Insulin initiation therapy for type 2 diabetes–Interpretation of the Chinese guidelines for the prevention and treatment of type 2 diabetes (2010 edition) Yang Guoqing, Department of Endocrinology, Beijing 301 Hospital
According to the epidemiological survey of diabetes organized by the Chinese Diabetes Society (CDS) in 2008, the age-specific prevalence of diabetes was 9.7% in people over 20 years of age [1]. The chronic vascular complications of diabetes pose a great threat to the life and quality of life of patients, causing great suffering to the family as well as to the individual patient, and also imposing a heavy economic burden on the family, the state, and society. The complex pathogenesis of diabetes mellitus has not yet led mankind to find a cure, but effective glycemic control can significantly reduce or delay the occurrence and development of chronic complications of diabetes mellitus [2]. In order to achieve early, effective and lasting glycemic attainment, diabetes education, improvement of patients’ self-glycemic management ability, lifestyle guidance and rational drug treatment are all crucial. Due to the rapid development of evidence-based medicine in epidemiology, diagnosis and treatment of diabetes in recent years, the CDS published the 2010 Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes in 2011 after making a lot of modifications and additions to the 07 edition of the Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes, based on recent research results, especially a large amount of evidence-based medical data from the population in mainland China. For the majority of patients with type 2 diabetes, insulin therapy may eventually be required to achieve target blood glucose levels [3]. The new version of the guidelines is now interpreted with regard to insulin initiation therapy for type 2 diabetes.
1 Basal insulin initiation therapy
The 2007 American Diabetes Association (ADA) guidelines for the treatment of diabetes established the importance of basal insulin in the treatment of diabetes. The guidelines recommend that for patients with type 2 diabetes, the addition of basal insulin is the most effective strategy for glycemic control when lifestyle interventions plus one oral hypoglycemic agent (OHA) are not controlling blood glucose well. In the 07th edition of the Chinese Type 2 Diabetes Guidelines, it is also pointed out that basal insulin therapy can be initiated when HbA1c is not achieved with 2 or more OHAs on the basis of lifestyle interventions. Chinese patients with type 2 diabetes have poor pancreatic β-cell function and relatively mild insulin resistance, so timely initiation of basal insulin therapy is a treatment strategy in line with the characteristics of Chinese type 2 diabetes itself. Basal insulin not only effectively controls fasting blood glucose and thus achieves full compliance with blood glucose standards, but more importantly, it can maximize the preservation of more β-cell function and delay the progression of type 2 diabetes. Currently, basal insulins in clinical application include neutral protamine hagedorn (NPH) and long-acting insulin analogs. The new version of the guidelines states that insulin therapy is required when oral hypoglycemic drugs are not effective in controlling blood glucose. Among them, basal insulin is still the insulin regimen of choice when glycemic control is not achieved in OHA treatment. The advantages of choosing basal insulin are simplicity, good patient compliance, better control of fasting glucose and relatively less hypoglycemia.
NPH is the first basal insulin used for blood glucose control and can effectively control fasting blood glucose, but because NPH is a suspension of crystalline insulin, patients need to shake it well before each injection, its absorption has certain variability and fasting blood glucose fluctuates, thus the incidence of hypoglycemia is higher when blood glucose control is achieved. Therefore, it also cannot control the basal blood glucose level well throughout the day. With the development of molecular biology technology and insulin preparations, more insulins that conform to physiological insulin secretion have been developed, and glargine insulin and digest insulin are the clinically available long-acting insulin analogues. The new version of the guideline states that when only insulin is administered, it is not necessary to use the same dose. The new guidelines state that when basal insulin therapy is used only, it is not necessary to discontinue insulin agonists and adopt a basal insulin combined with OHA regimen.
