Henriette Mersebach

Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: A pre-planned meta-analysis of phase 3 trials

Hypoglycaemia and the fear of hypoglycaemia are barriers to achieving normoglycaemia with insulin. Insulin degludec (IDeg) has an ultra‐long and stable glucose‐lowering effect, with low day‐to‐day variability. This pre‐planned meta‐analysis aimed to demonstrate the superiority of IDeg over insulin glargine (IGlar) in terms of fewer hypoglycaemic episodes at equivalent HbA1c in type 2 and type 1 diabetes mellitus (T2DM/T1DM).

Low-Volume Insulin Degludec 200 Units/mL Once Daily Improves Glycemic Control Similarly to Insulin Glargine With a Low Risk of Hypoglycemia in Insulin-Naïve Patients With Type 2 Diabetes: A 26-week, randomized, controlled, multinational, treat-to-target trial: The BEGIN LOW VOLUME trial

OBJECTIVE The 200 units/mL formulation of insulin degludec (IDeg 200 units/mL) contains equal units of insulin in half the volume compared with the 100 units/mL formulation. We compared the efficacy and safety of IDeg 200 units/mL once daily with 100 units/mL insulin glargine (IGlar) in insulin-naïve subjects with type 2 diabetes (T2DM) inadequately controlled with oral antidiabetic drugs. RESEARCH DESIGN AND METHODS In this 26-week, open-label, treat-to-target trial, subjects (n = 457; mean HbA1c 8.3% [67 mmol/mol], BMI 32.4 kg/m2, and fasting plasma glucose [FPG] 9.6 mmol/L [173.2 mg/dL]) were randomized to IDeg 200 units/mL or IGlar, both given once daily in combination with metformin with or without a dipeptidyl peptidase-4 inhibitor. Basal insulin was initiated at 10 units/day and titrated weekly to an FPG target of <5 mmol/L (<90 mg/dL) according to mean prebreakfast self-measured blood glucose values from the preceding 3 days. RESULTS By 26 weeks, IDeg reduced HbA1c by 1.30% and was not inferior to IGlar. Mean observed FPG reductions were significantly greater with IDeg than IGlar (−3.7 vs. −3.4 mmol/L [–67 vs. –61 mg/dL]; estimated treatment difference: −0.42 [95% CI −0.78 to −0.06], P = 0.02). Despite this difference, rates of overall confirmed hypoglycemia were not higher with IDeg than with IGlar (1.22 and 1.42 episodes/patient-year, respectively), as were rates of nocturnal confirmed hypoglycemia (0.18 and 0.28 episodes/patient-year, respectively). Mean daily basal insulin dose was significantly lower by 11% with IDeg 200 units/mL compared with IGlar. IDeg was well-tolerated, and the rate of treatment-emergent adverse events was similar across groups. CONCLUSIONS In this treat-to-target trial in insulin-naïve patients with T2DM, IDeg 200 units/mL improved glycemic control similarly to IGlar with a low risk of hypoglycemia.

Comparison of Insulin Degludec/Insulin Aspart and Biphasic Insulin Aspart 30 in Uncontrolled, Insulin-Treated Type 2 Diabetes: A Phase 3a, Randomized, Treat-to-Target Trial

OBJECTIVE Insulin degludec/insulin aspart (IDegAsp) is the first combination of a basal insulin with an ultralong duration of action, and a rapid-acting insulin in a single injection. This trial compared IDegAsp with biphasic insulin aspart 30 (BIAsp 30) in adults with type 2 diabetes inadequately controlled with once- or twice-daily (OD or BID) pre- or self-mixed insulin with or without oral antidiabetic drugs. RESEARCH DESIGN AND METHODS In this 26-week, randomized, open-label, multinational, treat-to-target trial, participants (mean age 58.7 years, duration of diabetes 13 years, BMI 29.3 kg/m2, and HbA1c 8.4% [68 mmol/mol]) were exposed (1:1) to BID injections of IDegAsp (n = 224) or BIAsp 30 (n = 222), administered with breakfast and the main evening meal and dose titrated to a self-measured premeal plasma glucose (PG) target of 4.0–5.0 mmol/L. RESULTS After 26 weeks, mean HbA1c was 7.1% (54 mmol/mol) for both groups, with IDegAsp achieving the prespecified noninferiority margin for mean change in HbA1c (estimated treatment difference [ETD] –0.03% points [95% CI –0.18 to 0.13]). Treatment with IDegAsp was superior in lowering fasting PG (ETD –1.14 mmol/L [95% CI –1.53 to –0.76], P < 0.001) and had a significantly lower final mean daily insulin dose (estimated rate ratio 0.89 [95% CI 0.83–0.96], P = 0.002). Fewer confirmed, nocturnal confirmed, and severe hypoglycemia episodes were reported for IDegAsp compared with BIAsp 30. CONCLUSIONS IDegAsp BID effectively improves HbA1c and fasting PG levels with fewer hypoglycemia episodes versus BIAsp 30 in patients with uncontrolled type 2 diabetes previously treated with once- or twice-daily pre- or self-mixed insulin.

