Oral Insulin: A Comparison With Subcutaneous Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVE

To determine the pharmacokinetic and pharmacodynamic properties of an oral insulin (OI) formulation compared with subcutaneously injected regular human insulin (RHI).

RESEARCH DESIGN AND METHODS

Ten male patients with type 2 diabetes (means ± SD; A1C 7.0 ± 1.1%; BMI 28.3 ± 2.7 kg/m²) received either 300 units of insulin combined with 400 mg of delivery agent orally or 15 units RHI subcutaneously under isoglycemic clamp conditions.

RESULTS

Maximum insulin concentration was greater and onset of action was faster with OI (C_max 93 ± 71 vs. 33 ± 11 μU/ml; AUC_GIR^(0−1h) 173 ± 86 vs. 27 ± 32 mg/kg; P < 0.05). Mean insulin concentration and glucose infusion rate returned to baseline within 3 h after OI administration. Relative bioavailability of OI was 7 ± 4% (1st 2 h).

CONCLUSIONS

This proof-of-concept study demonstrated that absorption of OI is feasible under fasting conditions. OI has a fast onset and a short duration of action but also shows a rather high between-subject variability in absorption.Oral administration of insulin has the potential advantage of a more physiological action by its direct effect on hepatic glucose production (1,2). Thus far various oral insulin approaches however have only partially produced satisfactory results (1,3,4). Gastrointestinal absorption of insulin is hampered by factors such as enzymatic degradation and lack of permeation through epithelial cells (5). Noncovalent interaction of the novel drug-carrier molecule monosodium N-(4-chlorosalicyloyl)-4-aminobutyrate (4-CNAB) with insulin might create more favorable physico-chemical properties for gastrointestinal insulin absorption (6,7). In this study, 4-CNAB has been combined with human insulin to facilitate gastrointestinal insulin absorption.     

Randomized Study Comparing a Basal-Bolus With a Basal Plus Correction Insulin Regimen for the Hospital Management of Medical and Surgical Patients With Type 2 Diabetes: Basal Plus Trial

OBJECTIVE

Effective and easily implemented insulin regimens are needed to facilitate hospital glycemic control in general medical and surgical patients with type 2 diabetes (T2D).

RESEARCH DESIGN AND METHODS

This multicenter trial randomized 375 patients with T2D treated with diet, oral antidiabetic agents, or low-dose insulin (≤0.4 units/kg/day) to receive a basal-bolus regimen with glargine once daily and glulisine before meals, a basal plus regimen with glargine once daily and supplemental doses of glulisine, and sliding scale regular insulin (SSI).

RESULTS

Improvement in mean daily blood glucose (BG) after the first day of therapy was similar between basal-bolus and basal plus groups (P = 0.16), and both regimens resulted in a lower mean daily BG than did SSI (P = 0.04). In addition, treatment with basal-bolus and basal plus regimens resulted in less treatment failure (defined as >2 consecutive BG >240 mg/dL or a mean daily BG >240 mg/dL) than did treatment with SSI (0 vs. 2 vs. 19%, respectively; P < 0.001). A BG <70 mg/dL occurred in 16% of patients in the basal-bolus group, 13% in the basal plus group, and 3% in the SSI group (P = 0.02). There was no difference among the groups in the frequency of severe hypoglycemia (<40 mg/dL; P = 0.76).

CONCLUSIONS

The use of a basal plus regimen with glargine once daily plus corrective doses with glulisine insulin before meals resulted in glycemic control similar to a standard basal-bolus regimen. The basal plus approach is an effective alternative to the use of a basal-bolus regimen in general medical and surgical patients with T2D.Inpatient hyperglycemia in patients, with or without diabetes, is associated with poor hospital outcomes, including prolonged hospital stay, infections, and disability after hospital discharge, and death (1–3). Several clinical trials in critically ill patients have reported that improvement of glycemic control reduces hospital complications (4–6), hospital stay, and mortality (6–8). In patients with T2D admitted to general medicine and surgery services, recent randomized, controlled trials have shown that treatment with a basal-bolus regimen results in significantly lower mean daily blood glucose (BG) and in a higher percentage of BG within target range than does treatment with sliding scale regular insulin (SSI) (9,10). In addition, in general surgical patients, the basal-bolus approach results in a significant reduction in the frequency of composite complications, consisting of postoperative wound infection, pneumonia, bacteremia, and acute renal and respiratory failure (10). On the basis of these results, clinical practice guidelines have recommended the use of the basal-bolus approach as the preferred insulin regimen for the management of patients with diabetes not in the intensive care unit (ICU) (11–13).Despite the benefits of a basal-bolus regimen in improving glycemic control in non-critically ill patients (2,7,9,10,14), many health care providers and hospitalists are reluctant to integrate this approach into their clinical practice, probably because of its complexity and a fear of hypoglycemia (15–18). Because most patients in the hospital have reduced caloric intake as a result of medical illness or surgical procedures, we hypothesized that a single daily dose of basal insulin might result in similar glucose control and lower the rate of hypoglycemia relative to a basal-bolus regimen. Accordingly, we tested the efficacy and safety in general medical and surgical patients with T2D of a daily dose of basal insulin plus corrective doses with a rapid-insulin analog given by sliding scale (basal plus regimen) with a basal-bolus insulin regimen with glargine once daily and fixed doses of glulisine before meals and also with SSI (no basal insulin) given four times.     

Expanded Basal Insulin Options for Type 2 Diabetes Mellitus

Basal insulin is a component of therapy for many patients with diabetes mellitus. Several concentrated basal insulins are newly available. Nurse practitioners should be aware and informed of the various concentration options as they manage their patients. This article reviews the available concentrated products with a focus on degludec insulin. Nurse practitioners should be knowledgeable of the resulting safety considerations, particularly during transitions of care, or conversions between products.     

