Under the continuous effect of insulin resistance, the islet function of type 2 diabetic patients gradually declines, which is still an insurmountable “law” today, and neither insulin stimulants nor insulin sensitizers can reverse or stop this trend. As shown in the UKPDS study, the proportion of patients who could maintain a glycosylated hemoglobin (HbA1c) <7% with monotherapy decreased each year during the follow-up period, suggesting that monotherapy is not effective for long-term glycemic control [1]. 2008, the results of the ACCORD and ADVANCE studies showed that the majority of patients with type 2 diabetes require more than one glucose-lowering drug. Therefore, the American Diabetes Association (ADA) guidelines also mention that most patients eventually need combination therapy. In 2006, a survey of type 2 diabetes patients' medication use in 30 hospitals in China showed that the proportion of patients treated with monotherapy decreased significantly compared to 1998 (75% vs. 50%), while the proportion of patients treated with combination medication reached 60%. At the same time, patients' glycemic control improved significantly (1998: 8.7% ± 2.0%; 2006: 7.6% ± 1.6%), and the proportion of patients with HbA1c < 7% increased significantly [2]. In this context, it is urgent to standardize the clinical combination of drugs. Principles to be followed for combination medications Due to the lack of sufficiently convincing evidence-based medical evidence, there is still a lack of specific referenceable norms regarding the combination of medications in patients with diabetes, relying instead on the experience of clinicians. Some guidelines, such as the 2008 Chinese Guidelines for Type 2 Diabetes and the 2008 ADA/European Association for the Study of Diabetes (EASD) Consensus on the Management of Hyperglycemia in Type 2 Diabetes, state that hypoglycemic drugs with different mechanisms of action should be used in combination. In view of the inspiration from clinical studies such as ACCORD, at the end of 2008 at the Shanghai Editorial Committee on New Developments in Diabetes, Chinese experts proposed the "REACH" strategy for glycemic management, which has explored new approaches to glycemic management in diabetes, which also particularly emphasizes the basic principles of combination drug use: diabetes treatment should be reasonably matched to avoid The basic principle of combination medication is also emphasized: diabetes treatment should be reasonably combined to avoid the increase of adverse reactions. The combination of hypoglycemic drugs with different mechanisms of action is advocated in order to achieve complementary effects of different drugs. According to the classification of glucose-lowering drugs in Joslin Diabetologia (15th edition) (according to the mechanism of action), the existing glucose-lowering drugs can be divided into four categories: insulin promoters, insulin sensitizers, α-glucosidase inhibitors and insulin. How far are patients on combination medications from safely reaching the target? The ACCORD study, which ended in 2008 due to increased mortality in the intensive care group, has brought many reflections to clinical practitioners, and scholars have analyzed and discussed the results of the ACCORD study from different perspectives. The results of the ACCORD study have been analyzed and discussed from a variety of perspectives, including the dosing regimens used in the study. In this study, the combination of three or more hypoglycemic agents in the intensive hypoglycemic group reached nearly 60%, and because insulin, sulfonylureas, and thiazolidinediones (TZDs) all had weight-increasing effects, they increased the weight of patients with a mean body mass index (BMI) of 32 kg/m2 by 3.5 kg, with nearly 28% of them gaining more than 10 kg [3]. It is well known that obesity itself is a risk factor for cardiovascular disease, and during weight gain, systolic blood pressure, diastolic blood pressure, total serum cholesterol and LDL cholesterol levels increase, increasing cardiovascular risk. Although glitazones in combination with insulin have a positive effect on beta cells and are effective in improving blood lipids, they have a synergistic effect on weight gain and the risk of water and sodium retention, and weight gain may also increase the risk of heart failure (heart failure). The AHA and ADA jointly state that combined insulin is a risk factor for heart failure in TZD therapy. In addition, the aggressive treatment regimen used in the ACCORD study resulted in a much higher incidence of hypoglycemia in the intensive group than in the conventional group (4.6% vs. 1.4%). Professor Leiter, who participated in both the ACCORD and ADVANCE studies, believes that it is not the intensive glucose lowering itself that increases the risk of death, but rather the irrational treatment regimen that is at fault. Although the analysis of the results of the ACCORD study is inconclusive, the analysis of the process suggests a shift from a focus on glucose lowering to a focus on both effectiveness and safety in glucose intervention strategies. As the VADT investigators found in their analysis of the results: severe hypoglycemia was a significant risk factor for all-cause mortality, cardiovascular death, and cardiovascular events in the VADT study. The American College of Cardiology Foundation (ACCF)/American College of Cardiology (ACC)/ADA Joint Statement also noted that a single episode of severe medically induced hypoglycemia or resulting cardiovascular event may offset the benefits of maintaining blood glucose in the normal range over a lifetime [4]. This suggests that caution must be exercised regarding the combination of hypoglycemic agents that can bring about hypoglycemia, such as the combination of a proliferative agent and insulin. It was found that the combination of insulin and sulfonylurea significantly increased the hypoglycemic wind compared to metformin alone (P<0.0001), i.e., significantly increased the incidence of hypoglycemia due to the fact that both increase insulin levels in the body. Unfortunately, it is not uncommon for sulfonylureas to be used in combination with insulin in clinical practice; in fact, only glimepiride is currently approved by the US FDA for use in combination with insulin. The combination of sulfonylureas with biguanides is commonly used clinically and accounts for a large proportion of the combined glucose-lowering regimens in Chinese patients with type 2 diabetes. However, a 2008 meta-study showed that the combination of sulfonylureas with biguanides, although not significantly increasing the risk of all-cause mortality, may significantly increase the risk of the composite endpoint of cardiovascular disease admission and death [5]. Although this result is still not universally accepted, the contradiction between clinical experience and evidence-based results suggests that more careful and comprehensive thinking should be done in the treatment of diabetes. Combination medication occupies an important position in the treatment of type 2 diabetes, and a reasonable combination of medications will not only give full play to the synergistic effects between drugs, but also minimize adverse effects, which will have a profound and positive impact on the treatment of type 2 diabetes. There are still irregularities in the combination of drugs in clinical practice, and the only way to improve these phenomena is to make it possible for patients to achieve the blood glucose standard safely. Conclusion Diabetes is a disease with complex etiology and development involving many pathophysiological processes. The majority of clinical patients with type 2 diabetes eventually require the combination of glucose-lowering drugs with different mechanisms of action. The combination of drugs should pay special attention to the rational combination of hypoglycemic drugs to avoid the increase of adverse effects. Studies have confirmed that bactrim, given its unique mechanism of action, can be used in combination with various types of glucose-lowering drugs and insulin, which not only helps to improve the attainment rate, but also has a better impact on weight, hypoglycemia and overall metabolic improvement, and is a good choice for patients with combination drugs to achieve the target safely. The combination of three drugs is also often chosen when the combination of other two drugs is unsatisfactory.