The INSIGHT study [5] published in 2006 looked at the glucose-lowering effects of glargine insulin and conventional treatment strategies in patients with type 2 diabetes of different disease duration. 405 patients with type 2 diabetes treated with 0 to 2 oral medications were randomized to receive glargine insulin and conventional treatment. The insulin group received nightly injections of glargine insulin at a starting dose of 10 U, adjusted to a goal of fasting glucose <5.5 mmol/L. The conventional treatment group received oral medication under the guidance of a physician, and the dose was adjusted with the goal of fasting blood glucose <5.5 mmol/L and HbA1c <7.0%. At the end of 24 weeks of treatment, the proportion of patients with 2 consecutive HbA1c <6.5% was 68% higher in the insulin group than in the conventional treatment group. This study showed that the efficacy of timely initiation of basal insulin therapy was clearer than optimized OHA therapy in patients with poor glycemic control on OHA.The Treat-to-Target [6] study was a randomized, open parallel-group controlled multicenter study that enrolled 756 patients with type 2 diabetes mellitus with poor glycemic control on one or two OHA treatments, on top of the original OHA therapy A total of 756 patients with type 2 diabetes mellitus who had poor glycemic control with one or two OHA treatments were enrolled in the study. As a result, both the NPH group and the glargine insulin group showed significant decreases in HbA1c and fasting plasma glucose (FPG) after treatment, and the effects of glucose reduction were comparable. However, the number of patients with symptomatic nocturnal hypoglycemia was much less in the glargine insulin group than in the NPH group (532 U886, P < 0.002). The incidence of nocturnal hypoglycemia with HbA1c ≤ 7% and undocumented was 33.2% and 26.7% in the two groups at the primary endpoint, respectively, with the glargine insulin group being significantly better than the NPH group (P < 0.05). This strongly suggests that the former is more likely to achieve HbA1c ≤ 7% and less frequent nocturnal hypoglycemia when glargine insulin is injected at bedtime compared with NPH. the LEAD study [7] and the LANMET [8] study compared the efficacy and safety of glimepiride and metformin treatment with NPH, respectively. the LEAD study enrolled a total of 695 patients who had previously taken oral hypoglycemic agents for at least 6 months Patients with type 2 diabetes were randomized into three groups and given NPH at bedtime, glargine insulin at bedtime and glargine insulin at breakfast on top of 3 mg of glimepiride (Amoril) at breakfast, and the insulin dose was adjusted to achieve an FPG of <5.6 mmol/L for a total of 24 weeks. The study showed that HbA1c was significantly reduced in all three groups after treatment, but the glucose-lowering effect of glargine insulin injection before breakfast was better than that of glargine insulin or NPH injection at dinner. The significant reduction in HbA1c in all three groups basically occurred at about 2 months and then could last for 24 weeks, but the maintenance effect was best in the group of pre-breakfast injection of glargine insulin. The trial defined HbA1c ≤ 8.0% as effective for treatment. The treatment efficiency of the three groups was 43.9% in the dinner injection NPH group, 53.8% in the dinner injection glargine insulin group, and 57.9% in the breakfast injection glargine insulin group, and the glargine insulin group was significantly higher than the NPH group. The incidence of nocturnal hypoglycemia in the three groups was 38.2%, 22.9% and 16.5%, respectively. The results of the LANMET study, published in 2006, reaffirmed these results. 110 patients with OHA (more than 90% sulfonylurea + metformin) with unsatisfactory efficacy Type 2 diabetic patients treated with glargine insulin plus metformin or NPH plus metformin, respectively, showed an average decrease in HbA1c of 2.4% after 9 months. Glargine insulin again showed outstanding benefits in reducing the incidence of hypoglycemia and better control of pre-dinner hyperglycemia.
Another new long-acting insulin analogue is diste insulin, which, like glargine insulin, has a duration of action of more than 24 hours and is characterized by less variability, less effect on body weight and less local irritation at the injection site. achieve the glycemic control goal of HbA1c <7% and in the last 4 weeks, nearly 50% achieved the control goal of HbA1c <7% without the occurrence of hypoglycemia. Several other studies have consistently shown that significantly improved glycemic control was accompanied by a significantly lower risk of nocturnal hypoglycemia with detergent insulin than with NPH, with one multicenter, open, randomized, parallel study in 504 patients with type 2 diabetes further demonstrating that after 20 weeks of treatment, once-a-day detergent insulin and NPH achieved similar glycemic control, but compared with NPH, the evening group of detergent insulin had all and nocturnal hypoglycemia were significantly reduced by 53% (P=0.019) and 65% (P=0.031), respectively [10].Hermansen et al [11] compared the efficacy and safety of the combination of detergent insulin and NPH with OHA treatment in 476 patients with type 2 diabetes and showed that HbA1c decreased by up to 1.8% in the detergent insulin group and that the detergent insulin group was associated with More importantly, the weight gain was also significantly lower in the NPH treatment group (1.2 kgU2.8 kg, P < 0.001). Weight gain associated with insulin therapy may be a major obstacle for patients to achieve adequate glycemic control. A large body of evidence suggests that detergent insulin may reduce weight gain in diabetic patients while effectively controlling blood glucose. A study conducted in patients with type 2 diabetes showed that similar glycemic control was achieved after 52 weeks of 1-day-dose of disulfiram versus glargine insulin treatment, but weight gain was significantly less in the disulfiram group than in the glargine group (2.3 kgU3.9 kg, P < 0.000 1). Another 1863 patients with type 2 diabetes mellitus treated with either diste insulin or glargine for 3 months had significantly improved glycemic control, but patients in the diste insulin group had a weight loss of 0.5 kg (P < 0.000 1) and those with a BMI (body mass index) >35 kg/m2 had a weight loss of up to 1.5 kg (P < 0.000 1) [12].Five clinical trials involving type 2 diabetes showed a significant weight advantage of detergent insulin compared to NPH insulin or glargine insulin. Among them, the study by Philis-Tsimikas et al. showed that weight gain was lower in the digitonin-treated group than in the NPH group at similar glycemic control (0.7 kg and 1.6 kg, P=0.005). A meta-analysis of six multicenter, open, randomized clinical trials showed a weight advantage with improved glycemic control with disproportionate insulin compared with NPH [13].
