Sherry Martin

Advancing Insulin Therapy in Type 2 Diabetes Previously Treated With Glargine Plus Oral Agents: Prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/lispro) therapy

OBJECTIVE—The purpose of this study was to compare two analog insulin therapies (prandial premixed therapy [PPT] versus basal/bolus therapy [BBT]) in type 2 diabetic patients previously treated with insulin glargine (≥30 units/day) plus oral agents, with the aim of demonstrating noninferiority of PPT to BBT. RESEARCH DESIGN AND METHODS—Patients were randomly assigned to PPT (lispro mix 50/50: 50% insulin lispro protamine suspension and 50% lispro; n = 187) t.i.d. with meals or BBT (glargine at bedtime plus mealtime lispro; n = 187) in a 24-week, multicenter, open-label, noninferiority trial. Investigators could replace lispro mix 50/50 with lispro mix 75/25 at the evening meal if the fasting plasma glucose target was unachievable. RESULTS—Baseline A1C was similar (PPT 8.8%; BBT 8.9%; P = 0.598). At week 24, A1C was lower with BBT (6.78 vs. 6.95%, P = 0.021). A1C was reduced significantly from baseline for both therapies (P < 0.0001). The difference in A1C change from baseline to the end point (BBT minus PPT) was −0.22% (90% CI −0.38 to −0.07). Noninferiority of PPT to BBT was not demonstrated based on the prespecified noninferiority margin of 0.3%. The percentages of patients achieving target A1C <7.0% (PPT versus BBT, respectively) were 54 vs. 69% (P = 0.009) and for target ≤6.5% were 35 vs. 50% (P = 0.01) but did not differ for target ≤6.0% or <7.5%. Rates of hypoglycemia were similar for both groups. CONCLUSIONS—Although noninferiority of PPT to BBT was not demonstrated, findings for A1C reduction, percentage of patients achieving A1C targets, hypoglycemia, and number of required injections should be considered in the individual decision-making process of advancing insulin replacement to PPT versus BBT in type 2 diabetes.

Racial and Ethnic Differences in Mean Plasma Glucose, Hemoglobin A1c, and 1,5-Anhydroglucitol in Over 2000 Patients with Type 2 Diabetes

CONTENT Recent studies have reported hemoglobin A(1c) (A1c) differences across racial/ethnic groups. Our diverse population allows for further investigation of potential differences in measurements of glycemia. OBJECTIVES Our objectives were to describe and explore baseline racial/ethnic differences in self-monitored plasma glucose profiles, A1c, and 1,5-anhydroglucitol (1,5-AG) in patients with type 2 diabetes enrolled in the Assessing DURAbility of Basal vs. Lispro Mix 75/25 Insulin Efficacy trial. DESIGN, SETTING, PATIENTS The trial enrolled 2094 patients with type 2 diabetes, ages 30-80 yr, from 11 countries. MAIN OUTCOME MEASURES Estimated mean plasma glucose (MPG), A1c, and 1,5-AG were compared among racial/ethnic groups before and after adjusting for factors affecting glycemia: age, sex, duration of diabetes, body mass index, and MPG. RESULTS Baseline estimated MPG +/- sd was 220.0 +/- 82.0 mg/dl, mean A1c was 9.0 +/- 1.3%, and 1,5-AG was 5.0 +/- 4.1microg/ml. Estimated MPG did not differ between Caucasian and non-Caucasian groups. A1c was higher in Hispanics (9.4 +/- 1.4%; P < 0.001), Asians (9.2 +/- 1.4%; P < 0.01), and patients of other racial/ethnic groups (9.7 +/- 1.5%; P < 0.001) compared with Caucasians (8.9 +/- 1.2%). Paradoxically, 1,5-AG was higher for Asian (5.7 +/- 4.6 microg/ml) and African patients (6.2 +/- 5.4 microg/ml) vs. Caucasians (4.9 +/- 3.9 microg/ml) (P < 0.01). After adjusting for factors affecting glycemia, A1c was higher (all P <or= 0.002) in Hispanics, Asians, Africans, and patients of other racial/ethnic groups, and 1,5-AG was higher in Asian and African patients (P < 0.001) vs. Caucasians. CONCLUSIONS There were differences in A1c and 1,5-AG, but not MPG, among racial/ethnic groups. Comparisons of glycemia across racial/ethnic groups using these parameters may be problematic due to inherent biological variability and methodological issues.

