Effects of Age on Glycemic Control in Patients With Type 2 Diabetes Treated with Insulin Detemir: A Post-Hoc Analysis of the PREDICTIVE™ 303 Study.

BACKGROUND: This post-hoc sub-analysis investigated whether age (<65 years vs ≥65 years) affects glycemic control or hypoglycemic risk in patients with type 2 diabetes mellitus (T2DM) treated with once-daily insulin detemir. METHODS: This was a 26-week, randomized, open-label, phase IV trial involving 2812 patients at 1083 predominantly primary care sites throughout the United States, of which 541 were designated for investigator-led insulin titration. The main efficacy measure was change in HbA1c (A1C) from baseline to Week 26. Patients were stratified by age in the sites designated for the investigator-led titration of insulin detemir. Safety measures included adverse events and change in hypoglycemic event rates from baseline to Week 26. RESULTS: At Week 26, mean A1C and fasting plasma glucose decreased in both groups, but mean differences in change from baseline were not significant between groups. Within the group ≥65 years, significant reductions occurred for all daytime hypoglycemia, but there was no significant change from baseline in the other categories. In the group <65 years, reductions from baseline were significant for all hypoglycemic event categories. Changes in hypoglycemia rates from baseline were not significantly different between the age groups and there was no weight increase in either age group. CONCLUSIONS: This analysis demonstrates that insulin detemir has similar efficacy and safety profiles for patients with T2DM ≥65 years compared with <65 years when treated via an investigator-led algorithm.

The science of hypoglycemia in patients with diabetes.

The risk of hypoglycemia with anti-hyperglycemic agents is an important limiting factor in the management of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. While hypoglycemia is more common in T1DM, the incidence is high in T2DM patients who use insulin or secretagogues, particularly patients with longer duration of diabetes. The underlying cause of hypoglycemia in diabetes is a complex interaction between hyperinsulinemia and compromised physiologic and behavioral responses to falling glucose levels. Pancreatic dysfunction also causes loss of normal therapeutic response to hypoglycemia--a reduction in circulating insulin (in T2DM only) and an increase in glucagon secretion. In T1DM and advanced T2DM, the third defense against hypoglycemia is increase in adrenomedullary sympathoadrenal epinephrine secretion, which is also compromised, causing the syndrome of defective glucose counterregulation. Diminished increase in epinephrine, also called hypoglycemia-associated autonomic failure (HAAF), is largely responsible for defective glucose counterregulation. HAAF can result in recurrent hypoglycemia and lowering of glycemic threshold that typically triggers sympathoadrenal response to hypoglycemia. This results in hypoglycemia without warning symptoms, or "hypoglycemia unawareness," which increases the risk of severe hypoglycemia associated with substantial morbidity and mortality. Long-term effects of severe hypoglycemia, aside from causing accidents, may include adverse cardiovascular outcomes and cognitive impairment. To reduce the impact of hypoglycemia, it is important to identify patients at risk and use careful consideration when choosing antidiabetes medications. Newer insulin analogs that more accurately replicate endogenous insulin secretion and incretin therapies that cause glucose-sensitive insulin secretion may ultimately reduce the risk of hypoglycemia.

Efficacy and safety of biphasic insulin aspart 70/30 in type 2 diabetes patients of different race or ethnicity (INITIATEplus trial).

