A clinical situation during the development of type 2 DM is that it might be inadequately controlled by OADs. A typical response is to intensify the therapeutic regimen. Intensive treatment of patients with type 2 DM is in line both with the consensus algorithm and the guidelines.30
In 2007, a Cochrane database analysis was published that evaluated advantages of the treatment with basal insulin analogs in comparison with NPH insulin in type 2 DM. Six studies with insulin glargine and two studies with detemir were analyzed. Their duration was from 24 to 54 weeks. No differences between basal insulin analogs and NPH insulin in HbA1c
have been shown; however, a significantly lower rate of symptomatic, overall and nocturnal hypoglycemia were found in favor of basal insulin analogs.31
This review concluded: “For insulin therapy in diabetes mellitus, NPH is an effective, safe substance which has been tested over decades. In such cases where a proven effective therapy is available, the introduction of new substances should only be advised if there is a major improvement in efficacy, or if the new substance is proven both effective and safe”.
In the meantime, from this Cochrane analysis new data on the significance of hypoglycemia for the risk of fatal cardiovascular complications in patients with type 2 DM were published.32
For these novel findings, the importance of lowering the risk of hypoglycemia has become a major issue of the treatment. This was also reflected in a recent Consensus Statement of the American Association of Clinical Endocrinologists/American College of Endocrinology. The authors of this document recommend achieving an HbA1c
of 6.5% as the primary goal of the treatment of type 2 DM.33
A novel statement of this panel is to use the basal synthetic analogs, insulin glargine and insulin detemir, instead of NPH insulin because the basal analogs provide a relatively peakless profile for approximately 24 hours and yield better reproducibility and consistency, both between patients and within patients, and a corresponding reduction in the risk of hypoglycemia.
First were two studies with insulin detemir in type 2 DM with a similar design. They were multinational, open-label, randomized, parallel group trials comparing efficacy and safety of basal-bolus therapy using either insulin detemir in combination with meal-time insulin aspart versus NPH insulin in combination with meal-time regular human insulin34
or basal-bolus insulin regimen comprising either insulin detemir or NPH insulin both in combination with mealtime insulin aspart.35
Patients received basal insulin either once or twice daily according to their pretrial insulin treatment and insulin aspart or regular insulin at mealtimes. In the first study,34
a 22-week long therapy of 395 people with type 2 DM resulted in comparable HbA1c
between treatments, with decreases from their baselines of 0.65% and 0.58% in the detemir and the NPH group, respectively. Treatment with insulin detemir + aspart was associated with a significantly lower within-person variation in self-measured FPG, as well as a lower body weight gain than that of NPH plus regular insulin (0.51 versus 1.13 kg, P
= 0.038). The relative risk of nocturnal hypoglycemia was significantly lower in the detemir group (RR 0.54, 95% CI 0.30 to 0.97; P
In a second study,35
a 26-week long therapy of 505 patients resulted in comparable glycemic control but significantly lower within-subject variability and less weight gain in the detemir group compared to patients treated with NPH insulin (1.0 and 1.8 kg, respectively, P
= 0.017). Insulin detemir was well tolerated and had a similar safety profile to NPH insulin.
Efficacy and tolerability of insulin detemir or NPH insulin added to oral therapy for type 2 DM was examined in a treat-to-target titration protocol.36
In a parallel-group, multicenter trial, 476 patients with high levels of HbA1c
were randomized to addition of twice-daily insulin detemir or NPH insulin. Over 24 weeks, insulin doses were titrated toward pre-breakfast and pre-dinner plasma glucose targets of ≤6.0 mmol/L. This resulted in comparable reductions of HbA1c
for detemir and NPH (from 8.6 to 6.8 and from 8.5 to 6.6%, respectively). Compared with NPH insulin, in patients treated with insulin detemir the risk for all and for nocturnal hypoglycemia was reduced by 47% and 55%, respectively (P
< 0.001). They profited as well from significantly lower weight gain.
Another trial examined the effect of an evening detemir, a pre-breakfast detemir, or an evening NPH insulin administered at initial doses of 10 IU in 498 patients treated with ≥1 OAD.37
Similar reductions of HbA1c
of all three regimens were found after titration of administered insulins. All-day and nocturnal hypoglycemia were reduced significantly with morning and evening detemir. Nocturnal hypoglycemia was reduced further, by 87%, with morning detemir compared with evening NPH (P
< 0.001). Less weight gain was observed for evening detemir vs NPH (P
In a 26-week multinational, multicenter, randomized treat-to-target trial, OADs were discontinued and subjects were randomized to analog basal-bolus therapy (insulin detemir once daily and insulin aspart at mealtimes) or biphasic insulin aspart 30, twice daily.38
Both insulin analog regimens enabled a majority of people with type 2 DM to reach HbA1c
≤ 7.0% after the failure of OADs and OAD-basal insulin therapy. Insulin-treated patients had more benefit from the transfer to analog basal-bolus therapy, while insulin-naive individuals had more benefit from the biphasic analog regimen.
