Antihyperglycemic agent therapy for adult patients with type 2 diabetes mellitus 2017: a position statement of the Korean Diabetes Association

published a position statement on the use of antihyperglycemic agents for patients with type 2 diabetes mellitus (T2DM). The KDA regularly updates its Clinical Practice Guidelines, but since the last update in 2015, many results from clinical trials have been introduced, and domestic data from studies performed in Korean patients with T2DM have been published. Recently, evidence from large clinical studies assessing cardiovascular outcomes following the use of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in patients with T2DM were incorporated into the recommendations. Additionally, new data from clinical trials using dipeptidyl peptidase 4 inhibitors and thiazolidinediones in Korean patients with T2DM were added. Following a systematic review and assessment of recent evidence, the KDA updated and modified its clinical practice recommendations regarding the use of antihyperglycemic agents and revised the treatment algorithm for Korean adult patients with T2DM.

# Introduction
The Clinical Practice Guidelines for type 2 diabetes mellitus (T2DM) provided by the Korean Diabetes Association (KDA) include comprehensive and evidence-based treatment and management guidelines to improve the level of care for adults with T2DM in Korea according to Korean standards. The target users of this guideline are primary care physicians and other healthcare professionals who treat adults with T2DM. Since the first edition was published in 1990, the Clinical Practice Guidelines for adult patients with T2DM have been periodically updated by the Committee of Clinical Practice Guidelines of the KDA [bib_ref] Clinical practice guidelines for type 2 diabetes in Korea, Ko [/bib_ref]. However, since the fifth edition was published in 2015, many results from large clinical trials of antidiabetic drugs have been introduced, and clinical evidence from studies assessing Korean patients with T2DM who use dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 receptor agonists (GLP-1RAs), or sodium-glucose cotransporter 2 (SGLT2) inhibitors have accumulated [bib_ref] Addition of ipragliflozin to metformin treatment in Korean patients with type 2..., Min [/bib_ref] [bib_ref] Efficacy and safety of empagliflozin in patients with type 2 diabetes from..., Yoon [/bib_ref] [bib_ref] Exenatide versus insulin lispro added to basal insulin in a subgroup of..., Yoon [/bib_ref]. All novel evidence and results were reviewed to extract recommendations for the treatment of these patients.
The 2017 KDA position statement was written by the Committee of Clinical Practice Guidelines under a formal review process after a systematic and extensive review of articles published from January 1, 2015 to May 31, 2017. The grading system for the scientific evidence was defined by the KDA and modeled after the evidence-grading system of the American Diabetes Associ-ation (ADA) with some modifications. Therefore, the level of evidence and strength of the recommendation were not treated as separate entities. The KDA classified recommendation levels into four ratings (A, B, C, and E) according to the quality of evidence [fig_ref] Table 1: Evidence-grading system of the Korean Diabetes Association [/fig_ref]. If domestic data were limited or evidence was difficult to apply to Korean patients with T2DM, the Committee of Clinical Practice Guidelines made a final decision after intensive discussion. In the absence of qualified supporting evidence, or if the recommendation was based on the consensus of the Expert Committees, a grade E was assigned.