Insulin Degludec/Insulin Aspart Administered Once Daily at Any Meal, With Insulin Aspart at Other Meals Versus a Standard Basal-Bolus Regimen in Patients With Type 1 Diabetes: A 26-week, phase 3, randomized, open-label, treat-to-target trial

OBJECTIVE To evaluate efficacy and tolerability of a co-formulation of insulin degludec and insulin aspart (IDegAsp) with insulin aspart (IAsp) at other meals compared with basal-bolus therapy using insulin detemir (IDet) and IAsp. RESEARCH DESIGN AND METHODS Adults (n = 548) with type 1 diabetes (A1C 7.0–10.0%; BMI ≤35.0 kg/m2) were randomized 2:1 in a 26-week, multinational, parallel-group, treat-to-target trial to IDegAsp or IDet. IDegAsp was given with a meal, and IDet was given in the evening, with a second (breakfast) dose added if needed. RESULTS Non-inferiority for IDegAsp versus IDet was confirmed; A1C improved by 0.75% with IDegAsp and 0.70% with IDet to 7.6% in both groups (estimated treatment difference IDegAsp − IDet: –0.05% [95% CI –0.18 to 0.08]). There was no statistically significant difference between IDegAsp and IDet in the rates of severe hypoglycemia (0.33 and 0.42 episodes/patient-year, respectively) or overall confirmed (plasma glucose <3.1 mmol/L) hypoglycemia (39.17 and 44.34 episodes/patient-year, respectively). Nocturnal confirmed hypoglycemia rate was 37% lower with IDegAsp than IDet (3.71 vs. 5.72 episodes/patient-year, P < 0.05). Weight gain was 2.3 and 1.3 kg with IDegAsp and IDet, respectively (P < 0.05). Total insulin dose was 13% lower in the IDegAsp group (P < 0.0001). No treatment differences were detected in Health-Related Quality of Life, laboratory measurements, physical examination, vital signs, electrocardiograms, fundoscopy, or adverse events. CONCLUSIONS IDegAsp in basal-bolus therapy with IAsp at additional mealtimes improves overall glycemic control and was non-inferior to IDet, with a reduced risk of nocturnal hypoglycemia and fewer injections in comparison with IDet + IAsp basal-bolus therapy.

A novel insulin combination of insulin degludec and insulin aspart achieves a more stable overnight glucose profile than insulin glargine: results from continuous glucose monitoring in a proof-of-concept trial

Purpose: Insulin degludec coformulated with insulin aspart (as IDegAsp) can cover 24 h basal insulin and postprandial insulin requirements after a main meal with one injection. We compared glycemic stability following IDegAsp or insulin glargine (IGlar) given before the evening meal in patients with type 2 diabetes. Methods: A subset of 112 insulin-naïve type 2 diabetes patients from a randomized, parallel-group trial (IDegAsp versus IGlar, each added to metformin) underwent 72 h continuous interstitial glucose (IG) monitoring after 16 weeks of treatment. End points included mean IG concentrations, 2 h postprandial IG increments and postprandial peak, IG fluctuation (summed area above and below mean IG), within-subject coefficient of variation (day-to-day variation) in mean nocturnal IG, and episodes of low (<3.5 mmol/liter) and high (>10 mmol/liter) IG. Values were derived for the entire 72 h, with the nocturnal interval (0001–0559 h) also assessed. Results: The postdinner IG increment observed with IGlar did not occur with IDegAsp [IDegAsp — IGlar, −1.42 (−2.15, −0.70) mmol/liter]. Nocturnal IG fluctuation was 21% lower with IDegAsp [IDegAsp/IGlar, 0.79 (0.66, 0.96) mmol/liter], with 48% fewer nocturnal high IG episodes [ratio IDegAsp/IGlar, 0.52 (0.32, 0.87)]. Conclusions: IDegAsp given with the evening meal reduces postdinner glucose excursion and provides more stable nocturnal glycemia as compared with IGlar.

Safety and efficacy of insulin degludec/insulin aspart with bolus mealtime insulin aspart compared with standard basal-bolus treatment in people with Type 1 diabetes: 1-year results from a randomized clinical trial (BOOST(®) T1).