OBJECTIVE: To determine if self-titration using biphasic insulin aspart 70/30 (BIAsp 30) had a different impact on efficacy and safety across different racial/ethnic subgroups. RESEARCH DESIGN/METHODS: This was an exploratory, post hoc analysis by race (White vs. Black/African-American) and ethnicity (Hispanic/Latino vs. non-Hispanic/Latino) of data from the INITIATEplus trial. Participants were treated twice-daily with BIAsp 30 over 24 weeks. TRIAL REGISTRATION: NCT00101751. MAIN OUTCOME MEASURES: Efficacy endpoints included reductions in mean glycated hemoglobin (A1C) and fasting plasma glucose (FPG). Safety endpoints included hypoglycemia rates (events/patient-year) and adverse events. Body weight changes were also measured. RESULTS: Glycemic control improved by a similar extent for all demographic groups. Observed mean decreases in A1C ranged from 2.4% to 2.6% after 24 weeks' treatment. Baseline-adjusted mean A1C decreases for White vs. Black/African-American subjects were 2.56% and 2.13% (p < 0.0001), and for Hispanic/Latino vs. non-Hispanic/Latino subjects were 2.45% and 2.42% (p = 0.677), respectively. Final FPG values were similar among all groups (141-146 mg/dL [7.83-8.10 m mol/L]), and baseline-adjusted FPG decreases were not significantly different (p > 0.025) between groups. Hypoglycemia was low for White, Black/African-American, Hispanic/Latino, and non-Hispanic/Latino subjects (0.08, 0.04, 0.03, and 0.07 major events/patient-year, with 0.60, 0.30, 0.37, and 0.52 minor events/patient-year, respectively). Body weight increases were 3.17 and 3.06 kg (White vs. African-American) and 2.69 and 3.19 kg (Hispanic/Latino vs. non-Hispanic/Latino). Final weight-adjusted total daily insulin doses were 0.60 U/kg for Black/African-American subjects vs. 0.78 U/kg for White subjects (p < 0.0001), and 0.71 U/kg for Hispanic/Latino subjects vs. 0.74 U/kg for non-Hispanic/Latino subjects (p = 0.42). LIMITATIONS: The trial was not designed or powered for comparisons across racial or ethnic groups, subjects were not stratified for pre-baseline medication regimens between each race and ethnic group, and unequal subject numbers and baseline A1C disparities existed between the pairs of groups being compared. CONCLUSIONS: Diabetes self-management with BIAsp 30 using an easily followed self-titration algorithm produced low hypoglycemia rates. All subgroups achieved A1C reductions >2.1% and FPG declines >82 mg/dL that were similar across groups, demonstrating that self-titration of BIAsp 30 can successfully be pursued in a primary care setting by patients who had previously failed to meet ADA A1C targets under oral antidiabetes therapy, with race or ethnicity not an obstacle to achieving better glycemic control.

Efficacy and tolerability of self-titrated biphasic insulin aspart 70/30 in patients aged >65 years with type 2 diabetes: an exploratory post hoc subanalysis of the INITIATEplus trial.

BACKGROUND: The Initiation of Insulin to reach A1C Target (INITIATEplus) trial studied the effect of self-titrating biphasic insulin aspart 70/30 (BiAsp 30) twice daily during 24 weeks in insulin-naïve patients with type 2 diabetes who were poorly controlled by oral medication, and originally randomized according to frequency of dietary counseling interventions. OBJECTIVE: The purpose of this study was to compare the efficacy and tolerability of biphasic insulin aspart 70/30 (BIAsp 30, NovoLog Mix 70/30) in INITIATEplus patients ≤65 versus >65 years old, irrespective of dietary counseling frequency, and to test the hypothesis that self-titrating BIAsp 30 in patients >65 years old could be well-tolerated and effective in this age group. METHODS: An exploratory post hoc subanalysis, using standard statistical methods, was performed on patients stratified according to age. Data collected from 3492 patients in the intent-to-treat population who were ≤65 years old and 716 patients who were >65 years old compared glycosylated hemoglobin (HbA(1c)) and plasma glucose changes from baseline. Hypoglycemia rates and adverse event (AE) incidence were compared for the tolerability population of 4007 patients ≤65 years old and 805 patients >65 years old. RESULTS: Baseline-adjusted HbA(1c) changes for patients ≤65 versus >65 years old were -2.38% versus -2.73% (P < 0.0001), with final HbA(1c) achieving 7.55% and 7.06%, respectively. Thirty-nine percent of patients ≤65 years old achieved HbA(1c) ≤7% compared with 51% of patients >65 years old. Baseline-adjusted fasting plasma glucose decreases were greater for the >65 year old population (85.2 vs 91.2 mg/dL; P = 0.004; ≤65 vs >65 years old, respectively). Minor hypoglycemia was reported in 9.7% and 7.7% of patients ≤65 versus >65 years old, respectively (0.52 vs 0.41 episodes per patient per year [ppy]; P = 0.01). Major hypoglycemia occurred in 1.5% and 3.1% of patients (0.05 vs 0.14 episodes ppy, ≤65 vs >65 years old, respectively; P < 0.0001). Nocturnal major hypoglycemia was reported for 0.4% and 0.6% of patients (P = 0.0028), whereas nocturnal minor hypoglycemia was reported for 3.8% and 2.6% (P = 0.007) of patients ≤65 and >65 years old, respectively. AEs were reported for 24% and 28% of patients ≤65 and >65 years old, respectively, serious AEs were reported for 4% and 9% of patients, respectively, and AE-related withdrawals were reported for 1.3% and 2% of patients, respectively. CONCLUSIONS: Self-titrated biphasic insulin aspart 70/30 was found to be well-tolerated and effective in type 2 diabetes patients >65 years old, as well as in patients ≤65 years old. HbA(1c) and fasting plasma glucose decreases were significantly (P < 0.05) higher for patients >65 years old versus patients ≤65 years old. Tolerability was indicated by major and minor hypoglycemia rates at or below <0.5 episodes ppy in both age groups. Overall rates of AE and serious AEs were higher among patients > 65 years; withdrawals related to AEs were 2% compared with 1.3% in the younger age group.

