Insulin Detemir Improves Glycemic Control With Less Hypoglycemia and No Weight Gain in Patients With Type 2 Diabetes Who Were Insulin Naive or Treated With NPH or Insulin Glargine: Clinical Practice Experience From a German Subgroup of the PREDICTIVE Study

Meneghini LF, Rosenberg KH, Koenen C, Merilainen MJ, Luddeke HJ. Diabetes Obes Metab. 2007;9:418-427.

Despite strong recommendations from the American Association of Clinical Endocrinologists and the American Diabetes Association (ADA) to set more stringent glycemic goals in patients with diabetes, the proportion of patients with type 2 diabetes achieving glycemic control (A1C < 7%) declined from 44.5% in the National Health and Nutrition Examination Survey (NHANES) 1988-1994 to 35.8% in NHANES 1999-2000. The latest basal insulin analog to become available for the treatment of diabetes, insulin detemir, has demonstrated in several controlled clinical trials in patients with type 2 diabetes (either as an add-on to oral antidiabetic drugs [OADs] or in basal–bolus therapy) a similar efficacy, a reduced risk of hypoglycemia (particularly nocturnal hypoglycemia), and less weight gain compared with NPH insulin or insulin glargine therapies. In a recent analysis of the results from a subset of the German cohort of the Predictable Results and Experience in Diabetes through Intensification and Control to Target: an International Variability Evaluation (PREDICTIVE) Study (a 12-week, open-label, nonrandomized observational study with an enrollment of 30,000 patients worldwide), the authors determined the safety and efficacy of insulin detemir in 3 subgroups of patients with type 2 diabetes who, on advice given by their physician in a normal clinical practice setting, transitioned to insulin detemir as the only insulin therapy ± OADs from a prestudy regimen of 1) OADs only (n = 1321), 2) NPH insulin ± OADs (n = 251), or 3) insulin glargine ± OADs (n = 260).

At baseline, patients had a mean age of 62.3 ± 10.6 years, with a body mass index (BMI) of 29.8 ± 5.0 kg/m² and a duration of diabetes of 7.3 ± 5.2 years. The group as a whole (n = 1832) had a mean A1C level and fasting blood glucose (FBG) of 8.31% ± 1.29% and 176.5 mg/dL ± 43.2 mg/dL, respectively. The OAD-only group comprised 72% of the total sample size. The most commonly used oral agents were metformin and sulfonylureas (78% of all OADs used). Of patients taking NPH insulin and insulin glargine prior to study participation, 63% and 75%, respectively, were also taking OADs. A variety of reasons were given by the treating physicians for starting a patient on, or transferring a patient to, insulin detemir, including 1) to improve glycemic control (89%), 2) to reduce plasma glucose variability (53%), 3) patient dissatisfaction with current therapy (33%), and 4) to improve weight control (29%). Eleven out of the 1832 patients (0.6%) in this subgroup analysis withdrew from the study without reporting a specific reason for their withdrawal.