Randomized Controlled Trial of Insulin Supplementation for Correction of Bedtime Hyperglycemia in Hospitalized Patients With Type 2 Diabetes

OBJECTIVE

Clinical guidelines recommend point-of-care glucose testing and the use of supplemental doses of rapid-acting insulin before meals and at bedtime for correction of hyperglycemia. The efficacy and safety of this recommendation, however, have not been tested in the hospital setting.

RESEARCH DESIGN AND METHODS

In this open-label, randomized controlled trial, 206 general medicine and surgery patients with type 2 diabetes treated with a basal-bolus regimen were randomized to receive either supplemental insulin (n = 106) at bedtime for blood glucose (BG) >7.8 mmol/L or no supplemental insulin (n = 100) except for BG >19.4 mmol/L. Point-of-care testing was performed before meals, at bedtime, and at 3:00 a.m. The primary outcome was the difference in fasting BG. In addition to the intention-to-treat analysis, an as-treated analysis was performed where the primary outcome was analyzed for only the bedtime BG levels between 7.8 and 19.4 mmol/L.

RESULTS

There were no differences in mean fasting BG for the intention-to-treat (8.8 ± 2.4 vs. 8.6 ± 2.2 mmol/L, P = 0.76) and as-treated (8.9 ± 2.4 vs. 8.8 ± 2.4 mmol/L, P = 0.92) analyses. Only 66% of patients in the supplement and 8% in the no supplement groups received bedtime supplemental insulin. Hypoglycemia (BG <3.9 mmol/L) did not differ between groups for either the intention-to-treat (30% vs. 26%, P = 0.50) or the as-treated (4% vs. 8%, P = 0.37) analysis.

CONCLUSIONS

The use of insulin supplements for correction of bedtime hyperglycemia was not associated with an improvement in glycemic control. We conclude that routine use of bedtime insulin supplementation is not indicated for management of inpatients with type 2 diabetes.     

Closed-Loop Basal Insulin Delivery Over 36 Hours in Adolescents With Type 1 Diabetes: Randomized clinical trial

OBJECTIVE

We evaluated the safety and efficacy of closed-loop basal insulin delivery during sleep and after regular meals and unannounced periods of exercise.

RESEARCH DESIGN AND METHODS

Twelve adolescents with type 1 diabetes (five males; mean age 15.0 [SD 1.4] years; HbA_1c 7.9 [0.7]%; BMI 21.4 [2.6] kg/m²) were studied at a clinical research facility on two occasions and received, in random order, either closed-loop basal insulin delivery or conventional pump therapy for 36 h. During closed-loop insulin delivery, pump basal rates were adjusted every 15 min according to a model predictive control algorithm informed by subcutaneous sensor glucose levels. During control visits, subjects’ standard infusion rates were applied. Prandial insulin boluses were given before main meals (50–80 g carbohydrates) but not before snacks (15–30 g carbohydrates). Subjects undertook moderate-intensity exercise, not announced to the algorithm, on a stationary bicycle at a 140 bpm heart rate in the morning (40 min) and afternoon (20 min). Primary outcome was time when plasma glucose was in the target range (71–180 mg/dL).

RESULTS

Closed-loop basal insulin delivery increased percentage time when glucose was in the target range (median 84% [interquartile range 78–88%] vs. 49% [26–79%], P = 0.02) and reduced mean plasma glucose levels (128 [19] vs. 165 [55] mg/dL, P = 0.02). Plasma glucose levels were in the target range 100% of the time on 17 of 24 nights during closed-loop insulin delivery. Hypoglycemia occurred on 10 occasions during control visits and 9 occasions during closed-loop delivery (5 episodes were exercise related, and 4 occurred within 2.5 h of prandial bolus).

CONCLUSIONS

Day-and-night closed-loop basal insulin delivery can improve glucose control in adolescents. However, unannounced moderate-intensity exercise and excessive prandial boluses pose challenges to hypoglycemia-free closed-loop basal insulin delivery.Closed-loop insulin delivery is an emerging technology that may transform management of type 1 diabetes (1). Coupling subcutaneous continuous glucose monitoring (2,3) and insulin pump delivery (4), the closed-loop technology delivers insulin in a continually glucose-responsive fashion to reduce the risk of hypoglycemia and to improve overall glucose control (5,6).This novel approach differs from conventional pump therapy through the use of a control algorithm that directs subcutaneous insulin delivery according to subcutaneous sensor glucose levels (7). Previous randomized studies with an adaptive algorithm controlling basal insulin demonstrated effectiveness of closed loop during sleep (8,9). Application after a standard evening meal and late-afternoon exercise resulted in a 20% improvement in the number of glucose levels overnight within the target range while reducing the risk of nocturnal hypoglycemia in children and adolescents (8). Similar improvements were observed in adults after a standard dinner and a large evening meal accompanied by alcohol (9). Feasibility of closed-loop control has also been explored in pregnancy (10,11). The future challenge is to determine whether closed-loop insulin delivery can maintain glycemic control after meals, physical exercise, and snacks, where to date, published studies have been encouraging but have lacked a conventional therapy comparator (12,13).Meals and physical activity cause rapid fluctuations in blood glucose levels, which challenge the closed-loop approach because of delays associated with the subcutaneous route of insulin delivery and glucose sensing errors. We addressed this question by evaluating closed-loop basal insulin delivery systems with proven efficacy overnight during a 36-h period that comprised waking hours and common daily activities, including a typical school day, and behaviors of adolescents.     

