Monotherapy in patients with type 2 diabetes mellitus

Principles of initial management after diagnosis of type 2 diabetes mellitus

Principles of treatment with antihyperglycemic agents

Selection of topics, organization of the working group, and determination of methods

In March 2017, the Clinical Practice Guideline (CPG) update was discussed at the Committee of Clinical Practice Guideline in the KDA. The committee decided to carry out an amendment in this revision that reflects the new diabetes medications. For this task, the committee formed a working group for revising the relevant content of the CPG. The guidelines were revised based on a systematic review of the newly published literature, along with the other national and international CPG contents. The details of this process are described in detail in other documents [11].

Key question selection

The task of the authors of the current article was evaluating the monotherapy of oral hypoglycemic agents for the working group. We have determined the key questions for revising the CPG according to the results of the discussion within the group. The first question is whether metformin is appropriate as a first-line choice for Korean patients with T2DM. The second question is how to choose the other first-line agent if metformin is not available. Finally, cardiovascular outcome with metformin or other monotherapy was determined to be the third key question.

Literature review

For the purpose of revising the guidelines, various domestic and international guidelines have been referred to. We referred to the KDA guidelines and the Korea National Diabetes Program (KNDP) guidelines as domestic guidelines [12,13] and referred to the guidelines of the American Diabetes Association (ADA), National Institute for Health and Care Excellence (NICE), International Diabetes Federation (IDF), Canadian Diabetes Association (CDA), and American Association of Clinical Endocrinologists and American College of Endocrinology (AACE) as foreign guidelines [14-18]. References that meet our key questions were adopted. In addition, a systematic review was conducted to obtain the latest evidence. A master database for systematic review was built by professional librarians and delivered to group members. The evidence levels of the articles in the database were evaluated according to individual reviews of the group members. Thereafter, a list of articles was prepared by mutual review and agreement of group members. A final list was established by independent committee members separate from the working group [11].

Drafting, public hearing, and final approval of board of directors

The revised recommendations were circulated and evaluated by members of the committee other than the working group. Based on peer review, a draft CPG update was prepared. In July 2017, an initial draft was released at a public hearing. A final draft of the CPG update was prepared in accordance with the opinions gathered at the hearing. In August 2017, the final manuscript was approved by the Board of Directors, KDA.

Oral hypoglycemia agent as a monotherapy

For patients with T2DM who have not satisfactorily met therapeutic goals with LSM, a first-line oral hypoglycemic monotherapy should be administered. In monotherapy, approximately 0.5% to 1.5% of glycosylated hemoglobin (HbA1c) reduction is observed depending on the medication [19]. Although there are some differences depending on the class, the maximal effect of the drug is usually observed 4 to 6 months after treatment [20]. In general, the higher the patient’s HbA1c, the greater the extent of HbA1c reduction with medication [19]. Postprandial glucose control becomes more important for further improvement of HbA1c when blood glucose approaches the generally recommended level (less than 7.3% of HbA1c) [21]. Some studies have shown that postprandial glucose is an independent risk factor for cardiovascular disease and death regardless of fasting glucose [22,23]. However, the evidence for whether postprandial improvement of blood glucose is effective in improving additional cardiovascular disease outcomes is not yet clear.

Metformin as an initial treatment regimen

Metformin is recommended as the drug for initial treatment in most diabetes-related CPGs worldwide [12-18]. Metformin is recommended as the first choice for patients with T2DM because of its excellent blood glucoselowering effect, relatively low adverse effects, long-term safety, low risk of hypoglycemia, and low weight gain. These recommendations are based on a cohort study in which metformin monotherapy in overweight T2DM patients was associated with more marked blood glucose-lowering effects and less weight gain and hypoglycemia compared to sulfonylurea or insulin monotherapy [24]. Potential cardiovascular disease prevention effect is also included in the reason for choosing metformin as the initial treatment [24,25]. However, the preventive effect of metformin on cardiovascular disease has yet to be ascertained.