Regarding the use of basal insulin initiation therapy, the new version of the guidelines states that the combination of intermediate-acting human insulin or a long-acting insulin analogue is given at bedtime on top of continued oral hypoglycemic therapy. The starting dose is 0.2 U/(kg・d). The insulin dosage is adjusted according to the patient’s fasting blood glucose level, usually every 3-5 days, and 1-4 U each time according to the blood glucose level until the fasting blood glucose standard is reached. If fasting glucose control is satisfactory but HbA1c does not reach the standard after 3 months, adjustment of insulin treatment regimen should be considered.
2 Premixed insulin initiation therapy
Pre-mixed insulin is an insulin preparation that premixes rapid-acting and intermediate-acting insulins in a certain ratio, which can meet both mealtime and basal insulin needs. Depending on the chemical structure of insulin, it is divided into premixed human insulin and premixed insulin analogues. Compared with premixed human insulin, premixed insulin analogs are closer to physiological insulin secretion and have more advantages in glycemic control, especially postprandial glycemic control and reduction in the incidence of hypoglycemia, as well as in dosing flexibility [14].
The new version of the guidelines recommends that patients with type 2 diabetes mellitus can start combined oral medication and insulin therapy if their blood glucose still does not reach the standard based on lifestyle changes and combined oral hypoglycemic medication. In addition to basal insulin, a once- or twice-daily premixed insulin initiation regimen is also available, depending on the patient’s specific situation.
In a large observational study, 71.4% of the 21,729 Chinese patients with type 2 diabetes who participated in the study were treated with diphasic menthol insulin 30 for 26 weeks, and 71.4% had HbAlc <7%; patients who had not received prior treatment had an average decrease in HbAlc and fasting glucose of 3.27% and 6.06 mmol/L, and patients who had only received OHA had an average decrease in HbAlc and fasting glucose decreased by an average of 2.57% and 4.54 mmol/L in patients treated with OHA only [15]. In a study by Bebakar et al [16], 192 patients with type 2 diabetes were randomized in a 2U1 ratio to diphasic menthol insulin 30 and oral hypoglycemic therapy, and patients who received twice daily diphasic menthol insulin 30 had a 1.34% decrease in HbAlc, significantly better than the 0.67% in the oral drug group (p < 0.01). In the INITIATE study, patients without previous insulin therapy and with HbAlc ≥ 8% were randomly assigned to receive either twice daily dose of biphasic menthol insulin 30 or once daily dose of glargine insulin, and after 28 weeks, the decrease in HbAlc was more significant in patients treated with biphasic menthol insulin 30 than in those treated with glargine insulin [(-2.79 0.11) %U ( -2.36 0.11)%, P < 0.01]; the proportion of patients obtaining HbAlc < 7.0% in the diphasic mentored insulin 30-treated group and the glargine insulin-treated group was 66% and 40%, respectively (P < 0.001) [17]. The new version of the guidelines recommends that diet control and exercise should be continued after starting insulin therapy, and patient education should be strengthened to encourage and guide patients to perform self-glucose testing to facilitate insulin dose adjustment and prevent hypoglycemia, and insulin proliferators should be discontinued while using twice-daily premixed insulin therapy. The use of premixed insulin twice daily is as follows: the starting dose of premixed insulin is 0.4-0.6 U/(kg・d), distributed in the ratio of 1 U1 before breakfast and before dinner. The insulin dosage before breakfast and before dinner is adjusted according to fasting blood glucose, blood glucose after breakfast and blood glucose before and after dinner, respectively, every 3 to 5 days, and the dosage is adjusted by 1 to 4 U each time according to blood glucose level until the blood glucose standard is reached.