两种胰岛素强化方案治疗2型糖尿病的疗效比较

目的:比较采用两种胰岛素强化方案治疗2型糖尿病的有效性及安全性。方法:2型糖尿病患者180例,随机分为A、B两组。A组82例,每日三餐前10min皮下注射双时相门冬胰岛素30;B组98例,三餐前10min皮下注射门冬胰岛素注射液,并在睡前皮下注射甘精胰岛素注射液。比较两组治疗前后空腹血糖、餐后2h血糖、每日胰岛素用量、低血糖发生率、随访3个月后两组脱落率及糖化血红蛋白(HbA1C)。结果:A、B组患者的日胰岛素平均用量分别为(38.65±7.77)U、(40.27±11.72)U(P>0.05);A组在治疗期间发生低血糖11例(13.41%),B组发生低血糖10例(10.20%),两组差异无统计学意义(P>0.05);两组治疗后空腹血糖、餐后2h血糖水平均较治疗前显著下降(P<0.01),但组间比较差异无统计学意义;随访3个月后A、B组的HbA1C水平分别为(6.91±0.74)%和(6.91±0.71)%,差异无统计学意义(P>0.05);A组脱落5例(6.10%),B组17例(17.35%),两组脱落率比较差异有统计学意义(P<0.05)。结论:两种强化治疗方案均安全、有效,但每日3次皮下注射双时相门冬胰岛素30的方案更方便,患者的依从性更好。     

Randomized Crossover Study to Examine the Necessity of an Injection-to-Meal Interval in Patients With Type 2 Diabetes and Human Insulin

OBJECTIVE

Patients with diabetes and insulin therapy with human insulin were usually instructed to use an interval of 20–30 min between the injection and meal. We examined the necessity of the injection-to-meal interval (IMI) in patients with type 2 diabetes mellitus (T2DM) and flexible insulin therapy with human insulin.

RESEARCH DESIGN AND METHODS

In this randomized, open crossover trial, 100 patients with T2DM (47% men, mean age = 66.7 years) were randomized to the IMI first group (phase 1, IMI 20 min; phase 2, no IMI) or IMI last group (phase 1, no IMI; phase 2, IMI 20 min). The main outcome measures were HbA_1c, blood glucose profile, incidence of hypoglycemia, quality of life, treatment satisfaction, and patient preference.

RESULTS

Forty-nine patients were randomized to the IMI first group and 51 patients to the IMI last group. Omitting the IMI only slightly increases HbA_1c (average intraindividual difference = 0.08% [95% CI 0.01–0.15]). Since the difference is not clinically relevant, a therapy without IMI is noninferior to its application (P < 0.001). In the secondary outcomes, the incidence of mild hypoglycemia also did not differ between no IMI and IMI significantly (mean of differences = −0.10, P = 0.493). No difference in the blood glucose profile of both groups was found. Treatment satisfaction increased markedly, by 8.08, if IMI was omitted (P < 0.001). The total score of the quality of life measure did not show differences between applying an IMI or not. Insulin therapy without IMI was preferred by 86.5% of patients (P < 0.001).

CONCLUSIONS

An IMI for patients with T2DM and preprandial insulin therapy is not necessary.Type 2 diabetes mellitus (T2DM) affects ∼5% of the German population (1). About 30% of those patients are treated with insulin (2). In the preanalog-insulin era, patients with diabetes were usually instructed to use an interval of 20–60 min between the injection and meal consumption to compensate for the process of absorbing regular insulin preparations. This recommendation has been supported by pharmacodynamic studies measuring the rate of appearance of insulin in the serum (3,4). However, half of the patients with type 1 diabetes (T1DM) and T2DM do not use any injection-to-meal interval (IMI). The other half is using a fixed or flexible IMI. In contrast to the many recommendations to apply an optimal IMI of 20–30 min, most patients use a shorter IMI of 17–18 min (5–7).There are some studies with considerable limitations on the IMI in patients with T1DM (9–12). However, almost no information is available for patients with T2DM, although they represent the largest group of insulin-treated patients. The few small, short studies on T1DM were published between 1980 and 1995, a time in which animal insulins were predominantly used. It is known that animal insulins induce anti-insulin autoantibodies more frequently than human insulin. This is evident particularly for bovine insulin (8). At that time, the therapy strategy was conventional insulin therapy, with one or two injections of a mix of short- and intermediate-acting insulin per day, and patients did not regularly self-monitor their blood glucose. If reported, patients usually had insufficient metabolic control, indicated by HbA_1c values between 9 and 11%. None of the studies dealing with the IMI were long enough to show any differences in HbA_1c (9–12).In 1996, the first short-acting insulin analog was introduced to diabetes therapy. The fact that short-acting analogs do not need an IMI at all was claimed to be a great advantage, although it is questionable, according to current data, if the IMI is really necessary (13–15). In Germany, the most commonly used diabetes teaching and treatment programs do not necessarily recommend an IMI, with either regular human insulin or short-acting analogs (16). This randomized, two-phase crossover study examines the necessity of an IMI in patients with T2DM and flexible insulin therapy with human regular insulin for metabolic control and its impact on treatment satisfaction and quality of life.     

The Effect of Discontinuing Continuous Glucose Monitoring in Adults With Type 2 Diabetes Treated With Basal Insulin

OBJECTIVETo explore the effect of discontinuing continuous glucose monitoring (CGM) after 8 months of CGM use in adults with type 2 diabetes treated with basal without bolus insulin.RESEARCH DESIGN AND METHODSThis multicenter trial had an initial randomization to either real-time CGM or blood glucose monitoring (BGM) for 8 months followed by 6 months in which the BGM group continued to use BGM (n = 57) and the CGM group was randomly reassigned either to continue CGM (n = 53) or discontinue CGM with resumption of BGM for glucose monitoring (n = 53).RESULTSIn the group that discontinued CGM, mean time in range (TIR) 70–180 mg/dL, which improved from 38% before initiating CGM to 62% after 8 months of CGM, decreased after discontinuing CGM to 50% at 14 months (mean change from 8 to 14 months −12% [95% CI −21% to −3%], P = 0.01). In the group that continued CGM use, little change was found in TIR from 8 to 14 months (baseline 44%, 8 months 56%, 14 months 57%, mean change from 8 to 14 months 1% [95% CI −11% to 12%], P = 0.89). Comparing the two groups at 14 months, the adjusted treatment group difference in mean TIR was −6% (95% CI −16% to 4%, P = 0.20).CONCLUSIONSIn adults with type 2 diabetes treated with basal insulin who had been using real-time CGM for 8 months, discontinuing CGM resulted in a loss of about one-half of the initial gain in TIR that had been achieved during CGM use.     

