Nueva generación de insulinas: glargina U300: Resumen de evidencia clínica / New generation of insulins: glargine U300. Summary of clinical evidence

La diabetes mellitus tipo 2 tiene evolución crónica y progresiva, prevalencia creciente y aún es diagnosticada tardíamente. Esto conlleva mayor incidencia de complicaciones crónicas, con incremento de costos en salud. Existe retraso en el inicio de insulinoterapia por causas relacionadas tanto al paciente como al médico. A pesar de los avances en su tratamiento, una baja proporción de enfermos logra control glucémico adecuado. La alta prevalencia de hipoglucemia en pacientes insulino-tratados, impulsó el desarrollo de una nueva generación de insulinas basales de acción prolongada, mayor estabilidad con menor variabilidad y riesgo de hipoglucemias. El programa EDITION evaluó la eficacia y seguridad de glargina U300 vs. glargina U100 en pacientes con diabetes tipo 1 y 2, en distintas etapas de la enfermedad. Glargina U300 es una nueva formulación de insulina glargina con perfil farmacocinético y farmacodinámico más estable y prolongado que glargina U100. Glargina U300 demostró eficacia y tolerabilidad comparable a glargina U100, con descenso significativo del riesgo de hipoglucemias nocturnas y en 24 horas, aportando mayor flexibilidad en el horario de inyección, con una ventana de 6 horas. Además, no se observó mayor aumento de peso que con glargina U100. El estudio Bright (2018) comparó glargina U300 vs. degludec U100, demostrando mayor beneficio en relación al riesgo de hipoglucemia con Gla-300 durante el período de titulación. Gla-300 es una insulina basal de última generación, disponible para mejorar el control metabólico, con menor riesgo de hipoglucemia.

Type 2 diabetes is a chronic, progressive disease with increasing prevalence and still late diagnostic. This leads to an increase in the incidence of chronic complications, with signifi cantly increasing health costs. There is also a delay in the onset of insulin therapy in patients with type 2 diabetes for causes related to both patients and physicians. Despite advances in treatment, a low proportion of patients achieve adequate glycemic control. The high hypoglycemia prevalence, consequence of insulin, has led to the development of a new generation long-acting basal insulins to achieve a more stable and prolonged action profile, reducing the variability and risk of hypoglycemia. The EDITION program evaluated the efficacy and safety of glargine U300 compared to glargine U100 in patients with type 1 and 2 diabetes at different stages of the disease. Gla-300 is a new formulation of insulin glargine which has a more stable and prolonged pharmacokinetic and pharmacodynamic profile. Gla-300 demonstrated efficacy and tolerability comparable to glargine U100, with a significant decrease in the risk of hypoglycemia, at night and in 24 hours, providing greater flexibility in the injection schedule, with a window of 6 hours. No increase in weight was observed compared to glargine U100. Bright study (2018) compared glargine U300 vs. degludec U100, demonstrating greater benefit in relation to the risk of hypoglycemia with Gla-300 during titration period. Gla-300 is a last-generation basal insulin, available to improve metabolic control, with a lower risk of hypoglycemia.

Role of long-acting insulin analogues in the management of type 1 diabetes in children and adolescent / 中华内分泌代谢杂志

A recent national wide epidemiological study showed that the incidence of type 1 diabetes mellitus ( T1DM) was increased among children and adolescents in China. However, the glycemic control was not optimal, leading to high incidence of complications. Previous studies demonstrated that inappropriate insulin regimen was a major cause of sub-optimal glycemic control. Basal-bolus regimen recommended by international pediatric guidelines, significantly improved glycemic control with increased hypoglycemia risk. Given that basal insulin largely contributed to efficacy and safety profiles of base-bolus regimen, long-acting insulin analogues, such as insulin glargine ( 100U) , have ideal efficacy, safety profiles, especially lower hypoglycemia risk compared with neutral protamine Hagedorn ( NPH) . Therefore,long-acting insulin analogues is a good choice for basal-bolus regimen treatment in children and adolescents with T1DM.

