Effectiveness, safety, initial optimal dose, and optimal maintenance dose range of basal insulin regimens for type 2 diabetes: A systematic review with meta-analysis.

AIMS: To investigate the effectiveness, safety, optimal starting dose, optimal maintenance dose range, and target fasting plasma glucose of five basal insulins in insulin-naïve patients with type 2 diabetes mellitus. METHODS: MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched from January 2000 to February 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach was adopted. The registration ID is CRD42022319078 in PROSPERO. RESULTS: Among 11 163 citations retrieved, 35 publications met the planned criteria. From meta-analyses and network meta-analyses, we found that when injecting basal insulin regimens at bedtime, the optimal choice in order of most to least effective might be glargine U-300 or degludec U-100, glargine U-100 or detemir, followed by neutral protamine hagedorn (NPH). Injecting glargine U-100 in the morning may be more effective (ie, more patients archiving glycated hemoglobin < 7.0%) and lead to fewer hypoglycemic events than injecting it at bedtime. The optimal starting dose for the initiation of any basal insulins can be 0.10-0.20 U/kg/day. There is no eligible evidence to investigate the optimal maintenance dose for basal insulins. CONCLUSIONS: The five basal insulins are effective for the target population. Glargine U-300, degludec U-100, glargine U-100, and detemir lead to fewer hypoglycemic events than NPH without compromising glycemic control.

Use of basal insulin in the management of adults with type 2 diabetes: An Asia-Pacific evidence-based clinical practice guideline.

The objective of this study was to provide recommendations regarding effectiveness, safety, optimal starting dose, optimal maintenance dose range, and target fasting plasma glucose of five basal insulins (glargine U-300, degludec U-100, glargine U-100, detemir, and insulin protamine Hagedorn) in insulin-naïve adult patients with type 2 diabetes in the Asia-Pacific region. Based on evidence from a systematic review, we developed an Asia-Pacific clinical practice guideline through comprehensive internal review and external review processes. We set up and used clinical thresholds of trivial, small, moderate, and large effects for different critical and important outcomes in the overall certainty of evidence assessment and balancing the magnitude of intervention effects when making recommendations, following GRADE methods (Grading of Recommendations, Assessment, Development, and Evaluation). The AGREE (Appraisal of Guidelines, Research and Evaluation) and RIGHT (Reporting Items for practice Guidelines in HealThcare) guideline reporting checklists were complied with. After the second-round vote by the working group members, all the recommendations and qualifying statements reached over 75% agreement rates. Among 44 contacted external reviewers, we received 33 clinicians' and one patient's comments. The overall response rate was 77%. To solve the four research questions, we made two strong recommendations, six conditional recommendations, and two qualifying statements. Although the intended users of this guideline focused on clinicians in the Asia-Pacific region, the eligible evidence was based on recent English publications. We believe that the recommendations and the clinical thresholds set up in the guideline can be references for clinicians who take care of patients with type 2 diabetes worldwide.

Effects of basal and premixed insulin on glycemic control in type 2 diabetes patients based on multicenter prospective real-world data.

BACKGROUND: To investigate the different efficacies of glycemic control between basal and premixed insulin in participants with type 2 diabetes (T2DM) when non-insulin medications fail to reach treatment targets. METHODS: This was a prospective, large-scale, real-world study at 10 diabetes centers in China. Between June 2017 and June 2021, we enrolled 1104 T2DM participants initiated with either once-daily basal insulin or twice-daily premixed insulin when the glycosylated hemoglobin (HbA1c) control target was not met after at least two non-insulin agents were administered. A Cox proportional hazards regression model adjusting for multiple influencing factors was performed to compare the different effects of basal and premixed insulin on reaching the HbA1c control target. RESULTS: At baseline, basal insulin (57.3%) was prescribed more frequently than premixed insulin (42.7%). Patients with a higher body mass index (BMI) or higher HbA1c levels were more likely to receive premixed insulin than basal insulin (both p < 0.001). After a median follow-up of 12.0 months, compared to those with premixed insulin, the hazard ratio for reaching the HbA1c target to those with basal insulin was 1.10 (95% CI, 0.92-1.31; p = 0.29) after adjustment, and less weight gain was observed in those with basal insulin than with premixed insulin (percentage change of BMI from baseline -0.37[5.50]% vs 3.40[6.73]%, p < 0.0001). CONCLUSIONS: In this real-world study, once-daily basal insulin was more frequently prescribed and had similar glycemic control effects but less weight gain compared with twice-daily premixed insulin when used as initiation therapy for those in whom glycemic control with non-insulin medications failed.

Choice of basal insulin therapy is associated with weight and height development in type 1 diabetes: A multicenter analysis from the German/Austrian DPV registry in 10 338 children and adolescents.