Cost-effectiveness of Insulin Degludec Versus Insulin Glargine in Insulin-naive Chinese Patients With Type 2 Diabetes

Purpose

The goal of this study was to investigate the long-term economic outcomes of insulin degludec versus insulin glargine use in Chinese patients with type 2 diabetes mellitus (T2DM) whose oral antidiabetic drugs did not provide sufficient glycemic control.

Postprandial Vascular Effects of VIAject Compared With Insulin Lispro and Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVE

Recent studies suggested an impact of prandial insulin delivery on postprandial regulation of tissue blood flow. This study compared the effect of VIAject with human regular insulin and insulin lispro on postprandial oxidative stress and endothelial function in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Fourteen patients (seven men; aged 61.5 ± 1.8 years; duration of diabetes 6.6 ± 4.6 years; A1C 7.2 ± 0.5% [mean ± SEM]) received a prandial injection of VIAject, human regular insulin, and insulin lispro. At baseline and after a standardized liquid meal test (Ensure Plus), the postprandial increases in asymmetric dimethylarginine (ADMA) and nitrotyrosine levels were investigated. In addition, the postprandial effects on microvascular blood flow, skin oxygenation, and vascular elasticity were measured.

RESULTS

Treatment with VIAject resulted in a significant reduction in the peak postprandial generation of ADMA compared with human insulin and insulin lispro (VIAject −27.3 ± 22.6, human insulin 97.7 ± 24.4, and insulin lispro 66.9 ± 33.9 nmol/l; P < 0.05, respectively). The postprandial increases in nitrotyrosine levels were significantly less after VIAject than after human regular insulin (VIAject −0.22 ± 0.17 vs. human insulin 0.25 ± 0.15 μg/ml; P < 0.05), whereas nitrotyrosine after insulin lispro was in between (insulin lispro 0.09 ± 0.07 μg/ml; NS). In parallel, earlier and more pronounced increases in microvascular blood flow and skin oxygenation were obtained after VIAject compared with those after human insulin or insulin lispro (P < 0.05, respectively). All insulin formulations resulted in comparable improvements in central arterial elasticity.

CONCLUSIONS

Treatment with VIAject reduced postprandial oxidative stress and improved endothelial function compared with human regular insulin or insulin lispro.Type 2 diabetes is closely related to atherosclerosis and the development of cardiovascular complications such as myocardial infarction or stroke. Recent studies on cardiovascular end points in patients with type 2 diabetes call into question the value of A1C-focused treatments in reducing macrovascular complications of diabetes (1–3). Other markers such as glucose excursions, hypoglycemia, or postprandial generation of oxidative stress may add important information for the judgment of cardiovascular risk in patients with type 2 diabetes (1,2). Postprandial microvascular blood flow is under dynamic regulation and is diversely affected by changes in postprandial glucose and insulin levels (4). Increasing postprandial insulin levels stimulate microvascular blood flow by inducing the endothelial release of nitric oxide via the activation of the phosphatidylinositol 3-kinase system (5,6). In contrast, increasing blood glucose levels were shown to oppose the insulin effects on endothelial cells and to impair postprandial microvascular blood flow (7). A reduced first-phase insulin release with an augmented increase in postprandial glucose levels followed by an impairment in endothelial function and postprandial microvascular blood flow is an early feature of type 2 diabetes (4,8). These findings suggest that a physiological timing of prandial insulin release fulfills an important role not only in controlling postprandial blood glucose levels but also in maintaining normal tissue perfusion and nutrition. In addition, recent studies have shown that in insulin-treated patients with type 1 and type 2 diabetes, the pharmacokinetic profile of insulin formulations affects postprandial microvascular blood flow and that treatment with fast-acting insulin analogs reduces postprandial oxidative stress and restores endothelial function more effectively than treatment with human regular insulin (9–11).VIAject is a new, ultra–fast-acting insulin formulation shown to have more rapid insulin absorption than that for human regular insulin and insulin lispro. The aim of this study was to compare the effect of preprandial subcutaneous administration of insulin VIAject with preprandial application of human regular insulin and insulin lispro on several markers of endothelial and microvascular function after a standardized liquid meal test in patients with type 2 diabetes.     

Comparison of Glycemic Variability Associated With Insulin Glargine and Intermediate-Acting Insulin When Used as the Basal Component of Multiple Daily Injections for Adolescents With Type 1 Diabetes

