[Interview] New diabetes guidelines shift focus from metformin to personalized therapy
The Korean Diabetes Association (KDA)'s “2025 Diabetes Treatment Guidelines Revision Draft,” released in April, has sparked significant debate in clinical practice. Especially noteworthy was the decision to remove metformin—long used as the first-line treatment for type 2 diabetes—from the list of “first-line medications” and instead recommend personalized treatment tailored to each patient's characteristics and condition. To understand how these revised guidelines will impact clinical practice, Korea Biomedical Review spoke with Professor Kim Soo-kyoung of the Department of Endocrinology at Gyeongsang National University Hospital. Professor Kim also explained the latest trends in drug therapy, including the use of fixed-dose combinations (FDCs) tailored to the needs of patients requiring multiple medications.
Question: The exclusion of metformin from the first-line medications in the Korean Diabetes Association (KDA)'s clinical practice guidelines has drawn attention. What other notable changes are included in the revised guidelines?
Answer: This guideline revision was developed using an evidence-based PICO (Patient or Population, Intervention, Comparison, and Outcome) tool. The recommendations did not change significantly because the core questions were identified and evidence was gathered in response to them. However, there were four major changes in screening and other areas. First, the strength and level of recommendations for continuous glucose monitoring and web-based digital technology services were increased. Second, the recommendations for drug therapy, including metformin, have been revised. The algorithm has been modified in three areas: blood glucose lowering, treatment of pancreatic insufficiency, and management of cardiovascular and cardiac risk factors. Third, the treatment targets for hypertension have been set more strictly, reflecting the guidelines of the American Diabetes Association (ADA). The strength of recommendations for adjunctive therapy when using obesity medications has also been upgraded. Finally, the guidelines for type 2 diabetes in children and adolescents have been improved to enable early screening and intervention for children and adolescents with risk factors.
Q: What is the background for the exclusion of metformin from the first-line treatment in the clinical practice guidelines?
A: The exclusion of metformin from the “first-line drug recommendation” does not mean that metformin should no longer be used as a first-line drug. Diabetes requires customized drug selection based on individual patient characteristics, treatment acceptability, and the characteristics of the specific drugs. Using metformin uniformly for all patients may limit the range of drug options. The Japanese Diabetes Society also reports that in elderly diabetes patients, insulin secretion reduction is the primary mechanism rather than insulin resistance, so metformin may not be suitable as a first-line agent, depending on the metabolic state. Additionally, in cases of heart failure, chronic heart disease, or kidney disease, agents such as SGLT-2 inhibitors may offer greater benefits than metformin. In other words, metformin can be used for patients who are suitable for it, while other drugs can be used for patients who are not suitable (e.g., those with heart failure or heart disease).
Q: So, does this guideline revision mean that restrictions have been lifted to enable patient-tailored diabetes treatment?
A: Right. The most significant change in this guideline is that it emphasizes the importance of providing patient-tailored treatment from the outset.
Q: Are there any concerns about the revision of the treatment guidelines?
A: While the treatment guidelines have been revised, the reimbursement criteria have not yet been changed. As far as I know, discussions regarding changes to the reimbursement criteria are currently underway (by academic societies, etc.). If the reimbursement criteria are revised, the current practice of using metformin as the default treatment may shift toward prescribing medications such as SGLT2 inhibitors or GLP-1 agonists from the outset.
Some medications are more effective than metformin in terms of cardiovascular benefits, effects on non-alcoholic fatty liver disease, weight loss, and the risk of hypoglycemia. These medications can be tailored to the patient's characteristics. The essence of this guideline is that it is better to start with personalized treatment tailored to the patient from the beginning rather than following the traditional approach of prescribing metformin first and then moving on to other steps.
Q: Most patients receiving diabetes medication are on combination therapy. Various combination therapies are used in clinical practice to achieve cardiovascular protection or blood glucose-lowering effects. Do you think this guideline will influence this trend?
A: Diabetes is not a disease caused by a single mechanism. It arises from various pathophysiological mechanisms, so many patients require combination therapy. When administering combination therapy, it is essential to comprehensively consider the characteristics of the medications, the patient's current weight, comorbidities, and the potential for side effects. From this perspective, we anticipate that the use of combination therapy, excluding metformin, will continue to increase. In Korea, GLP-1 agonists are only available as injectable formulations, so there is a preference for oral drug combinations. Therefore, prescriptions for various combinations, including those that include SGLT-2 inhibitors and DPP-4 inhibitors, which are currently preferred, are expected to increase.
Q: What are the advantages of SGLT-2 inhibitors and DPP-4 inhibitors?
A: When selecting a single medication, the possibility of hypoglycemia or side effects should be considered first. This is because there is no significant difference in blood glucose-lowering effects between the medications. In elderly patients or those sensitive to side effects, DPP-4 inhibitors are preferred, while younger patients, who often have obesity or metabolic syndrome, are more likely to be prescribed SGLT-2 inhibitors.
Additionally, in patients with chronic heart failure or heart disease, metformin was previously used as the first-line agent if there were no side effects. Still, SGLT-2 inhibitors are now preferred even in these patients. Therefore, SGLT-2 inhibitors and DPP-4 inhibitors are likely to become the main combination for combination therapy. When combination therapy excluding metformin becomes available, combination therapy may be possible even in the initial treatment stage if the HbA1c level is 7.5 percent or higher. According to current guidelines, combination therapy may be recommended from the outset if this threshold is met. In such cases, fixed-dose combination (FDC) formulations, which combine two medications in a single tablet, can reduce the number of daily doses and offer cost benefits. Therefore, the frequency of using combination or concomitant therapy from the outset is expected to increase compared to previous practices.