In several subsequent observational studies and meta-analyses, there was evidence that metformin could be the drug of choice for initial treatment of diabetes patients compared to sulfonylurea, thiazolidinedione, and dipeptidyl peptidase 4 (DPP4) inhibitor, from the aspects of HbA1c reduction, side effects, weight gain, hypoglycemia, economic feasibility, and cardiovascular disease prevention [26-29]. In a prospective, multicenter clinical trial conducted in Korea, the effect of metformin monotherapy on HbA1c was similar to that of sulfonylurea or thiazolidinedione monotherapy [30]. Based on the above evidence, we also recommend metformin as an initial first-line medication in this CPG.

Clinical situations such as hepatic failure, chronic kidney disease (caution in estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2, contraindication in eGFR < 30 mL/min/1.73 m2), severe infection, dehydration, and heart failure are contraindications of metformin use and it should be used with caution [14,17]. Recently, a study suggesting that metformin use may be associated with vitamin B12 deficiency and anemia was published [31]. Vitamin B12 measurements may be considered for metformin users with peripheral neuropathy or anemia.

Monotherapy using other oral hypoglycemic agents

For patients who are contraindicated for metformin or who experience difficulties with metformin use, monotherapy of other hypoglycemic agents is considered as an initial treatment. Recently, as new drugs have been launched, various oral hypoglycemic agents have become available in clinical practice (Table 1) [11]. These drugs differ not only in their mechanism of action, but also in terms of cardiovascular disease prevention, side effects, contraindications, and price.

Table 1.

Oral antihyperglycemic agents for patients with type 2 diabetes mellitus used in Korea

The DPP4 inhibitors have been widely used as a substitute for patients who have difficulty in using metformin monotherapy; these inhibitors are used because of their low incidence of side effects such as hypoglycemia. Recently, a meta-analysis has been reported by Korean researchers that suggests the effect of DPP4 inhibitors on Asians may be superior to other ethnicities [32]. The effects of the DPP4 inhibitors on cardiovascular disease have been reported to be neutral according to multicenter, prospective, randomized controlled trials performed recently performed trials [33-35]. Although some DPP4 inhibitor have been reported to increase the risk of heart failure, systematic reviews have shown that the risk is not significant, and there is a slight difference in the risk of heart failure resulting from the use of DPP4 inhibitors [36,37].

The use of sodium-glucose cotransporter 2 (SGLT2) inhibitors has recently led to a significant reduction in the risk of cardiovascular disease and mortality in patients with diabetes in multicenter, prospective, randomized controlled trials, and the frequency of use of these inhibitors is increasing in clinical settings [38-41]. However, due to possible side effects such as urogenital infection, dehydration, and hypotension, caution should be paid to its administration to some individuals such as the elderly and patients with chronic kidney disease [38,40]. A recent multi-center, prospective, randomized controlled clinical trial has reported an increased risk of osteoporotic fractures and limb amputation associated with the use of this medication [41]. Further research on the long-term safety of this drug is needed.

A wide variety of previously used drugs such as sulfonylurea, meglitinide, thiazolidinedione, and α-glucosidase inhibitor can also be used as an effective substitute for metformin after securing various evidence on efficacy and safety when using this monotherapy [29,42-44]. There is some evidence that thiazolidinedione may reduce the cardiovascular disease risk in patients with T2DM who have a high risk of macrovascular events [45,46]. However, attention should be paid to increased edema, anemia, bone fracture, and heart failure risk in patients [46]. α-Glucosidase inhibitor is an effective agent for postprandial glucose control [47-49]; however, side effects such as gastrointestinal trouble are frequent, and there is a lack of evidence for cardiovascular outcome [48,49]. Sulfonylurea and meglitinide have an excellent blood glucoselowering effect. However, the cardiovascular benefit is not clear, and there is a risk of hypoglycemia [30,50]. Recent studies in Korea have shown that hypoglycemia is closely related to adverse outcomes of patients [51-54]. Care should be taken with the use of drugs that are highly likely to cause hypoglycemia.