In this 2017 position statement regarding pharmacological therapies for non-pregnant adult patients with T2DM, the KDA updated the previous recommendations published in 2015. In principle, these recommendations were based on extensive review of scientific evidences; therefore, criteria for the health insurance coverage in Korea were not considered. The treatment algorithm for use of antihyperglycemic agents was also revised. Specifically, the previous algorithm was divided into treatment with non-insulin antihyperglycemic agents and treatment with insulin, whereas the updated 2017 position statement is believed to provide the most recent evidence-based treatment recommendations for adult Korean patients with T2DM. Glycemic control within the target range has beneficial effects for reducing the risk of cardiovascular and/ or microvascular complications. The glycemic goal for non-pregnant adult patients with T2DM is ideally a glycosylated hemoglobin (HbA1c) level < 6.5%, but this can be tailored to individual circumstances [bib_ref] Clinical practice guidelines for type 2 diabetes in Korea, Ko [/bib_ref] [bib_ref] Consensus statement by the American association of clinical endocrinologists and American college..., Garber [/bib_ref]. Factors to consider when setting a glycemic target goal include age, duration of diabetes, life expectancy, presence of advanced diabetic complications, comorbidities, repeated episodes of hypoglycemia, cognitive dysfunction, and patient preference [bib_ref] Clinical practice guidelines for type 2 diabetes in Korea, Ko [/bib_ref] [bib_ref] Consensus statement by the American association of clinical endocrinologists and American college..., Garber [/bib_ref]. More stringent goals are required for preoperative and postoperative situations, pregnancy, and acute-onset disease. A patient-centered approach is emphasized to successfully achieve the glycemic goal [bib_ref] Clinical practice guidelines for type 2 diabetes in Korea, Ko [/bib_ref] [bib_ref] Consensus statement by the American association of clinical endocrinologists and American college..., Garber [/bib_ref] [bib_ref] Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update..., Inzucchi [/bib_ref].
LSM is an essential component of treatment for all patients with T2DM and should be initiated promptly and simultaneously with antidiabetic medications after diagnosis. Patient education within a structured program should be received from a healthcare professional at the time of diagnosis and then followed up with regular reinforcement checks [bib_ref] Factors associated with participation in diabetes education: the Korea National Health and..., Kim [/bib_ref] [bib_ref] Intensive individualized reinforcement education is important for the prevention of hypoglycemia in..., Yong [/bib_ref] [bib_ref] Current status of managing diabetes mellitus in Korea, Ha [/bib_ref]. For patients with newly diagnosed T2DM, LSM includes medical nutrition therapy, weight control, physical activity, smoking cessation, and avoidance of alcohol should be initiated. Although LSM is a very important component of treatment for T2DM, the administration of antihyperglycemic agents should not be delayed. Pharmacotherapy can be initiated simultaneously and in conjunction with LSM.
T2DM is a chronic metabolic disease with a progressive nature [bib_ref] An update on the effect of incretinbased therapies on -cell function and..., Chon [/bib_ref]. A gradual decline in -cell function and progressive increases in insulin resistance lead to a deteriorated glycemic control status and the need for increasingly intensive pharmacotherapies [bib_ref] Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type..., Turner [/bib_ref]. Therefore, in addition to LSM, a transition from monotherapy to combination therapy with antihyperglycemic agents is usually inevitable. The initiation or add-on to a current therapy of most oral antihyperglycemic agents yields an additional reduction in HbA1c levels of 0.5% to 1.25%, whereas thiazolidinediones (TZDs) and sulfonylureas (SUs) lower HbA1c levels by approximately 1.0% to 1.25% [bib_ref] The effect of oral antidiabetic agents on A1C levels: a systematic review..., Sherifali [/bib_ref].
