Short‐term intensive insulin therapy could be the preferred option for new onset Type 2 diabetes mellitus patients with HbA1c > 9%

Type 2 diabetes mellitus (T2DM) is a heterogeneous disease. Currently, the typical clinical therapeutic pathway for the disease consists of the stepwise addition of antihyperglycemic preparations over time, followed lastly by insulin therapy when functional β-cell capacity is severely deteriorated. Recognizing the complexity of disease management, personalized (precision) medicine approaches may enable the physician to tailor diabetes treatment based on HbA1c levels, body mass index (BMI), efficacy, risk of hypoglycemia, risk of weight gain, age, safety, cost, and even genetic characteristics. Although insulin therapy has traditionally been recommended as the last option in the sequential treatment algorithm of T2DM, it is notable that several guidelines and consensus statements suggest consideration of insulin as part of a first-line regimen. In the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) comprehensive T2DM 2017 management algorithm, insulin is recommended for T2DM patients presenting with symptoms and an HbA1c >9.0%. In addition, the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus statement recommends initial insulin therapy as an option when HbA1c ≥9%, and definite consideration with HbA1c ≥10-12%, and mentions that it may be possible to taper off insulin once initial glucotoxicity is reversed and to consider transfer to other types of non-insulin therapies. Based on accumulating evidence, an expert group has endorsed the concept of short-term intensive insulin (STII) therapy as an option for some patients with T2DM at the time of diagnosis. Notably, the latest Israeli guidelines suggest considering immediate, sometimes short-term, insulin treatment for patients with HbA1c >9% or with symptoms. It has been reported that nearly one-quarter (23%) of newly diagnosed T2DM patients in the US had an HbA1c ≥9.0% prior to initiation of treatment. For such patients, initiating insulin is difficult, although it has been almost 10 years since the ACE/AACE Diabetes Road Map suggested insulin therapy for treatment-naïve patients with high HbA1c. Lack of patient education resources in primary care and of provider knowledge as to approaches to insulin treatment (insulin initiation dosage, multiple daily injection or basal insulin supplement, insulin treatment duration) are major obstacles to selecting appropriately intensive but also timely therapy for newly diagnosed T2DM patients in clinical practice so as to minimize avoidable glycemic exposure. Treatment with STII early in the course of T2DM is of considerable interest. There is a wide range of evidence currently available supporting the use of STII therapy in newly diagnosed T2DM. For example, STII can quickly normalize glycemic control, improve β-cell function, restore first-phase insulin secretion, and even reduce glucagonemia in newly diagnosed T2DM, suggesting that it may provide unique capacity for modification of the natural process of diabetes. The largest and most robust clinical trial of STII therapy enrolled 382 newly diagnosed people with T2DM at nine centers in China and randomized them to either insulin (short-term continuous subcutaneous insulin infusion [CSII] or multiple daily injections [MDI]) or oral anti-hyperglycemic therapy. First-phase insulin secretion was increased in all three groups after 2 weeks of normoglycemia. Remission rates at 1 year were higher in the two insulin-treated groups (51.1% in the CSII group, 44.9% in the MDI group) than in the oral therapy group (26.7%). Furthermore, the increase in first-phase insulin response was maintained at 1 year in the two insulin-treated groups, but declined in the group allocated to oral medication (Fig. ). A beneficial effect of insulin therapy over oral anti-diabetic agents was also observed by Chen et al. [Figure: see text] A meta-analysis, including seven studies and 839 participants, further underscored the robustness of the evidence supporting STII therapy by showing that the proportion of patients in drug-free remission was 66.2% at 3 months, 58.9% at 6 months, 46.3% at 12 months, and 42.1% at 24 months. All but one study showed an improvement in β-cell function, as assessed by homeostatic model assessment of β-cell function (HOMA-B), and all but one study showed a decrease in insulin resistance, as assessed by homeostasis model assessment of insulin resistance (HOMA-IR). Therefore, STII has beneficial effects on both the fundamental pathophysiological mechanisms of T2DM (β-cell dysfunction and insulin resistance). Recent animal studies suggest a potential mechanism for such clinical benefits: β-cells dedifferentiate to endocrine progenitor-like cells during stress-induced hyperglycemia, and strictly normalizing blood glucose by insulin therapy could induce dedifferentiated cell redifferentiation to mature β-cells, and hence restoration of drug responsivity. In addition to its glucose-lowering activity, insulin may contribute to improved β-cell function by its antilipolytic, anti-inflammatory, and antiapoptotic effects. We recognized that not all newly diagnosed people with T2DM would experience improved β-cell function or achieve long-term remission following cessation of STII. It would be worthwhile to precisely identify the subpopulation more likely to benefit from this strategy. Previous studies have suggested that lower baseline fasting glucose, higher BMI, better early phase insulin secretion, and lower exogenous insulin requirements may be predictors of diabetes remission in newly diagnosed patients treated with STII therapy. A recent study demonstrated that a shorter duration of diabetes supplanted baseline HbA1c and β-cell function as an independent predictor of remission. In particular, diabetes duration <2 years predicted sustained remission, suggesting that the key determinant of inducing persistent drug-free diabetes remission with STII is early intervention. Although reluctance to initiate insulin treatment in T2DM is well described, it is interesting to see that when introduced early in the course of the disease as a short-term treatment, STII resulted in significant improvement in patient-reported quality of life and treatment satisfaction, demonstrating the patient acceptability of early insulin therapy. In our clinical experience, patients often request insulin resumption after a trial has ended because of the good clinical outcomes and the recognition that such treatment is much easier and better tolerated than expected. The pros and cons of STII therapy for new-onset T2DM patients with HbA1c >9%, based on current evidence and our understanding, are listed in Table . It is important that STII be considered an option at this early stage of the disease. Existing studies and clinical experience do indicate that this concept is very well received by patients and clinicians alike, especially when they realize that insulin only needs to be used for a few weeks, and that STII at that point in time does not necessarily require continuing long-term insulin therapy. Numerous public health, clinical efficacy and effectiveness, and cost-effectiveness questions need to be better understood before widespread adoption of this novel treatment regimen can be more endorsed. [Table: see text].