Pioglitazone-metformin and basal insulin for type 2 diabetes mellitus patients with overweight or obesity and poor blood glucose control: A comparison of efficacy and metabolic effects / 第二军医大学学报

Objective: To compare the efficacy and metabolic effects of pioglitazone-metformin and basic insulin therapy on type 2 diabetes mellitus (T2DM) patients with overweight or obesity and poor blood glucose control. Methods: A total of 153 T2DM patients with overweight or obesity and poor blood glucose control were enrolled in this study. They received treatment with pioglitazone-metformin (pioglitazone-metformin group, n = 77) or insulin glargine (basal insulin group, n = 76) for 6 months in addition to their previous oral hypoglycemic drugs. At baseline, 3 months and 6 months after treatment, glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), 2 h post-prandial blood glucose (2hBG), fasting insulin (FINS), 2 h post-prandial insulin (2hINS), fasting C peptide (FCp), 2 h post-prandial C peptide (2hCp), body mass index (BMI), total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), and hepatic fatty degeneration (expressed as controlled attenuation parameter [CAP] value) were observed and recorded. Results: At baseline, there were no significant differences in gender, age, BMI, HbA1c, FBG, 2hBG, FINS, 2hINS, FCp, 2hCp, TC, TG, HDL-C, LDL-C, CAP value, underlying diseases, or concomitant medicine between the two groups (all P>0.05). At 3 and 6 months after treatment, the HbA1c, FBG and 2hBG levels were significantly decreased versus those at the baseline in the two groups (all P0.05). Compared with the basal insulin group, the FINS, BMI and CAP values were significantly decreased in the pioglitazone-metformin group 3 and 6 months after treatment (P<0.05, P<0.01). After 6 months of treatment, there were no significant changes of blood lipid levels in both groups. Conclusion: In T2DM patients with overweight or obesity and poor blood glucose control, adding pioglitazone-metformin and basal insulin to their previous oral hypoglycemic drugs has similar hypoglycemic effect. However, patients receiving pioglitazone-metformin have better metabolic benefts such as lower BMI, lower insulin and improved hepatic fatty degeneration.

Favorable Glycemic Control with Once-Daily Insulin Degludec/Insulin Aspart after Changing from Basal Insulin in Adults with Type 2 Diabetes

BACKGROUND: Conflicting results have been reported on the efficacy of insulin degludec/insulin aspart (IDegAsp) compared to basal insulin in type 2 diabetes. We investigated the effects of changing basal insulin to IDegAsp on glycemic control and sought to identify factors related to those effects.METHODS: In this retrospective study of patients from three referral hospitals, patients with type 2 diabetes using basal insulin with hemoglobin A1c (HbA1c) levels less than 11.0% were enrolled. Basal insulin was replaced with IDegAsp, and data were analyzed from 3 months before to 3 months after the replacement.RESULTS: Eighty patients were recruited (52.5% male; mean age, 67.0±9.8 years; mean duration of diabetes, 18.9±8.5 years; mean HbA1c, 8.7%±1.0%). HbA1c levels increased during 3 months of basal insulin use, but significantly decreased after changing to IDegAsp (8.28%±1.10%, P=0.0001). The reduction was significant at 6 months in 35 patients whose longer-term data were available. Patients with a measured fasting plasma glucose (m-FPG) lower than their predicted FPG (p-FPG) by regression from HbA1c showed a significant HbA1c reduction caused by the change to IDegAsp, even without a significantly increased insulin dose. However, patients whose m-FPG was higher than their p-FPG did not experience a significant HbA1c reduction, despite a significantly increased insulin dose. Furthermore, the HbA1c reduction caused by IDegAsp was significant in patients with low fasting C-peptide levels and high insulin doses.CONCLUSION: We observed a significant glucose-lowering effect by replacing basal insulin with IDegAsp, especially in patients with a lower m-FPG than p-FPG.