As an initial therapy for newly diagnosed patients with an HbA1c level  7.5%, metformin monotherapy is recommended [bib_ref] Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes:..., Maruthur [/bib_ref] [bib_ref] Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in..., Palmer [/bib_ref]. Metformin should not be used in patients with an estimated glomerular filtration rate < [fig_ref] Figure 1: Antihyperglycemic therapy algorithm for adult patients with type 2 diabetes mellitus [/fig_ref]. The factors to consider when choosing an antihyper- glycemic medication include its efficacy, complementary mechanism of action, risk of hypoglycemia, effect on weight gain, side effects, patient preference, and comorbidities [bib_ref] Glycaemic durability with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a systematic..., Esposito [/bib_ref] [bib_ref] Benefits and harms of sodium-glucose co-transporter 2 inhibitors in patients with type..., Storgaard [/bib_ref] [bib_ref] Risk factors and adverse outcomes of severe hypoglycemia in type 2 diabetes..., Yun [/bib_ref] [bib_ref] Severe hypoglycemia and cardiovascular or all-cause mortality in patients with type 2..., Cha [/bib_ref]. In the Practical Evidence of Antidiabetic Monotherapy (PEAM) study, the glucose-lowering efficacies of SUs (glimepiride), biguanide (metformin), and TZDs (rosiglitazone) as antidiabetic monotherapies administered for 48 weeks were similar in drug-naive Korean patients with T2DM (decrease in HbA1c levels from 7.8% to 6.9% for glimepiride, p < 0.001; from 7.9% to 7.0% for metformin, p < 0.001; and from 7.8% to 7.0% for rosiglitazone, p < 0.001; p = 0.62) [bib_ref] Comparison of the efficacy of glimepiride, metformin, and rosiglitazone monotherapy in Korean..., Yoon [/bib_ref]. Glimepiride and rosiglitazone significantly increased body weight, while metformin reduced body weight. Symptomatic hypoglycemia was more frequent in the glimepiride group, while diarrhea was more frequent in the metformin group [bib_ref] Comparison of the efficacy of glimepiride, metformin, and rosiglitazone monotherapy in Korean..., Yoon [/bib_ref]. If the initial HbA1c level of a patient is  7.5% or the HbA1c target is not achieved within 3 months initiating monotherapy, dual combination therapy can be considered [bib_ref] Consensus statement by the American association of clinical endocrinologists and American college..., Garber [/bib_ref] [bib_ref] Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update..., Inzucchi [/bib_ref] [bib_ref] Efficacy and safety of empagliflozin as add-on to metformin for type 2..., Zhong [/bib_ref] [bib_ref] The efficacy and safety of DPP4 inhibitors compared to sulfonylureas as add-on..., Mishriky [/bib_ref] [bib_ref] The benefits and risks of DPP4-inhibitors vs. sulfonylureas for patients with type..., Zhou [/bib_ref] [bib_ref] Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on..., Prato [/bib_ref] [bib_ref] Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and..., Kim [/bib_ref]. If the HbA1c target is not achieved within 3 months of initiating dual therapy, a third agent with a complementary mechanism of action can be added for triple combination therapy [bib_ref] Efficacy and safety of antihyperglycaemic drug regimens added to metformin and sulphonylurea..., Mearns [/bib_ref]. Metformin is maintained as background therapy during dual or triple combination therapy. If metformin is not tolerable or is contraindicated, avoid the use of metformin and proceed to the next category in the algorithm [fig_ref] Figure 1: Antihyperglycemic therapy algorithm for adult patients with type 2 diabetes mellitus [/fig_ref]. The reductions in HbA1c values are similar across all drug classes used as monotherapies and metformin-based combinations. Body weight is reduced or maintained with metformin, DPP4 inhibitors, GLP-1RAs, and SGLT2 inhibitors but increased with SUs and TZDs [bib_ref] Efficacy and safety of empagliflozin as add-on to metformin for type 2..., Zhong [/bib_ref] [bib_ref] The efficacy and safety of DPP4 inhibitors compared to sulfonylureas as add-on..., Mishriky [/bib_ref] [bib_ref] The benefits and risks of DPP4-inhibitors vs. sulfonylureas for patients with type..., Zhou [/bib_ref] [bib_ref] Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on..., Prato [/bib_ref]. Hypoglycemia is more frequent with SUs [bib_ref] Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes:..., Maruthur [/bib_ref] [bib_ref] Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in..., Palmer [/bib_ref] [bib_ref] The benefits and risks of DPP4-inhibitors vs. sulfonylureas for patients with type..., Zhou [/bib_ref] [bib_ref] Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on..., Prato [/bib_ref]. As a monotherapy, DPP4 inhibitors exhibit a lower risk of hypoglycemia, lower risks of side effects and weight gain, and a better glucose-lowering efficacy in Asians compared with other ethnic groups [bib_ref] Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and..., Kim [/bib_ref]. When added to metformin and SUs, GLP-1RAs are associated with the lowest risk of hypoglycemia (odds ratio, 0.60; 95% confidence interval, 0.39 to 0.94) [bib_ref] Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in..., Palmer [/bib_ref] , but gastrointestinal side effects are highest with metformin and GLP-1RAs. SGLT2 inhibitors have greater associations with the potential side effects of urinary tract infection and euglycemic diabetic ketoacidosis [bib_ref] Efficacy and safety of empagliflozin as add-on to metformin for type 2..., Zhong [/bib_ref] [bib_ref] SGLT2 inhibitors may predispose to ketoacidosis, Taylor [/bib_ref].