Insulin detemir was compared with insulin glargine in the following randomized controlled trials ():
- The study by Hollander et al39 was one of the first to directly compare the efficacy of detemir with glargine in a basal-bolus regimen in patients with type 2 diabetes. It was a multinational, 52-week, open label, parallel-group, non-inferiority, treat-to-target trial. Type 2 DM patients who had been receiving an OAD or insulin (with or without OADs) were randomized in a 2:1 ratio to receive insulin detemir or glargine. Detemir could be administered once or twice daily, glargine was administered once daily. Insulin aspart was given at mealtimes. Insulin secre-tagogs and α-glucosidase inhibitors were discontinued at study entry, but other existing OADs were continued. Doses of detemir and glargine were titrated to achieve a pre-breakfast (and pre-dinner for detemir administered twice daily) plasma glucose target of ≤6.0 mmol/L. At 52 weeks, decreases of HbA1c from baseline for detemir and glargine were similar at −1.52% and −1.68%, respectively. The proportion of detemir-treated subjects who achieved an HbA1c ≤ 7% was 36.2%, compared with 36.7% of glargine-treated subjects. 82.7% of the detemir-treated subjects and 83.8% of the glargine-treated subjects failed to achieve pre-supper glucose levels of ≤6.0 mmol/L. Both insulin analogs were well tolerated, with no significant difference in the frequency of hypoglycemia. However, mean weight gain was significantly lower with detemir than with glargine (2.8 vs 3.8 kg, 95% CI −2.08 to −0.01; P < 0.05). Overall, the detemir-treated subjects used more insulin than the glargine-treated subjects (0.82 units/kg vs 0.69 units/kg, respectively), but this difference disappearred when comparing only single-dose detemir-treated subjects who used an average daily basal insulin dose of 0.69 units/kg.
- A second trial also had a 52-week duration.40 This study was multinational, randomized, open-label, parallel-group and non-inferiority. The aim was to examine clinical outcomes following supplementation of OADs with basal insulin analogs detemir or glargine in 582 insulin-naive type 2 DM patients. Insulin doses were in the evening titrated to target fasting plasma glucose ≤6.0 mmol/L. An additional morning insulin detemir dose was permitted if pre-dinner FPG was >7.0 mmol/L after achieving FPG <7.0 mmol/L. HbA1c and FPG decreased comparrably with detemir and glargine. 45% of participants treated with insulin detemir completed the study on once daily dosing and 55% of them completed on twice daily dosing, with no difference in HbA1c. Overall, 52% of patients achieved HbA1c ≤ 7.0%: 33% (detemir) and 35% (glargine) without hypoglycemia. Within-patient variability for self-monitored FPG and pre-dinner plasma glucose did not differ by insulin treatment, nor did the relative risk of overall or nocturnal hypoglycemia. Modest differences in less weight gain were seen with detemir vs glargine in completers (3.0 vs 3.9 kg, P = 0.01). Mean daily detemir dose was higher (0.78 IU/kg [0.52 with once-daily dosing, 1.00 IU/kg with twice-daily dosing]) than glargine (0.44 IU/kg). Injection site reactions were more frequent with detemir (4.5 vs 1.4%).
- Another trial comparing the two basal insulin analogs had a treat-to-target design.41 This 26-week study compared the efficacy and safety of insulin detemir and insulin glargine in a basal-bolus (insulin aspart) regimen in 385 type 2 DM patients who were randomized 2:1. Insulin detemir and glargine were both equally effective and safe treatments for glycemic control. HbA1c decreased significantly from the baseline in detemir to 7.1% (−1.1%, P < 0.001) and in glargine to 6,9% (−1.3%, P < 0.001). There was significantly less weight gain in the detemir group at comparable basal insulin dosage (1.2 ± 3.96 vs 2.7 ± 3.94 kg, P = 0.001; 95% CI −2.19 to −0.56). At the end of this study, 87.4% of detemir-treated patients remained on a once-daily basal insulin regimen.
- The aim of another trial was to determine whether glargine was non-inferior to detemir for the percentage of patients reaching HbA1c < 7% without symptomatic hypoglycemia ≤ 3.1 mmol/L.42 This 24-week trial examined 973 insulin-naive type 2 diabetes patients on stable OADs and HbA1c 7.0% to 10.5%, who were randomized to glargine once daily or detemir twice daily. Insulin doses were systematically titrated. A similar proportion of type 2 DM patients reached the primary outcome with glargine and detemir, demonstrating the non-inferiority of glargine. However, more detemir-treated patients reached HbA1c < 6.5% (P = 0.017), while hypoglycemia risk was similar. Weight gain was higher for glargine (1.44 ± 3.2 and 0.6 ± 2.9 kg; difference: 0.77 kg, P < 0.001) and glargine doses were lower than detemir doses: 43.5 ± 29.0 versus 76.5 ± 50.5 units/day (P < 0.001).
Randomized trials comparing insulin detemir and insulin glargine in type 2 diabetes mellitus (DM)
Effects of complex insulin regimens were examined in a 3-year open-label, multicenter trial that examined 708 patients taking metformin and sulfonylurea. These subjects were randomly assigned to receive biphasic insulin aspart twice daily, prandial insulin aspart 3 times daily, or basal insulin detemir once daily (twice if required).43
Sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable during the first year of the study or subsequently if HbA1c
levels were more than 6.5%. HbA1c
were similar for all regimens. A level of 6.5% or less was achieved in 31.9% of patients in the biphasic group, in 44.7% of patients in the prandial group (P
= 0.006) and in 43.2% of patients in the basal group (P
= 0.03). A second type of insulin was taken by 67.7%, 73.6%, and 81.6% of patients, respectively (P
= 0.002). Fewer hypoglycemic episodes and less weight gain occurred in patients adding basal insulin.
Predictable Results and Experience in Diabetes through Intensification and Control to Target: an International Variability Evaluation (PREDICTIVE) was a multi-national, open-label, prospective, observational study assessing the safety and efficacy of insulin detemir in clinical practice. A post-hoc analysis in type 2 DM insulin-naïve patients has shown a benefit from adding a once-daily insulin detemir.44
Improvement of glycemic control was achieved, with good tolerability, including a low risk of hypoglycemia and a weight-sparing effect.