The efficacy of daily compared to twice weekly Basal Insulin Titration Algorithms among patients with Type II Diabetes Mellitus: A 12-week randomized controlled trial

Introduction@#There are a significant number of diabetic patients who remain uncontrolled despite basal insulin therapy due to lack of intensification of treatment. Different insulin titration algorithms are recommended by different treatment guidelines. This study compared two basal insulin titration algorithms in terms of time to achieve target glucose, adherence, hypoglycemia episodes, and HbA1c reduction.@*Methods@#This is a 12-week randomized clinical trial conducted on insulin-naïve patients with uncontrolled type 2 diabetes mellitus from outpatient clinic of St. Luke’s Medical Center Quezon City. Patients on oral hypoglycemic agent/s with HbA1c seven percent and above were included in the study. They were randomized to either daily titration or twiceweekly insulin titration algorithms using basal insulin glargine. @*Results@#Forty-one patients were included in the study. The daily titration algorithm achieved target capillary blood glucose (CBG) at stable insulin dose earlier (33 vs 41.3 days, p-value=0.042) than the twice-weekly titration. Better adherence was also seen among patients on daily titration algorithm as compared to twice weekly (94.94% vs. 91.12%, p-value = 0.009). There was no significant difference in incidence of hypoglycemia (p-value 0.0.62) for both algorithms. All patients from the two groups had significant HbA1c reduction at the end of the study period.@*Conclusion@#Daily titration algorithm achieved earlier target fasting plasma glucose and better patient adherence as compared to twice-weekly titration in the adjustment of basal insulin dose. HbA1c reduction and risk of hypoglycemia were similar in both titration algorithms.

Reduction of Sulfonylurea with the Initiation of Basal Insulin in Patients with Inadequately Controlled Type 2 Diabetes Mellitus Undergoing Long-Term Sulfonylurea-Based Treatment

BACKGROUND: There were a limited number of studies about β-cell function after insulin initiation in patients exposed to long durations of sulfonylurea treatment. In this study, we aimed to evaluate the recovery of β-cell function and the efficacy of concurrent sulfonylurea use after the start of long-acting insulin. METHODS: In this randomized controlled study, patients with type 2 diabetes mellitus (T2DM), receiving sulfonylurea for at least 2 years with glycosylated hemoglobin (HbA1c) >7%, were randomly assigned to two groups: sulfonylurea maintenance (SM) and sulfonylurea reduction (SR). Following a 75-g oral glucose tolerance test (OGTT), we administered long-acting basal insulin to the two groups. After a 6-month follow-up, we repeated the OGTT. RESULTS: Among 69 enrolled patients, 57 completed the study and were analyzed: 31 in the SM and 26 in the SR group. At baseline, there was no significant difference except for the longer duration of diabetes and lower triglycerides in the SR group. After 6 months, the HbA1c was similarly reduced in both groups, but there was little difference in the insulin dose. In addition, insulin secretion during OGTT was significantly increased by 20% to 30% in both groups. A significant weight gain was observed in the SM group only. The insulinogenic index was more significantly improved in the SR group. CONCLUSION: Long-acting basal insulin replacement could improve the glycemic status and restore β-cell function in the T2DM patients undergoing sulfonylurea-based treatment, irrespective of the sulfonylurea dose reduction. The dose reduction of the concurrent sulfonylurea might be beneficial with regard to weight grain.

Effect of insulin injection and protamine biosynthetic human insulin injection on basal insulin level in pregnant women with diabetes mellitus / 中国生化药物杂志

Objective To explore the effect of insulin injection and protamine biosynthetic human insulin injection on basal insulin level in pregnant women with diabetes mellitus.Methods Retrospective analysis of 89 cases of pregnant women with diabetes mellitus from January 2013 to May 2016 in department of obstetrics and gynecology,tianjin red bridge hospital,the patients were divided into group A (n=38 cases) and group B (n=51 cases),the group A treatment with insulin injection,the group B treatment with protamine biosynthetic human insulin injection,compare the two groups of patients before and after treatment of three meals a day rate of blood glucose compliance, treatment compliance and satisfaction.Results Before treatment, there was no significant difference in the blood glucose compliance rate between the two groups before and after treatment;After treatment,the blood glucose compliance rate of two groups was significantly higher than before treatment ( P<0.05 ) , there was no significant difference in the compliance rate of fasting blood glucose between two groups,the compliance rate of blood glucose before dinner in group A was 81.58%,significantly higher than that in group B 60.78%(P<0.05).Conclusion Both insulin injection and protamine biosynthetic human insulin injection can maintain the basic insulin levels of pregnant women with diabetes mellitus,insulin injection can better control the blood glucose levels before dinner,with higher compliance and satisfaction.The compliance rate and satisfaction rate of pregnant women in group A were 97.37% and 97.37%,which were significantly higher than those in group B 82.35% and 80.39%(P<0.05).