If postprandial hyperglycemia occurs, meglitinides, AGIs, DPP4 inhibitors, or GLP-1RAs can be considered [bib_ref] The role of glucagon-like peptide-1 receptor agonists in type 2 diabetes: understanding..., Oh [/bib_ref] [bib_ref] Nateglinide and acarbose for postprandial glucose control after optimizing fasting glucose with..., Kim [/bib_ref]. The early initiation of combination therapy is preferred over maximizing the dosage of a single agent after considering glucose-lowering efficacy and side effects [bib_ref] A treatment strategy implementing combination therapy with sitagliptin and metformin results in..., Olansky [/bib_ref] [bib_ref] Early combination therapy for the treatment of type 2 diabetes mellitus: systematic..., Phung [/bib_ref]. SUs or DPP4 inhibitors are not associated with increased risks of major cardiovascular events in patients with T2DM, irrespective of comparator or background medications [bib_ref] The association between sulfonylurea use and all-cause and cardiovascular mortality: a meta-analysis..., Varvaki Rados [/bib_ref]. However, for patients with longstanding suboptimally controlled T2DM and established atherosclerotic cardiovascular disease, the ADA recommends empagliflozin or liraglutide, because these drugs have been shown to reduce cardiovascular and all-cause mortality rates. Ongoing studies investigating the cardiovascular benefits of the SGLT2 inhibitors, DPP4 inhibitors, and GLP-1RAs are being conducted. Insulin therapy should be initiated if the patient fails to achieve the target glycemic goal despite the appropriate treatment with oral antihyperglycemic agents. The KDA recommends insulin therapy in two circumstances: as the initial treatment after diagnosis of T2DM and after oral antihyperglycemic agent failure.

## Injections for patients with type 2 diabetes mellitus: insulin and glp-1ras
Initiation of insulin treatment at the diagnosis of T2DM is recommended if the patient has severe hyperglycemia (HbA1c levels > 9.0%) with hyperglycemic symptoms (polyuria, polydipsia, and weight loss) and/ or metabolic decompensation [bib_ref] Clinical practice guidelines for type 2 diabetes in Korea, Ko [/bib_ref] [bib_ref] The glycemic efficacies of insulin analogue regimens according to baseline glycemic status..., Hwang [/bib_ref]. Insulin therapy should also be considered in patients with decompensated hepatic or renal insufficiency, myocardial infarction, stroke, and/or critical illness, as well as those undergoing major surgery [bib_ref] Clinical practice guidelines for type 2 diabetes in Korea, Ko [/bib_ref] [bib_ref] Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including..., Griesdale [/bib_ref].