If patients cannot accept 2 daily injections at the beginning, 1 daily premixed insulin can also be used as the starting insulin regimen. In the 1-2-3 study, patients who had not been treated with insulin or who had previously been treated with glargine insulin or human insulin that did not meet glycemic standards were switched to diphasic menthol insulin 30 once daily injections, which enabled 41% of patients to achieve an HbAlc of 7.0% or less; switching to twice daily injections in patients who still did not meet glycemic standards enabled 70% of patients to achieve an HbAlc of <7.0% [18 ]. The new guidelines recommend that the starting dose of once-daily premixed insulin injections is generally 0.2 U/(kg・d), given before dinner. If FPG is between 4.4 and 6.1 mmol/L and HbAlc > 7% with 1 daily premixed insulin injection, or FPG > 6.1 mmol/L and hypoglycemia occurs when the injection dose is adjusted, treatment can be switched to diphasic menthol insulin 30 twice daily [19]. If fasting blood glucose ≤6.1 mmol/L, 3 U is injected before breakfast; if fasting blood glucose >6.1 mmol/L, 6 U is injected before breakfast. insulin dose is adjusted every 3 to 5 days according to the patient’s pre-breakfast and pre-dinner blood glucose levels until glycemic control is achieved. It can be combined with metformin, but in principle, insulin stimulants should be stopped.
3 Intensive insulin therapy
The new version of the guidelines also points out that for patients with initial type 2 diabetes mellitus with high blood glucose, oral medication is difficult to bring about satisfactory glycemic control and improve hyperglycemic symptoms in the short term, and insulin therapy can be used for a short time. In a domestic study [20], 138 newly diagnosed type 2 diabetic patients with fasting glucose >11.1 mmol/L were given 2 weeks of intensive treatment with continuous subcutaneous insulin infusion (CSII), and 126 patients had good glycemic control in an average of 6.3 ± 3.9 days. The patients had good glycemic control within 6.3 ± 3.9 days, and 72.6%, 67.0%, 47.1% and 42.3% of the patients had normal blood glucose levels at 3, 6, 12 and 24 months after the end of CSII treatment, respectively. They also studied patients with severe hyperglycemia who were given intensive insulin therapy [multiple daily injections (MDI or CSII) and OHA (gliclazide and/or metformin), respectively, in patients with first-episode type 2 diabetes [21], and 92% of the total 382 patients in both groups achieved glycemic control goals in an average of 8 days ( fasting and 2-hour postprandial glucose were below 110 mg/dl and 144 mg/dl, respectively), and glucose-lowering drugs were discontinued 2 weeks after glycemic target was reached and lifestyle interventions alone were given. Patients who were previously treated with insulin achieved the standard in more cases than those in the OHA group, and the time required to achieve the standard was significantly shorter than those treated with OHA. HOMA-B (islet beta-cell function index) and HOMA-IR (insulin resistance index) were similar in both groups after discontinuation, but 1 year after discontinuation, the remission rate was significantly higher in the insulin-intensified group (MDI: 45%, CSII: 51%) than in the OHA group (27%), and the acute insulin response was significantly lower in the OHA group, whereas it was similar to that after treatment in the insulin-intensified group. Another study comparing the effects of insulin and OHA (gliphenylurea) therapy on glycemic control and β-cell function in primary type 2 diabetes also found that long-term glycemic control and β-cell function were significantly better in the insulin-treated group than in the OHA-treated group [22]. Moreover, there was no difference in the change in body weight between the insulin-treated and OHA-treated groups in these studies, and no severe hypoglycemic events occurred. These studies show that intensive treatment with insulin in patients with initial type 2 diabetes with high blood glucose levels significantly improves insulin resistance and decreased β-cell function caused by hyperglycemia. Of course, the treatment plan should be adjusted according to the condition when hyperglycemia is controlled and symptoms are relieved, such as switching to oral drug therapy or medical nutrition therapy and exercise therapy alone. Attention should be paid to strengthen the monitoring of blood glucose, adjust the insulin dose in time and pay attention to avoid hypoglycemia as much as possible.
In conclusion, type 2 diabetes mellitus patients should promptly start insulin therapy when glycemic control is not achieved by 2 or more types of OHA treatment. In particular, premixed insulin analogs have the advantages of more flexible and convenient use and low incidence of hypoglycemic events. Therefore, clinicians should follow the guidelines in clinical practice, combine the specific clinical characteristics of patients, and focus on individualization when choosing the starting insulin treatment regimen.
[1] Corresponding author: G. Yang Email: [email protected]