BACKGROUND: Available basal insulin regimes differ in pharmacokinetic profiles, which may be related to subsequent changes in anthropometry in patients with type 1 diabetes. This analysis elucidates the standardized height and body mass index development (height and BMI standard deviation score [height-SDS and BMI-SDS]) in pediatric type 1 diabetes patients depending on the choice of basal insulin. METHODS: Longitudinal data of 10 338 German/Austrian patients from the Diabetes Prospective Follow-up (DPV, Diabetes Patienten Verlaufsdokumentation) database were analyzed. Patients aged 5.0 to 16.9 years were treated exclusively with neutral protamine Hagedorn (NPH), insulin detemir (IDet), insulin glargine (IGla), or continuous subcutaneous insulin infusion (CSII) for at least 3 years. Population-based German reference data were used to calculate height-SDS and BMI-SDS. Multiple linear regression was conducted. RESULTS: BMI-SDS increased significantly in all regimes (NPH P = .0365; IDet P = .0003; IGla P < .0001; and CSII P < .0001). Direct comparison of the therapies revealed a favorable association only for NPH vs IGla. A rise in BMI-SDS was observed for all insulins in females, but only for IGla in males. BMI-SDS increment was not observed before 8 years of age. Initially and at the end of the observation period, mean height was above the 50th percentile of the reference population. Across the cohort, height-SDS declined during the observation period, except for CSII. Apart from the 5.0- to 7.9-year-old subgroup, long-acting insulin analogues were associated with a significant loss of height-SDS. CONCLUSIONS: Choice of basal insulin regimen might influence height development. CSII appeared to have a favorable effect on growth trajectories. All therapies were associated with an increase of BMI-SDS, most evident in females.

Observational study evaluating the effectiveness of physician-targeted education for improving glycemic management of patients with type 2 diabetes (BEYOND II).

BACKGROUND: Because there has been no quality improvement initiatives targeting patients with type 2 diabetes (T2D) receiving basal insulin therapy, this study evaluated the effectiveness of physician-targeted education for optimizing glycemic management in these patients in China. METHODS: This multicenter open-label observational study conducted across China had a baseline sample survey, followed by a 6-month education program, and ended with a post-education sample survey. Education based on T2D treatment guidelines was given at Months 1 and 3, and was reinforced by self-audit every month. Each hospital enrolled 100 patients with T2D receiving basal insulin at both the baseline and post-education survey. The primary outcome was the proportion of hospitals meeting individual improvement goals. The goal setting was based on the proportion of patients achieving HbA1c <7.0% in each hospital at the time of the baseline survey. RESULTS: Overall, the individual improvement goal was achieved by 35 centers (49%). Hospitals with poor glycemic management at the baseline survey had higher possibility to improve at post-education survey. Two large sample surveys at baseline and post-education showed improved glucose management among these hospitals. A higher proportion of patients achieved HbA1c <7.0% in the post-education survey (27.2% vs 36.5%; P < 0.001) with reduced HbA1c levels (8.10% vs 7.72%; P < 0.001). Questionnaires from 723 physicians showed that confidence and practice of basal insulin use were significantly improved. CONCLUSIONS: Physician-targeted education improved glycemic management of patients with T2D in 71 hospitals in China, and was more effective at hospitals with poor glycemic management at the baseline survey.

Patient characteristics and 6-month dose of basal insulin associated with HbA1c achievement <7.0% in Chinese people with type 2 diabetes: results from the Observational Registry of Basal Insulin Treatment (ORBIT).

BACKGROUND: The efficacy of basal insulin (BI) for adequate glycemic control in patients with type 2 diabetes mellitus (T2DM) has been well documented by randomized clinical trials. This post hoc analysis of the Observational Registry of Basal Insulin Treatment (ORBIT) study was performed to explore the 6-month dose of BI used in insulin-naïve T2DM patients achieving HbA1c target (<7%) and determine the patient characteristics that affect the 6-month dose of BI in the setting of real-world clinics in China. METHODS: This multicenter observational registry screened 19 894 adult T2DM patients with inadequately controlled hyperglycemia and treated with oral antidiabetic drugs (OADs) in China. Of these patients, 5191 who continued to receive BI after 6 months and achieved HbA1c target were analyzed. Patient characteristics including age, body weight, fasting plasma glucose (FPG), use of OADs, insulin (type and dose), and glycemic control were recorded at baseline and 6-month follow-ups. RESULTS: The 6-month dose of BI needed for effective glycemic control was 0.20 ± 0.08 U/kg/day. High body mass index, high FPG, young age, longer duration of diabetes or OAD treatment, a greater number of OADs at baseline, and allocation to detemir and glargine were significant independent predictors for high dose of BI at 6 months. CONCLUSIONS: This post hoc analysis of the ORBIT registry provides key information on the 6-month dose of BI needed for effective glycemic control in Chinese T2DM patients. Furthermore, it identified crucial patient characteristics that are significant determinants of the dose of BI in a real-world setting.

Effect of basal insulin supplement therapy on diabetic retinopathy in short-duration type 2 diabetes: A one-year randomized parallel-group trial.

