has not been shown to prevent heart failure, suggesting that DCM is caused by pathogenic mechanisms other than hyperglycemia. However, the exact pathogenesis of DCM has not yet been elucidated [13–15], although there are several likely mechanisms. The current prevailing hypothesis is that the cascade of events in DCM, such as cardiomyocyte hypertrophy, inflammation, fibrosis, and death, starts with an increase in metabolites such as advanced glycation end products from hyperglycemia and a shift in energy source of cardiomyocytes, lipotoxicity from an increase in fatty acids due to insulin resistance, followed by mitochondrial dysfunction and a decrease in the efficiency of adenosine triphosphate production [24,25]. The mechanisms underlying the beneficial action of antidiabetic drugs in heart failure are also not fully understood, but research is ongoing to verify the potential role of these drugs based on the mechanisms described above [15]. Therefore, the focus has shifted from solely emphasizing the hypoglycemic effects of antidiabetic drugs to selecting a drug that does not increase the risk of CVDs and side effects such as weight gain or hypoglycemia. In other words, a “balanced and safe antidiabetic drug” has become a necessary and sufficient condition for blood glucose regulation in patients with type 2 diabetes (Fig. 1) [26,27].

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors (first introduced in 2005 and 2012, respectively) both offer significant benefits including a low risk of hypoglycemia and substantial weight loss effects. The EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose) trial [28] and the LEADER (Liraglutide Effect and Action in Diabetes) trial [29], published after 2015, marked significant progress in the management of type 2 diabetes. These studies demonstrated that SGLT2 inhibitors and GLP-1RAs not only regulate blood glucose but also control dyslipidemia and hypertension and provide benefits in managing CVDs even when antiplatelet agents are used (Table 1) [20]. SGLT2 inhibitors and GLP-1RAs have been shown to reduce MACEs in high-risk type 2 diabetes patients and have also exhibited primary prevention effects for CVDs. Furthermore, SGLT2 inhibitors have significantly reduced outcomes such as death from kidney-related diseases and hospitalizations due to kidney failure [30]. Beyond their impact on CVDs and DKD, additional mechanisms related to these benefits, aside from blood glucose regulation, have been identified [31]. Recent studies have also revealed that these two drug classes positively affect heart failure and CVDs in patients with heart failure who do not have a history of diabetes or in those who are overweight or obese, respectively [32,33]. These findings have prompted a shift in the guidelines for selecting antidiabetic medications in patients with type 2 diabetes, from a primarily glucocentric approach to one focused on organ protection to prevent the progression of comorbidities. This approach is reflected in the latest treatment guidelines from the Korean Diabetes Association. Metformin is recommended as the initial treatment, accompanied by diet and exercise, for patients with type 2 diabetes [12]. Additionally, it is important to identify risk factors such as atherosclerosis, heart failure, or DKD, and choose either GLP-1RAs or SGLT2 inhibitors based on these risks. It is recommended that individual agents from these two classes should be selected for their confirmed CVD benefits and that other classes should be considered as combination therapy for glycemic control based on the clinical characteristics of the individual patient. Moreover, it is advised to avoid TZDs in patients with heart failure or those at high risk (Fig. 1) [27,34].

"Medicine is an ever-changing science" [35]. This statement underscores the reality that medical standards can evolve based on new research and clinical experiences. Since the discovery of insulin in 1921 [36], the management of type 2 diabetes has undergone significant transformations. Initially, the focus was on a "glucocentric” concept, prioritizing "efficacy" through intensive blood glucose control. This approach later shifted to a "safety” concept, aimed at mitigating risks associated with weight gain, hypoglycemia, and CVDs. More recently, the focus has moved towards "organ protection," addressing serious complications such as CVDs and DKD, which are associated with mortality among diabetes patients. Furthermore, it is also anticipated that the results of cardiovascular outcome trials for new agents such as GLP1/glucose-dependent insulinotropic polypeptide (GIP) dual agonists and GLP1/GIP/glucagon triple agonists soon to be available in Korea will change the paradigm. Current management strategies for type 2 diabetes require a holistic approach that not only addresses hyperglycemia but also considers the risks associated with CVDs and DKD.