For patients with T2DM who fail to achieve the glycemic goal following adequate treatment with oral antihyperglycemic agents, insulin injection therapy is the next step [bib_ref] Consensus statement by the American association of clinical endocrinologists and American college..., Garber [/bib_ref] [bib_ref] Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in..., Palmer [/bib_ref] [bib_ref] An analysis of early insulin glargine added to metformin with or without..., Fonseca [/bib_ref] [bib_ref] Comparison between the therapeutic effect of metformin, glimepiride and their combination as..., Park [/bib_ref] [bib_ref] Effects of three injectable antidiabetic agents on glycaemic control, weight change and..., Zhong [/bib_ref]. Basal insulin alone or in combination with oral antihyperglycemic agents is easy to administer and is the preferred choice. Basal insulin alone, including both intermediate-acting and long-acting analogs, is the most convenient initial insulin regimen. Although the glucose-lowering effects are similar, hypoglycemia occurs less frequently with long-acting basal insulin analogs (insulin glargine or detemir) than with neutral prot amine Hagedorn (NPH) insulin (human isophane insulin) [bib_ref] Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2..., Horvath [/bib_ref]. A recently introduced ultra-long-acting insulin, degludec, showed a lower rate of nocturnal hypo-glycemia and reduced mean fasting plasma glucose level compared with glargine in patients with T2DM [bib_ref] Insulin degludec results in lower rates of nocturnal hypoglycaemia and fasting plasma..., Gall [/bib_ref] [bib_ref] Efficacy and safety of degludec versus glargine in type 2 diabetes, Marso [/bib_ref].
Basal insulin is typically combined with metformin and/or other classes of oral antihyperglycemic agents. The addition of DPP4 inhibitors to a basal insulin regimen results in significant improvements in glycemic control relative to placebo without increasing hypoglycemia or body weight [bib_ref] Effects of adding linagliptin to basal insulin regimen for inadequately controlled type..., Yki-Jarvinen [/bib_ref] [bib_ref] Improved glycaemic control with vildagliptin added to insulin, with or without metformin,..., Kothny [/bib_ref] [bib_ref] Comparison between sitagliptin as add-on therapy to insulin and insulin dose-increase therapy..., Hong [/bib_ref]. Compared with a 25% increase in the insulin dose, the addition of sitagliptin to an insulin-based regimen is more effective at lowering HbA1c levels and is associated with less hypoglycemia and weight gain in Korean patients with uncontrolled T2DM [bib_ref] Comparison between sitagliptin as add-on therapy to insulin and insulin dose-increase therapy..., Hong [/bib_ref]. SGLT2 inhibitors achieve better glycemic control and weight reduction than do DPP4 inhibitors without increasing the risk of hypoglycemia in patients with T2DM inadequately controlled by insulin [bib_ref] Comparison between SGLT2 inhibitors and DPP4 inhibitors added to insulin therapy in..., Min [/bib_ref].
The addition of a GLP-1RA to basal insulin or switching to a premixed insulin regimen (once or twice daily) is another option, but this depends on the patient's clinical situation [fig_ref] Table 3: HbA1c, glycosylated hemoglobin [/fig_ref] [bib_ref] Intensification of insulin therapy with basal-bolus or premixed insulin regimens in type..., Giugliano [/bib_ref]. Premixed insulin products contain a basal component as well as a prandial component (NPH/Regular 70/30, 70/30 aspart mix, 75/25 lispro mix, and 50/50 lispro mix), which provides coverage for both basal and prandial needs in a single injection [bib_ref] Consensus statement by the American association of clinical endocrinologists and American college..., Garber [/bib_ref] [bib_ref] Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update..., Inzucchi [/bib_ref]. For patients with T2DM who are unable to achieve glycemic control despite basal insulin titration, the addition of a GLP-1RA to the titrated basal insulin results in HbA1c reductions that are similar to those seen with standard basal-bolus or basal-plus insulin regimens, in conjunction with a lower relative risk of hypoglycemia and a greater decrease in body weight [bib_ref] Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin..., Diamant [/bib_ref] [bib_ref] Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management..., Eng [/bib_ref] [bib_ref] A comparison of adding liraglutide versus a single daily dose of insulin..., Mathieu [/bib_ref].
