Principles of initial management after diagnosis of type 2 diabetes mellitus

Principles of treatment with antihyperglycemic agents

Glycemic control within the target range has beneficial effects for reducing the risk of cardiovascular and/or microvascular complications [7]. 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 [1,8,9]. 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 [1,6,8]. 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 [1,6,8-10].

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 [11-13]. 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 [14]. A gradual decline in β-cell function and progressive increases in insulin resistance lead to a deteriorated glycemic control status and the need for increasingly intensive pharmacotherapies [15]. 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% [16].

As an initial therapy for newly diagnosed patients with an HbA1c level ≤ 7.5%, metformin monotherapy is recommended [17-19]. Metformin should not be used in patients with an estimated glomerular filtration rate < 30 mL/min/1.73 m², 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 inhibitors, SGLT2 inhibitors, TZDs, GLP-1RAs, SUs, glinides (meglitinide), α-glucosidase inhibitors (AGIs), and insulin according to patient circumstances (Table 2, Fig. 1). The factors to consider when choosing an antihyperglycemic medication include its efficacy, complementary mechanism of action, risk of hypoglycemia, effect on weight gain, side effects, patient preference, and comorbidities [20-23]. 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) [24]. 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 [24].

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 [6-10,25-30]. 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 [31]. 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. 1). 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 [25-29]. Hypoglycemia is more frequent with SUs [18,19,28,29]. 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 [30]. 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) [19], 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 [26,32].

If postprandial hyperglycemia occurs, meglitinides, AGIs, DPP4 inhibitors, or GLP-1RAs can be considered [33,34]. The early initiation of combination therapy is preferred over maximizing the dosage of a single agent after considering glucose-lowering efficacy and side effects [35,36]. SUs or DPP4 inhibitors are not associated with increased risks of major cardiovascular events in patients with T2DM, irrespective of comparator or background medications [6,37]. 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 [6,38,39]. Ongoing studies investigating the cardiovascular benefits of the SGLT2 inhibitors, DPP4 inhibitors, and GLP-1RAs are being conducted [6].

Indications for insulin treatment for patients with type 2 diabetes mellitus

Choice of type of insulin treatment

GLP-1RAs

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.

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 [1,6,40]. 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 [1,6,41,42].

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 [6-9,19,43-45]. 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 protamine Hagedorn (NPH) insulin (human isophane insulin) [46]. A recently introduced ultra-long-acting insulin, degludec, showed a lower rate of nocturnal hypoglycemia and reduced mean fasting plasma glucose level compared with glargine in patients with T2DM [47,48].

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 [49-51]. 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 [51]. 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 [52].

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 (Table 3) [53]. 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 [6-10]. 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 [54-56].

If glycemic control in patients treated with basal insulin 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 (Table 4, Fig. 2). 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) [6-10]. 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 [53].

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 [40,53].

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 [57].