Effectiveness evaluation of the mobile health patients management mode on treatment compliance and glycemic control for type 2 diabetes patients using basal insulin treatment for 12 weeks / 中华内分泌代谢杂志

Objective To assess the effectiveness of a novel mobile health patient management system involving doctors, nurses, and patients ( TRIO mode) on glycemic control and self-monitoring of blood glucose (SMBG) compliance among the type 2 diabetes mellitus ( T2DM) patients using basal insulin standardization treatment in China. Methods From April 2014 to April 2015, 416 hospitals in 110 cities of 30 provinces, municipalities, and autonomous regions across China were selected to participate in the program. A Online-to-Offline ( O2O) integrated mobile health patients management system with mobile terminals for the doctors, nurses, and patients was applied in the program for patient education, follow-up, and data collection. For all the newly recruited patients, the baseline information was collected and a first-day patient education program were provided by a designated nurse. In the 12-week follow-up period, data of basal insulin doses and fasting plasma glucose ( FPG) values were collected from the patients by text messages or tracking phone call by the nurse. The patients also received timely standardized patients health education and glycemic control guidance by participating in thepatient education forum anddoctors' hotline in order to help them achieve the glycemic control goals. Results A total of 102 524 patients using basal insulin treatment were eligible and enrolled in the program. 64 420 patients completed the 12 weeks follow-up and provided at least one FPG value at all five follow-ups. In total, 62. 6% (40 334 / 64 420) of the patients reached the FPG control target(FPG≤7. 0 mmol/ L) at the end of follow-up period. The weekly average FPG for patients with complete SMBG data decreased from 10. 58 mmol/ L to 6. 91 mmol/ L while the FPG control rates increased from 13. 4% to 69. 2% . The weekly average FPG for the patients provided incomplete SMBG data decreased from 10. 54 mmol/ L to 7. 13 mmol/ L while the FPG control rates increased from 13. 6% to 62. 2% . The FPG control rates for the patients provided complete SMBG were 1. 74 times higher than those patients provided incomplete SMBG. Based on a GEE model, the average decline of the FPG and the increase of the FPG control rates were significantly better for patients who provided complete SMBG as compared to the patients with incomplete SMBG data. The results of the multivariate logistic regression analysis showed that factors such as receiving the first-day education, participating in the follow-up patient education forum, and the doctors' hotline were significantly associated with the improvement of the SMBG compliance, the treatment adherence, and the FPG control rates. The SMBG compliance and the treatment adherence for patients who completed first-day education were 1. 68 times and 1. 22 times higher, respectively. For the patients who participated in follow-up education activities, their SMBG compliance and treatment adherence were 3. 17 times and 3. 36 times higher, respectively. Conclusion The innovativeTRIOmobile health patient management mode was feasible and effective for better managing the type 2 diabetes patients initiated on basal insulin treatment in China. Active participation in the first-day education program and the follow-up patient education activities can effectively improve the SMBG compliance and the treatment adherence, and therefore play an important role in helping patient achieving FPG control in a faster manner.

Insulin Initiation in Insulin-Naive Korean Type 2 Diabetic Patients Inadequately Controlled on Oral Antidiabetic Drugs in Real-World Practice: The Modality of Insulin Treatment Evaluation Study