OBJECTIVE—To compare the glucose variability associated with insulin glargine and NPH/Lente insulin used as the basal insulin component of a multiple daily injection (MDI) regimen in pediatric patients with type 1 diabetes.RESEARCH DESIGN AND METHODS—Continuous glucose monitoring data were collected from a subset of patients (n = 90) who agreed to use a continuous glucose monitoring system during an active-controlled, randomized, open-label study evaluating the safety and efficacy of insulin glargine and NPH/Lente insulin used with insulin lispro as part of an MDI regimen.RESULTS—Treatment with insulin glargine resulted in significant reductions in glucose variability as measured by the SD of glucose values (adjusted mean change from baseline to week 24: −13.4 mg/dl [−0.74 mmol/l]; P ≤ 0.05), mean amplitude of glycemic excursion (−34.4 mg/dl [−1.91 mmol/l]; P ≤ 0.0001), and M value (−9.6 mg/dl [−0.53 mmol/l]; P ≤ 0.03). The corresponding reductions in glucose variability for NPH/Lente were not significant.CONCLUSIONS—Insulin glargine is associated with greater reductions in glucose variability than NPH/Lente insulin in pediatric patients with type 1 diabetes.Improved glycemic control to prevent or delay microvascular complications is of paramount importance in children and adolescents with type 1 diabetes but is often achieved at the price of increased hypoglycemia (1,2). Persistent wide fluctuations in plasma glucose in the presence of lower mean glucose and A1C values may be an important reason why intensive therapy, as practiced in the Diabetes Control and Complications Trial, increases the risk of severe hypoglycemia (2,3). Several studies have suggested that glycemic variability may also play an independent role in the development of diabetes complications (4–8). Therefore, some investigators suggest that blood glucose variability, when combined with A1C levels, is an important indicator of glycemic control and the risk for long-term complications (9,10).Insulin glargine (Lantus; sanofi-aventis U.S., Bridgewater, NJ) is a basal insulin with little or no pronounced action peak and limited site absorption variation (11). Its use as part of a multiple daily injection (MDI) regimen demonstrated good glucose control with less hypoglycemia than NPH insulin in adults with type 1 or type 2 diabetes (12,13). However, only one major randomized clinical trial in pediatric patients has examined the relative efficacy of insulin glargine–based MDI versus MDI regimens utilizing intermediate-acting insulins, and this study did not examine glucose variability (14).Consequently, we performed a large randomized clinical trial in adolescents with type 1 diabetes to compare these two approaches to intensive insulin therapy. A secondary aim of this trial was to compare the glucose variability using insulin glargine with that using intermediate-acting insulin (NPH or Lente) as the basal insulin component of an MDI regimen. Both patient groups received premeal insulin lispro (Humalog; Eli Lilly and Co., Indianapolis, IN). This study reports the results of data analysis from a subset of patients who volunteered to use a continuous glucose monitoring system (CGMS) to assess glucose variability. Results from the entire randomized controlled trial are reported elsewhere (15).     

Switching to Once-Weekly Insulin Icodec Versus Once-Daily Insulin Glargine U100 in Type 2 Diabetes Inadequately Controlled on Daily Basal Insulin: A Phase 2 Randomized Controlled Trial

OBJECTIVEInsulin icodec (icodec) is a novel once-weekly basal insulin analog. This trial investigated two approaches for switching to icodec versus once-daily insulin glargine 100 units/mL (IGlar U100) in people with type 2 diabetes receiving daily basal insulin and one or more oral glucose-lowering medications.RESEARCH DESIGN AND METHODSThis multicenter, open-label, treat-to-target phase 2 trial randomized (1:1:1) eligible basal insulin–treated (total daily dose 10–50 units) people with type 2 diabetes (HbA_1c 7.0–10.0% [53.0–85.8 mmol/mol]) to icodec with an initial 100% loading dose (in which only the first dose was doubled [icodec LD]), icodec with no loading dose (icodec NLD), or IGlar U100 for 16 weeks. Primary end point was percent time in range (TIR; 3.9–10.0 mmol/L [70–180 mg/dL]) during weeks 15 and 16, measured using continuous glucose monitoring. Key secondary end points included HbA_1c, adverse events (AEs), and hypoglycemia.RESULTSEstimated mean TIR during weeks 15 and 16 was 72.9% (icodec LD; n = 54), 66.0% (icodec NLD; n = 50), and 65.0% (IGlar U100; n = 50), with a statistically significant difference favoring icodec LD versus IGlar U100 (7.9%-points [95% CI 1.8–13.9]). Mean HbA_1c reduced from 7.9% (62.8 mmol/mol) at baseline to 7.1% (54.4 mmol/mol icodec LD) and 7.4% (57.6 mmol/mol icodec NLD and IGlar U100); incidences and rates of AEs and hypoglycemic episodes were comparable.CONCLUSIONSSwitching from daily basal insulin to once-weekly icodec was well tolerated and provided effective glycemic control. Loading dose use when switching to once-weekly icodec significantly increased percent TIR during weeks 15 and 16 versus once-daily IGlar U100, without increasing hypoglycemia risk.     

Comparison of the Efficacy and Safety of Insulin Detemir and Insulin Glargine in Hospitalized Patients with Type 2 Diabetes: A Randomized Crossover Trial

Introduction

Previous studies comparing insulin detemir versus insulin glargine showed conflicting results, and included only outpatients. This study compared the two insulin analogs once daily in hospitalized patients with type 2 diabetes (T2D).

Methods

A total of 55 patients aged 18–80 years with hyperglycemia admitted to the endocrinology wards were screened between June 2014 and February 2015. Forty-two enrolled patients were randomly assigned to receive either insulin detemir followed by insulin glargine once daily (n = 21), or vice versa (n = 21). The two insulin analogs were titrated 0.1 U/kg once daily based on fasting blood glucose (FBG). After achieving FBG <7.8 mmol/L (the first period), subjects were switched from one analog to the other (the second period) with no change in the dose. The second period lasted for 3 days. When hypoglycemia occurred in the second period, the observation was discontinued. Six-point blood glucose including FBG, 2 h after breakfast, lunch, dinner, bedtime, and at 3:00 am was tested every day. The glucose profiles of the final days in the two periods were compared.

Results

At the end of the first period, days for achieving FBG target (4.0 ± 0.5 days vs. 3.3 ± 0.4 days, t = 1.079, P = 0.286) and total daily dose (30.1 ± 2.4 U vs. 30.1 ± 2.9 U, t = 0.002, P = 0.999) between insulin detemir and insulin glargine were similar. There was no significant difference in the 24-h glucose control between the two analogs. No hypoglycemia occurred with both analogs in the first period. However, in the second period, when insulin glargine was switched to insulin detemir, two, three and, one patients had hypoglycemia events on day 1, day 2 and day 3 of the second period, respectively. One patient had severe hypoglycemia on day 1.