Significant improvements in A1C levels and mean FBG values were observed during treatment with insulin detemir, and patients who transitioned from all 3 prestudy treatment regimens experienced a significant weight reduction. Overall, a 1.1 ± 0.03% (P < .0001[lp1] ) reduction in mean A1C at the end of the study from baseline was observed; mean A1C at the end of the study was 7.21 ± 0.02%. Patients transferred to insulin detemir from an OAD-only regimen experienced a decrease in A1C of – 1.29 ± [lp2] 0.03% (P < .0001) from baseline, which was a greater decrease from baseline than patients transitioning from basal insulin regimens (NPH insulin: – 0.60 ± 0.09%; insulin glargine: – 0.59 ± 0.06%; P < .0001 for change from baseline in both groups). A greater proportion of overall patients were able to achieve the ADA target A1C of less than 7% at study end compared with baseline (42.2% versus 10.8%; P < .0001). Mean FBG was reduced among the group as a whole (– 49.8 ± 1.1 mg/dL; P < .0001), although patients transitioning from an OAD-only regimen tended to have a greater reduction in FBG from baseline (– 58.1 ± 1.2 mg/dL; P < .0001) than patients transitioning from regimens of NPH ± OADs and insulin glargine ± OADs (– 29.1± 3.2 and – 24.6 ± 2.8 mg/dL, respectively; P < .0001). The variability in FBG levels was also significantly reduced among the total cohort (– 7.4 ± 0.5 mg/dL; P < .0001), as well as within each subgroup, transitioning from OADs only (– 8.2 ± 0.5 mg/dL; P < .0001), NPH ± OADs (– 5.7 ± 1.1 mg/dL; P < .0001), and insulin glargine ± OADs (– 5.1 ± 1.5 mg/dL; P = .0008) compared with baseline. Overall, improvements in glycemic control were accompanied by a 0.9 ± 0.1 kg weight reduction (P < .0001). Weight reductions of 0.9 ± 0.1 kg (P < .0001), 0.9 ± 0.3 kg (P = .0099), and 0.8 ± 0.2 kg (P < .0001) were observed in patients transitioning from OAD only, NPH ± OAD, and insulin glargine ± OAD regimens, respectively.

In terms of safety, there were no severe adverse drug reactions, including no major hypoglycemic events—the main outcome variable in the study—during the 3-month follow-up period. A major hypoglycemic event was defined as a hypoglycemic episode with symptoms of neuroglycopenia, in which the patient is unable to treat himself/herself and third-party intervention is needed. To meet the definition of a major hypoglycemic episode, the patient also had to have one of the following: 1) blood glucose (BG) < 50 mg/dL or 2) reversal of symptoms after either food intake or glucagon or intravenous glucose administration. Both the percentage of patients experiencing hypoglycemia and the frequency of hypoglycemic episodes were lower in patients using insulin detemir during the 4 weeks preceding the follow-up visit, compared with baseline (ie, 4 weeks prior to the first visit). A hypoglycemic event was defined as an episode with either symptoms of hypoglycemia that resolved with oral carbohydrate intake, glucagon, or intravenous glucose, or any symptomatic or asymptomatic BG < 50 mg/dL. Baseline total, daytime, and nocturnal hypoglycemic events (3.3, 2.0, and1.3 events per patient year, respectively) decreased by – 2.7, – 1.6, and – 1.2, respectively (P < .0001) during the study, as did the percentage of patients experiencing these events (7.2%, 5.5%, and 3.7% at baseline compared with 2.0%, 1.6%, and 0.5% at follow-up). A nocturnal hypoglycemic event was defined as an episode consistent with hypoglycemia that occurred between bedtime (after the evening insulin injection) and before waking in the morning.

The results of this subanalysis of the German cohort of the PREDICTIVE study, conducted in a real-world medical practice setting, compare favorably with the outcome of clinical studies with insulin detemir that have demonstrated less weight gain, less variation in FBG, and a lower risk of hypoglycemia than NPH insulin, and a lower risk of major and nocturnal hypoglycemia than insulin glargine. Taking into account that these results were achieved using similar dosing regimens (80% of patients used insulin detemir once daily) to those used in clinical studies, the favorable outcomes of this observational study do not appear to be attributable solely to a study-related effect. Nevertheless, the improvement in glycemic parameters observed in this study may be attributable in part to the tendency of physicians to use somewhat higher doses of insulin detemir in order to more aggressively pursue glycemic targets toward the end of the study. Safer adjustment of insulin doses may have also helped to achieve the improved glycemic outcomes. Additional limitations inherent in observational studies in general include their short-term nature, the heterogeneity of real-life populations, the lack of standardized treatment regimens, the lack of predefined endpoints, and, importantly, the absence of a control group. Despite these limitations, the similarity between 12-week data from the insulin-naive cohort of this subanalysis of the German cohort of the PREDICTIVE study and the findings of controlled clinical trials argues in favor of the veracity of the data obtained and indicates their utility for providing a more complete picture of the real-world use of insulin detemir.