BACKGROUND: The Modality of Insulin Treatment Evaluation (MOTIV) study was performed to provide real-world data concerning insulin initiation in Korean type 2 diabetes mellitus (T2DM) patients with inadequate glycemic control with oral hypoglycemic agents (OHAs). METHODS: This multicenter, non-interventional, prospective, observational study enrolled T2DM patients with inadequate glycemic control (glycosylated hemoglobin [HbA1c] > or =7.0%) who had been on OHAs for > or =3 months and were already decided to introduce basal insulin by their physician prior to the start of the study. All treatment decisions were at the physician's discretion to reflect real-world practice. RESULTS: A total of 9,196 patients were enrolled, and 8,636 patients were included in the analysis (mean duration of diabetes, 8.9 years; mean HbA1c, 9.2%). Basal insulin plus one OHA was the most frequently (51.0%) used regimen. After 6 months of basal insulin treatment, HbA1c decreased to 7.4% and 44.5% of patients reached HbA1c <7%. Body weight increased from 65.2 kg to 65.5 kg, which was not significant. Meanwhile, there was significant increase in the mean daily insulin dose from 16.9 IU at baseline to 24.5 IU at month 6 (P<0.001). Overall, 17.6% of patients experienced at least one hypoglycemic event. CONCLUSION: In a real-world setting, the initiation of basal insulin is an effective and well-tolerated treatment option in Korean patients with T2DM who are failing to meet targets with OHA therapy.

Effect observation of basal insulin combined with oral antidiabetic drugs in treating type 2 diabetes mellitus / 国际检验医学杂志

Objective To observe the effectiveness and safety of basal insulin plus oral antidiabetic drugs (OADs) in treating the patients with type 2 diabetic mellitus (T2DM ) ,who were poor blood sugar control by premixed insulin with or without OADs . Methods 32 cases of T2DM and poor blood sugar control by premixed insulin combinated with or without OADs stopped the premixed insulin therapy and changed to insulin glargine plus OADs for 16 weeks .Glycosylated haemoglobin (HbA1c) ,fasting blood glucose(FBG) ,postprandial blood glucose(PBG) ,body mass index (BMI) and mean daily insulin dose were compared among patients .And the episodes of hypoglycemia events were recorded .Results After 16‐week treatment ,HbA1c ,FBG ,PBG and BMI were all significantly decreased comapared with before treatment (P<0 .01) .The mean insulin glargine daily dose was significantly decreased compared with the premixed insulin dose at admission .2 cases (6% )appeared twice hypoglycemia episodes during the treatment period ,all were general hypoglycemia .Conclusion Basal insulin once daily can effectively improve the sugar metabolism in T2DM patients failed by premixed insulin with or without OADs ,moreover the body mass is not increased .

Intensive Insulin Therapy in Type 1 Diabetes / 임상당뇨병

The Epidemiology of Diabetes Interventions and Complications study, a prospective observational follow-up of the Diabetes Control and Complications Trial cohort, reported persistent benefits for micro- and macro-vascular complication in type 1 diabetes mellitus with intensive insulin therapy. It is the standard of care for most patients with type 1 diabetes. There are two modalities: continuous subcutaneous insulin infusion (CSII), so called insulin pump, and multiple dose of insulin. Both shows similar effects in frequency of severe hypoglycemia and progression of microvascular disease, but CSII provides slightly better in glycemic control. An important aspect of intensive insulin therapy is educating patients about basal insulin, and carbohydrate/insulin ratio, sensitivity index, the coordination of meals, activity, stress, and hormonal changes with frequent monitoring of blood glucose levels during pregnancy. It is important to identify and resolve emotional and attitudinal barriers of the patient and family for improving glycemic control during intensive diabetes management.

Adherencia terapéutica y flexibilidad en el uso de las insulinas basales

Desde 1921, los beneficios alcanzados por las investigaciones sobre insulinoterapia han sido constantes. Sin embargo, el temor a las hipoglucemias y la rigidez horaria para administrar la insulina aún interfieren sobre la adherencia al tratamiento, que es esencial para lograr un buen control de la glucemia y minimizar las complicaciones en los pacientes con diabetes. En este contexto, se analiza la posibilidad de utilizar un análogo de insulina ultra-lento (degludec) que posee un perfil farmacocinético prolongado y predecible por más de 24 horas. En ensayos clínicos demostró que, al administrarlo en un esquema de dosis flexible mantiene un buen control de la glucemia, sin que aumente el riesgo de hipoglucemias. Si bien en la práctica clínica es aconsejable seguir un plan establecido, la posibilidad de flexibilizar el horario en la aplicación diaria del análogo ultra-lento en caso de ser necesario, podría mejorar la adherencia en pacientes con una vida social y laboral activa y poco previsible.