Advancing Insulin Therapy in Type 2 Diabetes, Previously Treated with Glargine Plus Oral Agents: Prandial Premixed (Lispro/ILPS) vs. Basal/Bolus (Glargine/Lispro) Therapy

OBJECTIVE—The purpose of this study was to compare two analog insulin therapies (prandial premixed therapy [PPT] versus basal/bolus therapy [BBT]) in type 2 diabetic patients previously treated with insulin glargine (≥30 units/day) plus oral agents, with the aim of demonstrating noninferiority of PPT to BBT. RESEARCH DESIGN AND METHODS—Patients were randomly assigned to PPT (lispro mix 50/50: 50% insulin lispro protamine suspension and 50% lispro; n = 187) t.i.d. with meals or BBT (glargine at bedtime plus mealtime lispro; n = 187) in a 24-week, multicenter, open-label, noninferiority trial. Investigators could replace lispro mix 50/50 with lispro mix 75/25 at the evening meal if the fasting plasma glucose target was unachievable. RESULTS—Baseline A1C was similar (PPT 8.8%; BBT 8.9%; P = 0.598). At week 24, A1C was lower with BBT (6.78 vs. 6.95%, P = 0.021). A1C was reduced significantly from baseline for both therapies (P < 0.0001). The difference in A1C change from baseline to the end point (BBT minus PPT) was −0.22% (90% CI −0.38 to −0.07). Noninferiority of PPT to BBT was not demonstrated based on the prespecified noninferiority margin of 0.3%. The percentages of patients achieving target A1C <7.0% (PPT versus BBT, respectively) were 54 vs. 69% (P = 0.009) and for target ≤6.5% were 35 vs. 50% (P = 0.01) but did not differ for target ≤6.0% or <7.5%. Rates of hypoglycemia were similar for both groups. CONCLUSIONS—Although noninferiority of PPT to BBT was not demonstrated, findings for A1C reduction, percentage of patients achieving A1C targets, hypoglycemia, and number of required injections should be considered in the individual decision-making process of advancing insulin replacement to PPT versus BBT in type 2 diabetes.

DURAbility of Basal Versus Lispro Mix 75/25 Insulin Efficacy (DURABLE) Trial 24-Week Results Safety and efficacy of insulin lispro mix 75/25 versus insulin glargine added to oral antihyperglycemic drugs in patients with type 2 diabetes

OBJECTIVE To compare the ability of two starter insulin regimens to achieve glycemic control in a large, ethnically diverse population with type 2 diabetes. RESEARCH DESIGN AND METHODS During the initiation phase of the DURABLE trial, patients were randomized to a twice-daily lispro mix 75/25 (LM75/25; 75% lispro protamine suspension, 25% lispro) (n = 1,045) or daily glargine (GL) (n = 1,046) with continuation of prestudy oral antihyperglycemic drugs. RESULTS Baseline A1C was similar (LM75/25: 9.1 ± 1.3%; GL: 9.0 ± 1.2%; P = 0.414). At 24 weeks, LM75/25 patients had lower A1C than GL patients (7.2 ± 1.1 vs. 7.3 ± 1.1%, P = 0.005), greater A1C reduction (–1.8 ± 1.3 vs. –1.7 ± 1.3%, P = 0.005), and higher percentage reaching A1C target <7.0% (47.5 vs. 40.3%, P < 0.001). LM75/25 was associated with higher insulin dose (0.47 ± 0.23 vs. 0.40 ± 0.23 units · kg−1· day−1, P < 0.001) and more weight gain (3.6 ± 4.0 vs. 2.5 ± 4.0 kg, P < 0.0001). LM75/25 patients had a higher overall hypoglycemia rate than GL patients (28.0 ± 41.6 vs. 23.1 ± 40.7 episodes · pt−1· year−1, P = 0.007) but lower nocturnal hypoglycemia rate (8.9 ± 19.3 vs. 11.4 ± 25.3 episodes · pt−1· year−1, P = 0.009). Severe hypoglycemia rates were low in both groups (LM75/25: 0.10 ± 1.6 vs. GL: 0.03 ± 0.3 episodes · pt−1· year−1, P = 0.167). CONCLUSIONS Compared with GL, LM75/25 resulted in slightly lower A1C at 24 weeks and a moderately higher percentage reaching A1C target <7.0%. Patients receiving LM75/25 experienced more weight gain and higher rates of overall hypoglycemia but lower rates of nocturnal hypoglycemia. Durability of regimens will be evaluated in the following 2-year maintenance phase.