Q: We have heard that fixed-dose combination (FDC) is not preferred in some cases because dose adjustment is not easy for each patient.
A: I did not prefer prescribing fixed-dose combination drugs (FDCs) from the beginning. Typically, when HbA1c is 7.5 percent or higher, medication dosage adjustment is necessary, and in the past, many FDCs contained metformin. However, in such cases, the tablet size was too large, making it difficult for elderly patients aged 70 or older to swallow the medication. Additionally, the blood sugar-lowering effects and side effects of metformin vary depending on the dosage. If side effects such as heartburn, indigestion, or diarrhea occur, the dosage must be adjusted continuously, which can be cumbersome. For these reasons, I previously preferred FDCs less, but recently, FDCs combining SGLT2 inhibitors or DPP-4 inhibitors without metformin have become available. These combinations feature smaller tablet sizes, allowing metformin to be used as a single agent, which makes dose adjustment more convenient. Metformin was often difficult for patients to tolerate and required discontinuation in many cases. For example, when reducing metformin dosage is necessary before CT scans or in cases of impaired renal function, the ability to adjust the dose flexibly as needed makes it more convenient for healthcare providers. In this regard, I believe that the recent FDCs are much more flexible than before.
Q: What are the advantages of the recent combination prescriptions of SGLT-2 inhibitors and DPP-4 inhibitors over metformin-containing combination drugs?
A: In terms of blood glucose-lowering effects, there is no significant difference between the combination with metformin and the combination of SGLT-2 and DPP-4 inhibitors. Some data suggest that the combination with metformin is slightly better, but this has no clinical significance. SGLT-2 inhibitors act by blocking glucose reabsorption in the proximal tubules of the kidneys, independent of insulin action, so there are no issues with combining them with any other medication. On the other hand, DPP-4 inhibitors stimulate insulin secretion in the pancreas. In other words, the two drugs have different mechanisms of action.
In particular, SGLT2 inhibitors mainly lower fasting blood glucose, while DPP-4 inhibitors mainly lower postprandial blood glucose, making them complementary in terms of their blood glucose-lowering effects. Additionally, both drugs have minimal side effects, such as hypoglycemia or weight gain, and they promote weight loss, making them suitable for patients with obesity. However, SGLT2 inhibitors rarely cause related side effects such as urinary tract infections, so caution is necessary. Nevertheless, as experience with their use accumulates, many healthcare providers are prescribing them safely. The prescription rate for this combination has been steadily increasing over the past few years.
Q: Various SGLT-2 and DPP-4 inhibitors are used in Korea. We are curious to know if there are any specific criteria for selecting these ingredients.
A: SGLT-2 inhibitors are preferred for their cardiovascular and renal protective effects rather than their blood glucose-lowering effects. Recently, positive reports have also emerged regarding their effects on metabolic disorders and even cognitive decline (dementia). In other words, they are often selected due to their numerous benefits beyond lowering blood glucose. Of course, not all components have been thoroughly studied, and some are considered to have class effects. However, it is essential to select medications with clear clinical evidence whenever possible. In this regard, original medications like dapagliflozin and empagliflozin, which have established data, are considered relatively advantageous. When considering the effects on various organs in addition to blood glucose lowering, we prescribe medications with sufficient evidence.
Q: Are there any notable prescription cases related to SGLT-2 inhibitors?
A: Among young patients with type 2 diabetes in their 30s and 40s, the proportion of male patients is relatively high, and this patient group prefers medications with weight loss effects. SGLT-2 inhibitors generally expect an average weight loss of 2–3 kg, but one young patient lost approximately 7 kg. This is an outstanding result compared to most medications for obesity treatment. In elderly patients, losing this much weight could be problematic, but younger patients are satisfied with the weight loss. The patient in question had a BMI of about 27 and reasonable blood sugar control. Therefore, prescribing this medication yielded good results and left a lasting impression.
Q: There is growing concern about the increasing number of young diabetes patients. What results can be expected from SGLT2 or DPP-4 inhibitors for these patients?
A: According to health insurance reimbursement criteria, metformin is used first, followed by SGLT2 inhibitors. However, young patients often struggle to control their snacking habits and exhibit irregular meal patterns. They also tend to engage in high-intensity or irregular exercise, which raises concerns about hypoglycemia. While hypoglycemia is typically more concerning in older patients, younger patients with irregular lifestyles also require consideration for hypoglycemia. Therefore, SGLT-2 inhibitors are often used in combination with metformin, followed by DPP-4 inhibitors. There is also a tendency to avoid sulfonylurea (SU) agents in patients with poor glycemic control.
Q: If reimbursement criteria are not considered, using a combination of SGLT-2 inhibitors and DPP-4 inhibitors may be ideal for elderly patients, taking into account concerns such as hypoglycemia.
A: It is difficult to say that the combination of SGLT2 inhibitors and DPP-4 inhibitors is always beneficial for elderly patients. This is because, while approximately half of elderly patients are obese, about 30% do not experience weight gain. It is essential to consider the patient's characteristics and comorbidities. The combination of SGLT2 and DPP-4 is generally suitable for elderly patients who are significantly overweight or have indications such as heart failure or impaired kidney function. On the other hand, in the local area near Gyeongsang National University Hospital, many patients have poor overall health, multiple chronic conditions (comorbidities), or difficulty managing medication. In such cases, rather than prescribing medication uniformly, it is crucial to approach each elderly patient carefully, taking into account their condition.