If glycemic control in patients treated with basal in- sulin alone or in combination with oral antihyperglycemic agents is not within the target range, treatment intensification via addition of a prandial insulin, such as a rapid-acting insulin analog (lispro, aspart, or glulisine), at the main meal (basal-plus) or at each meal (basal-bolus) is recommended [fig_ref] Table 4: Properties of different insulins NPH/Regular 70/30 Premixed insulin products contain both a... [/fig_ref] , [fig_ref] Figure 2: Treatment algorithm for insulin therapy [/fig_ref]. An insulin intensification strategy might also consist of upward titration of the insulin dose and regimen modification. As prandial insulin, rapid-acting insulin analogs are preferred to regular insulin because of their rapid onset, lower frequency of hypoglycemia, and ease of use (injection before meal) [bib_ref] Consensus statement by the American association of clinical endocrinologists and American college..., Garber [/bib_ref] [bib_ref] Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update..., Inzucchi [/bib_ref]. If the HbA1c goal is not reached following the administration of premixed insulin given twice daily, consider switching to a premixed insulin analog (70/30 aspart mix, 75/25 lispro mix, 50/50 lispro mix) given three times daily for intensification. There are no clinically relevant differences in terms of the efficacies of basal-bolus versus premixed insulin regimens for decreasing HbA1c levels in patients with T2DM [bib_ref] Intensification of insulin therapy with basal-bolus or premixed insulin regimens in type..., Giugliano [/bib_ref]. The effects of two insulin-based strategies, glargine once daily and premixed insulin once or twice daily, were compared in subjects with T2DM who did not achieve adequate glycemic control with oral agents. More patients using premixed insulin achieved their target, with less frequent symptomatic hypoglycemia, compared with glargine. Glargine (with or without glulisine) and premix strategies result in similar rates of well-controlled diabetes without hypoglycemia, in that more patients achieve their target HbA1c levels with premixed insulin, whereas overall symptomatic hypoglycemia occurs less frequently with glargine [bib_ref] The glycemic efficacies of insulin analogue regimens according to baseline glycemic status..., Hwang [/bib_ref] [bib_ref] Intensification of insulin therapy with basal-bolus or premixed insulin regimens in type..., Giugliano [/bib_ref].
When deciding intensify an insulin regimen, physicians should consider the various advantages and disadvantages of each option, including flexibility, complexity, and the frequency of hypoglycemia. Furthermore, healthcare professionals should provide comprehensive self-care education that includes insulin injection skills, self-monitoring of blood glucose levels, hypoglycemia management, and simple dosage adjustment prior to the initiation of insulin therapy [bib_ref] Comparison of antidiabetic regimens in patients with type 2 diabetes uncontrolled by..., Choi [/bib_ref].

## Conflict of interest
No potential conflict of interest relevant to this article was reported. If the initial glycosylated hemoglobin (A1C) level is > 9.0% and symptomatic hyperglycemia or metabolic decompensation is present, insulin therapy can be initiated with or without oral antihyperglycemic agents (OHAs) in patients with newly diagnosed type 2 diabetes mellitus (T2DM). If the HbA1c target range is not achieved after implementing a basal insulin regimen, then proceed to intensification treatment, for example, addition of a glucagon-like peptide 1 receptor agonist (GLP-1RA) or a prandial insulin or switching to a premixed insulin regimen. (B) For adult patients with T2DM who have not achieved their glycemic target following adequate treatment using OHAs. When OHAs fail, proceed to basal insulin either with or without OHAs. The addition of a GLP-1RA or switching to a premixed insulin regimen could be another option depending on the patient's clinical situation. The width of each black line reflects the strength of the expert consensus recommendations.