BACKGROUND: In this study, we compared the effect on diabetic retinopathy (DR) between oral antidiabetic drugs (OADs) alone and in combination with basal insulin-supported OADs therapy (BOT). [Correction added on 11 November 2019, after first online publication: In Abstract under Background section, "DR" has been corrected into "diabetic retinopathy (DR)".] METHODS: Between January 2015 and January 2018, this study enrolled 290 patients (age 18-65 years) with diabetes duration between 0 and 5 years. Patients were randomly assigned to receive OADs or BOT after 14 days intensive insulin treatment. Examinations were performed at the beginning and end of the study. RESULTS: Fewer patients developed DR in the BOT than OADs group (8 [6.06%] vs 12 [8.3%], respectively), and all cases of DR were non-proliferative. Blood glucose concentrations were higher in the BOT than OADs group at the 3rd month, but lower in the former at the 6th and 12th month. The rate of reaching target HbA1c ≤7% was lower in the BOT than OADs group at the 3rd month (63.6% vs 72.2%, respectively), similar between the two groups at the 6th month (60.6% vs 66.6%, respectively) and higher in the BOT group at the 12th month (75.0% vs 61.1%, respectively). The SD of fasting blood glucose (FBG), coefficient of variation of FBG, SD of blood glucose (SDBG), and mean amplitude of glycemic excursions were lower in the BOT than OADs group. Changes in the levels of three cytokines (interleukin [IL]-1ß, IL-6, and IL-17α) were significantly less in the BOT than OADs group. CONCLUSIONS: Twelve months of BOT decreased the incidence of DR in short-duration type 2 diabetes by reducing glycemia more effectively, stably, and completely than OADs alone.

Steady state is reached within 2-3 days of once-daily administration of degludec, a basal insulin with an ultralong duration of action.

BACKGROUND: Various factors influence the pharmacokinetic and pharmacodynamic properties of insulin analogs. The aim of the present study was to determine time to steady state of insulin degludec (IDeg), a basal insulin analog with an ultralong duration of action, after once-daily subcutaneous administration in subjects of varying age, diabetes type, and ethnicity. METHODS: Time to steady state was analyzed in 195 subjects across five Phase I randomized single-center double-blind studies: three in subjects with type 1 diabetes (T1DM), including one in elderly subjects, and two in subjects with type 2 diabetes (T2DM), including one with African American and Hispanic/Latino subpopulations. Subjects received once-daily IDeg (100 U/mL, s.c.) at doses of 0.4-0.8 U/kg for 6-12 days. Time to clinical steady state was measured from first dose until the serum IDeg trough concentration exceeded 90% of the final plateau level. The IDeg concentrations were log-transformed and analyzed using a mixed-effects model with time from first dose and dose level (where applicable) as fixed effects, and subject as a random effect. RESULTS: Steady state serum IDeg concentrations were reached after 2-3 days in all subjects. In trials with multiple dose levels, time to steady state was independent of dose level in T1DM (P = 0.51) and T2DM (P = 0.75). CONCLUSIONS: Serum IDeg concentrations reached steady state within 2-3 days of once-daily subcutaneous administration in all subjects with T1DM or T2DM, including elderly and African American and Hispanic/Latino subjects. At steady state, serum IDeg concentrations were unchanged from day to day.

Safety of once-daily insulin detemir in patients with type 2 diabetes treated with oral hypoglycemic agents in routine clinical practice.

BACKGROUND: The aim of the present study was to identify demographic and treatment factors that were predictive of hypoglycemia in a large cohort of type 2 diabetic patients initiating insulin detemir. METHODS: The present 24-week observational study of insulin initiation included 17 374 participants from 10 countries. Severe hypoglycemia was defined as an event requiring third party assistance; minor hypoglycemia was defined as a daytime or nocturnal glucose measurement <3.1 mmol/L. RESULTS: Prior to initiating insulin therapy, 4.9% of the cohort reported hypoglycemia (pre-insulin hypoglycemia), with most (94.2%) reporting minor events and 9.6% reporting severe events. Compared with patients without pre-insulin hypoglycemia, those with pre-insulin hypoglycemia had a higher incidence of events of minor hypoglycemia (1.72 vs 4.46 events per patient-year [ppy], respectively), nocturnal hypoglycemia (0.25 vs 1.09 events ppy, respectively), and severe hypoglycemia (<0.01 vs 0.04 events ppy, respectively) at final visit. Age (P < 0.047), body mass index (P < 0.001), a prior history of microvascular disease (P < 0.001), pre-insulin hypoglycemia (P < 0.001), increased number of oral hypoglycemic agents (OHAs; P < 0.001), OHA intensification (P < 0.001), and the use of glinides (P = 0.004) were all found to be independently associated with the occurrence of hypoglycemia during the study. CONCLUSIONS: Once-daily insulin detemir therapy was safe and effective, and rates of hypoglycemia were low. Concerns about hypoglycemia should not deter the initiation of basal insulin analogs.