Since 1921, the benefits achieved by insulin therapy research have been constant. However, the fear of a hypoglycemia incidence and rigid time schedules of insulin therapy still interfere with treatment adherence, which is essential to achieve optimal glycemic control and minimize complications in diabetic patients. The possibility of using an ultra long-acting insulin analogue (degludec), which has an extensive and predictable pharmacokinetic profile over 24 hours, is analyzed in this context. Clinical trials have shown that this ultra long-acting insulin analogue administered in a flexible dosage treatment, reached a good glycaemic control with no increase on hypoglycemia risk. Although to follow a predefined plan in clinical practice is recommended, the possibility of flexibility in day to day dosage timing of this specific insulin analogue on requirement, could improve adherence in patients with a non-predictable and active social life and workday.

Premixed or basal insulin: the insulin initiation consideration in Chinese patients with type 2 diabetes mellitus / 中华内分泌代谢杂志

[Summary] The general status of glycemic control and insulin initiation are not optimistic in Chinese patients with type 2 diabetes.Chinese patients experience pancreatic β-cell dysfunction and reduction of early phase insulin spike earlier and more severely compared to Caucasians.These can cause more significant postprandial hyperglycaemia which is further deteriorated by traditional carbohydrate-rich Chinese diet.Therefore,premixed insulin may be a more appropriate option of insulin initiation therapy for Chinese patients with type 2 diabetes mellitus.

Glycemic Effects of Once-a-Day Rapid-Acting Insulin Analogue Addition on a Basal Insulin Analogue in Korean Subjects with Poorly Controlled Type 2 Diabetes Mellitus

BACKGROUND: The present study investigates the efficacy in glycemic control by adding once-a-day glulisine to glargine as a basal plus regimen and factors influencing glycemic control with the basal plus regimen in Korean subjects with type 2 diabetes. METHODS: In the present retrospective study, subjects previously treated with the basal plus regimens for at least 6 months were reviewed. Changes in glycemic profiles and clinical parameters were evaluated. RESULTS: A total of 87 subjects were ultimately enrolled in this study. At baseline, mean glycated hemoglobin (A1c) and glycated albumin were 8.5% (8.0% to 9.6%) and 25.2+/-7.6%, respectively. After treatment with the basal plus regimen, patients had significant reductions of A1c at 6 months (0.8+/-0.1%, P<0.001) and their postprandial glucose levels were decreased by 48.7+/-10.3 mg/dL (P<0.001). Multiple logistic regression showed old age (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.02 to 1.55), high initial A1c (OR, 22.21; 95% CI, 2.44 to 201.78), and lower amounts of glargine (OR, 0.85; 95% CI, 0.76 to 0.99), and glimepiride (OR, 0.23; 95% CI, 0.06 to 0.93) at baseline were independently associated with good responders whose A1c reduction was more than 0.5%. CONCLUSION: The authors suggest a basal plus regimen may be effective in reducing glucose levels of subjects with old age, high initial A1c, and patients on low doses of glimepiride and glargine. Despite the use of high doses of hypoglycemic agents, elderly patients with poorly-controlled diabetes are preferred for early initiation of the basal plus regimen.

Contribution of basal and early phase insulin secretion to plasma glucose level in patients with type 2 diabetes / 中华内分泌代谢杂志

Objective To investigate the effects of basal and early phase insulin secretion on plasma glucose level in type 2 diabetes. Methods Plasma glucose and true insulin levels were measured at 0, 30, 60, 120 min during standard meal test in 81 patients with type 2 diabetes. Insulin sensitivity index (ISI) and insulin secretion index (?I 30 /?G 30 ) were calculated for evaluating the insulin sensitivity. Contributions of basal and early insulin secretion to plasma glucose level were evaluated by multivariate regression analysis with SAS software. Results ISI and ?I 30 /?G 30 showed nearly equal effects on plasma glucose levels by multivariate regression analysis. Among insulin levels of different time points during standard meal test, basal and postprandial 60 min insulin levels played important roles in changes of plasma glucose levels. The effect of fasting insulin on the area under plasma glucose curve was stronger than that of ?I 30 /?G 30 . Conclusion Both basal and early insulin secretions greatly contribute to glycemic control.