The DURABLE Trial 24-week Results: Safety and Efficacy of Insulin Lispro Mix 75/25 Versus Insulin Glargine Added to Oral Antihyperglycemic Drugs in Patients with Type 2 Diabetes

OBJECTIVE To compare the ability of two starter insulin regimens to achieve glycemic control in a large, ethnically diverse population with type 2 diabetes. RESEARCH DESIGN AND METHODS During the initiation phase of the DURABLE trial, patients were randomized to a twice-daily lispro mix 75/25 (LM75/25; 75% lispro protamine suspension, 25% lispro) (n = 1,045) or daily glargine (GL) (n = 1,046) with continuation of prestudy oral antihyperglycemic drugs. RESULTS Baseline A1C was similar (LM75/25: 9.1 ± 1.3%; GL: 9.0 ± 1.2%; P = 0.414). At 24 weeks, LM75/25 patients had lower A1C than GL patients (7.2 ± 1.1 vs. 7.3 ± 1.1%, P = 0.005), greater A1C reduction (–1.8 ± 1.3 vs. –1.7 ± 1.3%, P = 0.005), and higher percentage reaching A1C target <7.0% (47.5 vs. 40.3%, P < 0.001). LM75/25 was associated with higher insulin dose (0.47 ± 0.23 vs. 0.40 ± 0.23 units · kg−1· day−1, P < 0.001) and more weight gain (3.6 ± 4.0 vs. 2.5 ± 4.0 kg, P < 0.0001). LM75/25 patients had a higher overall hypoglycemia rate than GL patients (28.0 ± 41.6 vs. 23.1 ± 40.7 episodes · pt−1· year−1, P = 0.007) but lower nocturnal hypoglycemia rate (8.9 ± 19.3 vs. 11.4 ± 25.3 episodes · pt−1· year−1, P = 0.009). Severe hypoglycemia rates were low in both groups (LM75/25: 0.10 ± 1.6 vs. GL: 0.03 ± 0.3 episodes · pt−1· year−1, P = 0.167). CONCLUSIONS Compared with GL, LM75/25 resulted in slightly lower A1C at 24 weeks and a moderately higher percentage reaching A1C target <7.0%. Patients receiving LM75/25 experienced more weight gain and higher rates of overall hypoglycemia but lower rates of nocturnal hypoglycemia. Durability of regimens will be evaluated in the following 2-year maintenance phase.

The DURAbility of Basal versus Lispro mix 75/25 insulin Efficacy (DURABLE) Trial Comparing the durability of lispro mix 75/25 and glargine