Conclusion

When both basal insulin analogs were given once daily in T2D, insulin detemir achieved similar efficacy to insulin glargine. On the other hand, there may be differences in action of the compared basal insulins. Further studies with larger patient samples are necessary to support evidence and reveal possible mechanisms.

     

格列美脲与胰岛素治疗2型糖尿病81例临床分析

目的:探讨应用格列美脲(万苏平)与胰岛素治疗2型糖尿病(T2DM)的血脂、血红蛋白、血糖临床疗效及安全性。方法:对81例T2DM患者,采用格列美脲与胰岛素治疗2型糖尿病进行临床治疗,观察格列美脲与胰岛素治疗糖尿病患者后其血糖、糖化血红蛋白(HbA1c)及血脂等指标的变化。结果:格列美脲与胰岛素治疗2糖尿病效果显著。结论:格列美脲与胰岛素可作为2型糖尿病患者的备选降糖药物。     

Incidence of Bladder Cancer in Patients With Type 2 Diabetes Treated With Metformin or Sulfonylureas

OBJECTIVE

Previous studies evaluating the effect of metformin on cancer risk have been impacted by time-related biases. To avoid these biases, we examined the incidence of bladder cancer in new users of metformin and sulfonylureas (SUs).

RESEARCH DESIGN AND METHODS

This cohort study included 87,600 patients with type 2 diabetes in The Health Improvement Network database. Use of metformin or an SU was treated as a time-dependent variable. Cox regression–generated hazard ratios (HRs) compared metformin use with SU use, adjusted for age, sex, smoking, obesity, and HbA_1c level.

RESULTS

We identified 196 incident bladder cancers in the metformin cohort and 66 cancers in the SU cohort. Use of metformin was not associated with decreased bladder cancer risk (HR 0.81 [95% CI 0.60–1.09]). This association did not differ by sex (P for interaction = 0.20). We observed no association with duration of metformin relative to SU use (3 to <4 years of use: 0.57 [0.25–1.34]; 4 to <5 years of use: 0.93 [0.30–2.85; ≥5 years of use: 1.18 [0.44–3.19]; P for trend = 0.26).

CONCLUSIONS

Use of metformin is not associated with a decreased incidence of bladder cancer. Similar methods should be used to study other cancers that have previously been identified as potentially preventable with metformin.     

The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone

OBJECTIVE

This 24-week trial assessed the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycemic control with metformin alone.

RESEARCH DESIGN AND METHODS

This was a randomized, double-blind, placebo-controlled study of saxagliptin (2.5, 5, or 10 mg once daily) or placebo plus a stable dose of metformin (1,500–2,500 mg) in 743 patients (A1C ≥7.0 and ≤10.0%). Efficacy analyses were performed using an ANCOVA model using last observation carried forward methodology on primary (A1C) and secondary (fasting plasma glucose [FPG] and postprandial glucose [PPG] area under the curve [AUC]) end points.

RESULTS

Saxagliptin (2.5, 5, and 10 mg) plus metformin demonstrated statistically significant adjusted mean decreases from baseline to week 24 versus placebo in A1C (−0.59, −0.69, and −0.58 vs. +0.13%; all P < 0.0001), FPG (−14.31, −22.03, and −20.50 vs. +1.24 mg/dl; all P < 0.0001), and PPG AUC (−8,891, −9,586, and −8,137 vs. −3,291 mg · min/dl; all P < 0.0001). More than twice as many patients achieved A1C <7.0% with 2.5, 5, and 10 mg saxagliptin versus placebo (37, 44, and 44 vs. 17%; all P < 0.0001). β-Cell function and postprandial C-peptide, insulin, and glucagon AUCs improved in all saxagliptin treatment groups at week 24. Incidence of hypoglycemic adverse events and weight reductions were similar to those with placebo.

CONCLUSIONS

Saxagliptin once daily added to metformin therapy was generally well tolerated and led to statistically significant improvements in glycemic indexes versus placebo added to metformin in patients with type 2 diabetes inadequately controlled with metformin alone.Saxagliptin is a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor, specifically designed for extended inhibition of the DPP-4 enzyme (1,2). DPP-4 rapidly cleaves and inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (1). GLP-1 and GIP regulate blood glucose homeostasis by stimulation of glucose-dependent insulin secretion (3). GLP-1 also delays gastric emptying and inhibits glucagon secretion (3,4). In rodents, GLP-1 has been shown to stimulate β-cell growth and differentiation and inhibit β-cell apoptosis (5). Such an approach is needed because the majority of patients with type 2 diabetes fail to achieve recommended glycemic targets with existing therapies, owing to safety and tolerability issues and loss of efficacy over time (6).Metformin is the most widely prescribed first-line agent for the management of type 2 diabetes and is standard first-line pharmacotherapy, along with diet and exercise (7). Mechanistically, metformin reduces hepatic glucose production and improves insulin sensitivity (8); however, metformin alone is frequently insufficient to maintain glycemic goals in the face of progressive β-cell failure and increasing insulin resistance (9). Consequently, many patients require multiple oral antihyperglycemic agents (9,10). Metformin works through pathways complementary to saxagliptin, and the combination of saxagliptin with metformin may improve glycemic control (11,12). Studies of other DPP-4 inhibitors in combination with metformin over 24 weeks have demonstrated increased efficacy versus placebo (13–15). The safety and efficacy of saxagliptin monotherapy in treatment-naive patients were established previously in a 12-week study across a dose range of 2.5 to 40 mg/day. Significant A1C reductions were demonstrated in all active treatment groups with maximal A1C efficacy observed with 5 mg saxagliptin. A test for log-linear trend across the treatment groups did not demonstrate a statistically significant dose response after 12 weeks of treatment. The overall frequency of adverse events was comparable across all treatment groups and placebo and did not appear to be dose related (16). The current trial (CV181-014) examined the efficacy and safety of saxagliptin in combination with metformin administered for up to 24 weeks in patients with type 2 diabetes inadequately controlled with metformin alone.     