## A b
[fig] Figure 1: Antihyperglycemic therapy algorithm for adult patients with type 2 diabetes mellitus (T2DM). The algorithm stratifies the choice of medications for T2DM based on initial glycosylated hemoglobin (HbA1c) levels and demonstrates drug arrangement in a centrifugal direction. This algorithm includes only U.S. Food and Drug Administration-approved classes of medications for T2DM that are prescribed in Korea. For newly diagnosed T2DM, begin with lifestyle modification (LSM) at the time of diagnosis and subsequently maintain these changes for the duration of treatment. The HbA1c target is < 6.5%; if this is not achieved within 3 months after implementing LSM, then the use of an antihyperglycemic agent should be initiated promptly. If the HbA1c level is < 7.5%, metformin monotherapy is the preferred choice for pharmacotherapy in conjunction with LSM. If there are contraindications for metformin or side effects, then consider other monotherapy options such as a dipeptidyl peptidase 4 inhibitor (DPP4i), sodium-glucose cotransporter 2 inhibitor (SGLT2i) thiazolidinedione (TZD), glucagon-like peptide 1 receptor agonists (GLP-1RAs), sulfonylurea (SU), -glucosidase inhibitor (AGI), or insulin as the initial therapy according to the patient's condition. If the initial HbA1c level is  7.5% or the HbA1c target is not achieved within 3 months of monotherapy, dual combination therapy can be considered. In this case, a second-line drug is added to metformin; however, any other combination of drugs with different mechanisms of action can be used depending on the patient's clinical characteristics. If the HbA1c target is not achieved within 3 months after commencing dual therapy, then proceed to triple combination therapy. In no particular order of preference, efficacy, risk of hypoglycemia, weight gain, impact on cardiovascular (CV) outcomes, and presence of clinical data in the Korean population should be considered for this arrangement. To aid the physician's choice, the characteristics of antihyperglycemic agent classes are shown as a bar scale. Efficacy (green), hypoglycemia risk (red), body weight gain (yellow), and CV benefit (blue color) were assigned ratings of low, intermediate, or high based on recently published studies identified in an extensive literature review; the scale bar is not constructed according to strict definitions but should be used as a guide for clinical decisions. GLN, glinide (meglitinide). a GLN can be used as dual combination therapy with metformin, TZD, AGI, or insulin or as a triple combination therapy with metformin and AGI, metformin and TZD, or metformin and insulin. [/fig]
[fig] Figure 2: Treatment algorithm for insulin therapy. (A) Initiation of insulin treatment. [/fig]
[table] Table 1: Evidence-grading system of the Korean Diabetes Association [/table]
[table] Table 2: Oral antihyperglycemic agents for patients with type 2 diabetes mellitus used in Korea Mechanism and common use Weight gain Hypoglycemia a HbA1c, glycosylated hemoglobin; GI, gastrointestinal; eGFR, estimated glomerular filtration rate; DPP4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide 1; GIP, gastric inhibitory polypeptide; CKD, chronic kidney disease; SGLT2, sodium-glucose cotransporter 2; DKA, diabetic ketoacidosis. www.kjim.org https://doi.org/10.3904/kjim.2017.298 30 mL/min/1.73 m 2 , severe renal or hepatic dysfunction, heart failure, severe infection, or dehydration [6-10]. If metformin is not tolerable or is contraindicated, the alternative choices for monotherapy include DPP4 inhib-itors, SGLT2 inhibitors, TZDs, GLP-1RAs, SUs, glinides (meglitinide), -glucosidase inhibitors (AGIs), and insulin according to patient circumstances (Table 2, Fig. [/table]
[table] Table 3: HbA1c, glycosylated hemoglobin; GLP-1, glucagon-like peptide 1; SC, subcutaneous; GI, gastrointestinal; MEN2, multiple endocrine neoplasia 2; MTC, medullary thyroid cancer. a Monotherapy. [/table]
[table] Table 4: Properties of different insulins NPH/Regular 70/30 Premixed insulin products contain both a basal and prandial insulin component to cover both basal and prandial glucose levels with a single injection Aspart 70/30 Lispro 75/25, 50/50 NPH, neutral protamine Hagedorn. www.kjim.org https://doi.org/10.3904/kjim.2017.298 [/table]