OBJECTIVE This study compared the durability of glycemic control of twice-daily insulin lispro mix 75/25 (LM75/25: 75% insulin lispro protamine suspension/25% lispro) and once-daily insulin glargine, added to oral antihyperglycemic drugs in type 2 diabetes patients. RESEARCH DESIGN AND METHODS During the initiation phase, patients were randomized to LM75/25 or glargine. After 6 months, patients with A1C ≤7.0% advanced to the maintenance phase for ≤24 months. The primary objective was the between-group comparison of duration of maintaining the A1C goal. RESULTS Of 900 patients receiving LM75/25 and 918 patients receiving glargine who completed initiation, 473 and 419, respectively, had A1C ≤7.0% and continued into maintenance. Baseline characteristics except age were similar in this group. Median time of maintaining the A1C goal was 16.8 months for LM75/25 (95% CI 14.0–19.7) and 14.4 months for glargine (95% CI 13.4–16.8; P = 0.040). A1C goal was maintained in 202 LM75/25-treated patients (43%) and in 147 glargine-treated patients (35%; P = 0.006). No differences were observed in overall, nocturnal, or severe hypoglycemia. LM75/25 patients had higher total daily insulin dose (0.45 ± 0.21 vs. 0.37 ± 0.21 units/kg/day) and more weight gain (5.4 ± 5.8 vs. 3.7 ± 5.6 kg) from baseline. Patients taking LM75/25 and glargine with lower baseline A1C levels were more likely to maintain the A1C goal (P = 0.043 and P < 0.001, respectively). CONCLUSIONS A modestly longer durability of glycemic control was achieved with LM75/25 compared with glargine. Patients with lower baseline A1C levels were more likely to maintain the goal, supporting the concept of earlier insulin initiation.

Initiating insulin therapy in elderly patients with Type 2 diabetes: efficacy and safety of lispro mix 25 vs. basal insulin combined with oral glucose‐lowering agents

Aims  To compare starter insulins in the elderly subgroup of the DURABLE trial 24‐week initiation phase.

Insulin and GLP-1 analog combinations in type 2 diabetes mellitus: a critical review

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists have been used in clinical management of type 2 diabetes since 2005. Currently approved agents were initially developed and approved for combination therapy with oral antidiabetic drugs (OADs). The potential for combined use with insulin has garnered increasing attention due to the potential to reduce side effects associated with insulin therapy and improve glycemic control. Areas covered: We reviewed published and other publicly released data from controlled and uncontrolled studies that included subjects treated with insulin/GLP-1 analog combination therapy. The currently available guidance for clinical practice when combining insulin and GLP-1 analogs was also summarized. Expert opinion: Limited data currently available from placebo-controlled trials support the use of exenatide twice daily or liraglutide once daily in combination with basal insulin and metformin in subjects with type 2 diabetes unable to attain treatment goals. Several randomized controlled trials are currently studying combinations of insulin with various GLP-1 analogs. Additional guidance on the clinical use of these combinations will likely be forthcoming once these studies are reported. Insulin/GLP-1 analog combinations will require optimization of blood glucose monitoring strategies and delivery systems to decrease the risk of administration errors and reduce the potential complexity of these regimens.

Continuous glucose monitoring in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonist dulaglutide in combination with prandial insulin lispro: an AWARD-4 substudy

To conduct a substudy, using 24‐hour continuous glucose monitoring (CGM), of the AWARD‐4 trial, which was designed to compare insulin + glucagon‐like peptide‐1 receptor agonist treatment with an insulin‐only regimen.

Effects of insulin initiation on patient-reported outcomes in patients with type 2 diabetes: Results from the DURABLE trial

AIM To examine changes in patient-reported outcome (PRO) measures in patients with type 2 diabetes (T2DM) on oral agents who initiated insulin (insulin lispro mix 25/75 [LM25] or insulin glargine) in the DURABLE trial (n=580). METHODS Subjects completed generic and diabetes-specific health-related quality-of-life measures (RAND-36 and Diabetes-39) and a symptom assessment measure (DSC-Revised) at baseline and 6 months post insulin initiation. Mean score change was evaluated. Effect size (ES; Cohens d) and analysis of covariance were used to examine extent and significance of change both within and between treatment groups. RESULTS Subject characteristics were mean age 57 years, males 59%, duration of diabetes 9.6 years, and baseline HbA1c 8.9%. In the total sample, significant (P<0.01) improvements (with small ES) were observed in four of eight RAND-36 subscales (ES range: 0.13-0.24), three of five Diabetes-39 subscales (ES range: 0.09-0.34), and five of eight DSC-Revised subscales (ES range: 0.15-0.38). While significance of within-group changes varied by treatment, only one subscale (physical functioning for LM25) showed deterioration. The changes were not significantly different (P>0.01) between regimens for any subscales. CONCLUSIONS Our findings suggest that insulin initiation improves selective PRO in patients with poorly controlled T2DM.