Pulsatile Stress in Middle-Aged Patients With Type 1 or Type 2 Diabetes Compared With Nondiabetic Control Subjects

OBJECTIVE

Arterial pulse pressure is considered to be an independent cardiovascular risk factor. We compared pulse pressure during an active orthostatic test in middle-aged patients with type 1 diabetes and with type 2 diabetes and corresponding nondiabetic control subjects.

RESEARCH DESIGN AND METHODS

Forty patients with type 1 diabetes (mean age 50 years, diabetes duration 23 years, and BMI 23.0 kg/m²) were compared with 40 nonhypertensive patients with type 2 diabetes (respectively, 50 years, 8 years, and 29.7 kg/m²). Patients taking antihypertensive agents or with renal insufficiency were excluded. All patients were evaluated with a continuous noninvasive arterial blood pressure monitoring (Finapres) in standing (1 min), squatting (1 min), and again standing position (1 min). Patients with type 1 or type 2 diabetes were compared with two groups of 40 age-, sex- and BMI-matched healthy subjects.

RESULTS

Patients with type 1 diabetes and patients with type 2 diabetes showed significantly higher pulse pressure, heart rate, and double product of pulse pressure and heart rate (PP×HR) (type 1: 5,263 vs. 4,121 mmHg/min, P = 0.0004; type 2: 5,359 vs. 4,321 mmHg, P = 0.0023) levels than corresponding control subjects. There were no significant differences between patients with type 1 diabetes and type 2 diabetes regarding pulse pressure (59 vs. 58 mmHg), heart rate (89 vs. 88/min), and PP×HR (5,263 vs. 5,359 mmHg/min).

CONCLUSIONS

Patients with type 1 diabetes have increased levels of peripheral PP, an indirect marker of arterial stiffness, and PP×HR, an index of pulsatile stress, comparable to those of nonhypertensive patients with type 2 diabetes at similar mean age of 50 years.Arterial pulse pressure, a surrogate marker of large artery stiffness, was shown to be an independent cardiovascular disease (CVD) risk factor in several large longitudinal studies in patients with type 2 diabetes (1,2). In patients with type 1 diabetes of the Finnish Diabetic Nephropathy (FinnDiane) study (3), higher systolic blood pressure and an earlier decrease in diastolic blood pressure resulted in a higher and more rapidly increasing pulse pressure compared with those in nondiabetic control subjects. In the EURODIAB study (4,5), pulse pressure was also an independent risk factor for CVD and total mortality in patients with type 1 patients.Middle-aged patients with type 1 diabetes are characterized by a long duration of the disease and therefore sustained exposure to chronic hyperglycemia, leading to accelerated progression of arterial stiffness and increased pulse pressure (6). In contrast, middle-aged patients with type 2 diabetes have a much shorter duration of diabetes but have other CVD risk factors such as abdominal obesity, insulin resistance, and metabolic syndrome, which could accelerate arterial stiffness (1,2). To our knowledge, no study has compared pulse pressure in patients with type 1 diabetes and in patients with type 2 diabetes at similar age. The primary aim of the present study was to investigate pulsatile stress in patients with type 1 diabetes and patients with type 2 diabetes at a similar mean age of 50 years. Each group of diabetic patients was compared with a group of nondiabetic control subjects, matched for age, sex, and BMI. Blood pressure and pulse pressure were monitored during an active postural test, the so-called squatting test, which has been shown by our group to amplify the pulse pressure increase according to diabetes duration in patients with type 1 diabetes (7,8).     

Factors Associated With Psychological Insulin Resistance in Individuals With Type 2 Diabetes

OBJECTIVE

To describe the predictive relationships of selected sociodemographic, biomedical, and psychosocial variables to reluctance to use insulin among patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A total of 178 patients with type 2 diabetes participated in this cross-sectional, observational study. Data were obtained by patient interview using validated measures of diabetes attitude, knowledge, self-efficacy, care communication, and perceived barriers to treatment, as well as sociodemographic and biomedical data.

RESULTS

Women and ethnic minorities with type 2 diabetes have more psychological barriers to insulin treatment (P < 0.05). The final regression model showed that individuals who believed in the value of tight glucose control, had strong self-efficacy, and had better interpersonal processes with their healthcare providers were less reluctant to use insulin treatment (R² = 0.403; P < 0.0001).

CONCLUSIONS

Diabetes self-efficacy and better interaction with clinicians were important in decreasing patients'' reluctance to use insulin, known as psychological insulin resistance.Despite the known benefits of insulin, many patients are reluctant to use insulin therapy (1–3). A patient''s reluctance to initiate insulin may be called “psychological insulin resistance” (PIR).Little is known about what factors influence PIR. We examined the relationships among PIR, sociodemographic, biomedical, and psychosocial factors identified in previous studies (4–7) and tested a predictive model of PIR.     

Prandial Insulin Dosing Using the Carbohydrate Counting Technique in Hospitalized Patients With Type 2 Diabetes

OBJECTIVE

To compare a modified fixed meal dosing strategy to flexible meal dosing in hospitalized patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Patients (N = 126) with refractory hyperglycemia or requiring at least 20 units of insulin per day were randomly assigned to fixed meal dosing (including withholding the dose if less than half of the meal tray was consumed) or flexible meal dosing based upon carbohydrate intake. The inpatient diabetes management team made all treatment adjustments. Outcomes included day 3 mean glucose, 72-h glucose trend analysis, hypoglycemia (<3.9 mmol/L), and inpatient diabetes treatment satisfaction.