To evaluate the long‐term safety and efficacy of a simplified basal–bolus regimen of once‐daily insulin degludec/insulin aspart (IDegAsp) with additional IAsp vs. a standard basal–bolus insulin regimen of insulin detemir (IDet) with IAsp in adults with Type 1 diabetes.

Efficacy and Safety of Once-Daily Insulin Degludec/Insulin Aspart versus Insulin Glargine (U100) for 52 Weeks in Insulin-Naïve Patients with Type 2 Diabetes: A Randomized Controlled Trial

Purpose The efficacy and safety of insulin degludec/insulin aspart (IDegAsp) once daily (OD) compared with insulin glargine U100 (IGlar) OD over 52 weeks in insulin-naïve adults with type 2 diabetes mellitus (T2DM) was investigated. Methods In this open-label, parallel-group treat-to-target trial, participants were randomized (1:1) to receive IDegAsp OD (breakfast, n = 266) or IGlar OD (as per label, n = 264). Participants then entered a 26-week extension phase (IDegAsp OD, n = 192; IGlar OD, n = 221). The primary endpoint was change from baseline to Week 26 in HbA1c. Results After 26 and 52 weeks, mean HbA1c decreased to similar levels in both groups. After 52 weeks, the mean estimated treatment difference was –0.08% (–0.26, 0.09 95%CI), confirming the non-inferiority of IDegAsp OD versus IGlar OD evaluated at Week 26. After 52 weeks, there was a similar reduction in mean fasting plasma glucose in both treatment groups. The rate of confirmed hypoglycemic episodes was 86% higher (p < 0.0001) whereas the rate of nocturnal hypoglycemia was 75% lower (p < 0.0001) for IDegAsp versus IGlar. Conclusion Nocturnal-confirmed hypoglycemia was higher with IGlar whereas overall and diurnal hypoglycemia were higher with IDegAsp dosed at breakfast. These results highlight the importance of administration of IDegAsp with the main meal of the day, tailored to the individual patient’s needs. Trial Registration ClinicalTrials.gov: NCT01045707 [core]) and NCT01169766 [ext]

PATIENTS ACHIEVING GOOD GLYCEMIC CONTROL (HBA1c <7%) EXPERIENCE A LOWER RATE OF HYPOGLYCEMIA WITH INSULIN DEGLUDEC THAN WITH INSULIN GLARGINE: A META-ANALYSIS OF PHASE 3A TRIALS

OBJECTIVE Meta-analysis to compare hypoglycemia rates of basal insulin degludec (IDeg) with insulin glargine (IGlar) in patients with diabetes achieving good glycemic control (hemoglobin A1c [HbA1c] <7% at end of trial). METHODS In a preplanned meta-analysis, patient data from 7 randomized, treat-to-target, 26- or 52-week trials in patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) who administered IDeg (n = 2,899) or IGlar (n = 1,431) once daily were analyzed. Using a negative binomial regression model, this meta-analysis compared hypoglycemia rates in patients achieving HbA1c <7% at end of trial with IDeg (n = 1,347) and IGlar (n = 697). RESULTS In all trials, IDeg was noninferior to IGlar in HbA1c reduction from baseline. At end of trial, 2,044 patients (T2DM, n = 1,661; T1DM, n = 383) achieved HbA1c <7%. The overall confirmed hypoglycemia rate, defined as plasma glucose <56 mg/dL or severe hypoglycemia if requiring assistance, was significantly lower with IDeg versus IGlar (estimated rate ratio [ERR] IDeg:IGlar, 0.86; 95% confidence interval [CI], 0.76 to 0.98). The nocturnal confirmed hypoglycemia rate, defined as occurring between midnight and 6:00 am, was significantly lower with IDeg (ERR, 0.63; 95% CI, 0.52 to 0.77). In the maintenance period (16 weeks onward when average insulin dose and glycemic levels stabilized), the overall confirmed hypoglycemia rate was significantly lower (ERR, 0.79; 95% CI, 0.68 to 0.92) and the nocturnal confirmed hypoglycemia rate was significantly lower (ERR, 0.57; 95% CI, 0.45 to 0.72) with IDeg versus IGlar. CONCLUSION Patients with T1DM and T2DM achieved HbA1c <7% with significantly lower rates of overall and nocturnal confirmed hypoglycemia with IDeg versus IGlar. The lower hypoglycemia rate with IDeg was more pronounced in the maintenance period.

Elderly Patients Experience a Lower Rate of Nocturnal Hypoglycemia with Insulin Degludec Than with Insulin Glargine: A Meta-Analysis of Phase 3a Trials

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