RESULTS

The mean glucose on day 3 was 9.5 and 8.8 mmol/L in the fixed and flexible meal groups, respectively (P = 0.26). The frequency of hypoglycemia was 23 and 39% overall in the fixed and flexible meal groups (P = 0.08), with half of events occurring in the morning. There was a wide range of carbohydrate intake (median 51 g/meal, 10–90% range 26–72 g on day 3). The fixed dose group required significantly more prandial insulin overall and more correction insulin over time. There was no difference in composite treatment satisfaction or dosing miscalculations between groups.

CONCLUSIONS

A fixed meal dosing strategy provided similar glucose control as flexible meal dosing, when managed by an inpatient diabetes treatment team. However, a larger sample size would be needed to definitively evaluate a treatment effect of flexible meal dosing in the hospital. Further study is needed to improve the delivery of bolus insulin in hospitalized patients.Hyperglycemia is common in the hospital (1) and is associated with poor outcomes (2). Subcutaneous insulin is traditionally favored for most general surgical and medical patients outside of the intensive care unit, using a regimen that includes basal, prandial, and correction insulin components (3,4). However, there are limited data to support individualized treatment approaches, particularly outside of the intensive care unit, where most patients receive care. In general, glycemic control is related to the intake of carbohydrates (5) and is limited by the occurrence of hypoglycemia. Data suggest that the most common cause of hypoglycemia in hospitalized patients with diabetes is a reduction in caloric intake (6,7). Variable carbohydrate exposure may be a result of tests that require fasting, late meal trays, patient food preferences, or symptoms that interfere with nutritional intake, such as anorexia and nausea. Therefore, optimizing prandial insulin dosing may provide better glycemic control.One approach to optimize prandial insulin coverage is to deliver meals with fixed carbohydrate content, thereby enabling fixed meal dosing (4). However, this does not guarantee that a patient will eat the entire meal or that the patient will not consume additional carbohydrates. An alternative approach is to administer prandial insulin based upon carbohydrate intake. In a retrospective study, the introduction of flexible meal dosing according to carbohydrate intake resulted in an improvement in glycemic control compared with sliding scale alone (8). Carbohydrate counting has shown probable glycemic benefit in outpatients with type 1 diabetes (9), but less clearly in outpatients with type 2 diabetes (10). Unlike hospitalized patients, outpatients are generally otherwise healthy, with good oral intake and recognition of impending hypoglycemia.The Centers for Medicare and Medicaid Services is increasingly emphasizing value-based purchasing decisions (11), recognizing that patient satisfaction is closely linked to clinical quality measures (12). Flexible meal plans are becoming more popular as a means of improving overall patient satisfaction in hospitals (13). A 2008 survey of 270 health care food and nutrition practitioners, suppliers, and manufacturers affiliated with the National Society of Healthcare Foodservice Management reported that 37% of respondents offered restaurant-style room service, with many more planning to make the conversion (13). Such meal plans generally still fall within the prescribed diet order, but it is less clear how this is carried out in practice among patients with diabetes. In patients with diabetes, food choices have received the lowest scores on inpatient diabetes treatment satisfaction questionnaires (14). A flexible meal plan was associated with more hypoglycemia but may improve treatment satisfaction and opportunities for nutrition education (15). Thus, it has become increasingly important to establish glycemic control strategies that address this growing trend.This is the first randomized study to examine the use of prandial insulin dosing according to carbohydrate intake in hospitalized patients.     

A 24-Week, Randomized, Treat-to-Target Trial Comparing Initiation of Insulin Glargine Once-Daily With Insulin Detemir Twice-Daily in Patients With Type 2 Diabetes Inadequately Controlled on Oral Glucose-Lowering Drugs

OBJECTIVE

To determine whether glargine is noninferior to detemir regarding the percentage of patients reaching A1C <7% without symptomatic hypoglycemia ≤3.1 mmol/l.

RESEARCH DESIGN AND METHODS

In this 24-week trial, 973 insulin-naive type 2 diabetic patients on stable oral glucose-lowering drugs with A1C 7.0–10.5% were randomized to glargine once daily or detemir twice daily. Insulin doses were systematically titrated.

RESULTS

27.5 and 25.6% of patients reached the primary outcome with glargine and detemir, respectively, demonstrating the noninferiority of glargine. Improvements in A1C were −1.46 ± 1.09% for glargine and −1.54 ± 1.11% for detemir (P = 0.149), with similar proportions of patients achieving A1C <7% (P = 0.254) but more detemir-treated patients reaching A1C <6.5% (P = 0.017). Hypoglycemia risk was similar. Weight gain was higher for glargine (difference: 0.77 kg, P < 0.001). Glargine doses were lower than detemir doses: 43.5 ± 29.0 vs. 76.5 ± 50.5 units/day (P < 0.001).

CONCLUSIONS

In insulin-naive type 2 diabetic patients, glargine reached similar control as detemir, with more weight gain, but required significantly lower doses.The “treat-to-target” clinical trials have demonstrated that the addition of systematically titrated basal insulin to existing oral therapy results in adequate glycemic control in the majority of patients with type 2 diabetes (1–3). The basal insulin analogs, insulin glargine and insulin detemir, achieve this with a reduced risk of hypoglycemia compared with the conventional NPH insulin (1,2). The aim of this study was to compare the efficacy, safety, and the effect on quality of life of once-daily glargine with twice-daily detemir in insulin-naive patients with type 2 diabetes inadequately controlled on oral glucose-lowering drugs (OGLDs), including metformin. The primary objective was to determine whether glargine was noninferior to detemir regarding the percentage of patients reaching A1C <7% without symptomatic hypoglycemia with plasma glucose (PG) ≤3.1 mmol/l.