A(1c) control in a primary care setting: self-titrating an insulin analog pre-mix (INITIATEplus trial).

PURPOSE: To study glycemic control and hypoglycemia development upon initiation of insulin through a self-titration schedule in a 24-week trial, conducted with 4875 insulin-naïve patients with poorly controlled type 2 diabetes, predominantly in a primary care setting. METHODS: Subjects initiated twice-daily biphasic insulin aspart 70/30 with 6 units prebreakfast and 6 units presupper, self-titrating according to self-measured blood glucose values. Subjects were randomized (1:1:1) to telephone counseling provided by a registered dietician: no counseling (NC), 1 counseling session (1C), or 3 sessions (3C). RESULTS: Mean baseline HbA(1c) (9.9% across groups) decreased approximately 2.5% to 7.49% + or - 1.48, 7.48% + or - 1.50, and 7.44% + or - 1.46 in the NC, 1C, and 3C groups, respectively. Within these groups, a hemoglobin A(1c) (HbA(1c)) value <7% was achieved by 40.2%, 41.6%, and 41.8% of subjects, respectively. Eight-point blood glucose profiles were substantially improved from baseline for all groups. Hypoglycemia was experienced by 10.2%-11.4% of the subjects in each group. Rates of minor and major hypoglycemia were low but decreased as dietary counseling increased (minor hypoglycemia: 56 vs 50 vs 45 episodes per 100 patient-years; major hypoglycemia, 9 vs 6 vs 4 episodes per 100 patient-years, for the NC vs 1C vs 3C groups, respectively; P <.001, 3C vs NC). Weight increased by 3.13, 3.40, and 2.88 kg for the NC, 1C, and 3C groups, respectively. CONCLUSION: In the primary care setting, self-titration of biphasic insulin aspart 70/30 was effective in achieving recommended HbA(1c) goals even with minimal dietary counseling.

Quantitative assessment of diabetic peripheral neuropathy with use of the clanging tuning fork test.

OBJECTIVE: To describe the clanging tuning fork (CTF) test, a novel method for using the C 128-Hz tuning fork to test for diabetic peripheral neuropathy (DPN), to evaluate the accuracy and reproducibility of this technique, and to compare it with the 5.07 (10 g) Semmes-Weinstein monofilament test. METHODS: To determine the mean and standard deviation for the CTF test, repeated measurements were taken on one toe of 12 patients with diabetes during one visit. After these tests, 30 randomly selected patients were tested on both feet, with right and left scores compared for reproducibility of the results. The scores of the CTF test were compared with the monofilament scores in 45 patients with diabetes. Presence of foot ulcers in 81 patients was correlated with both test scores. RESULTS: The mean duration of vibration sensation was 10.2 seconds, with a standard deviation of +/-1.3 seconds. The Pearson correlation coefficient comparing the right and the left foot scores for the same patient was 0.947 (P<0.05). Among patients with 8 seconds or less of vibration perception, results of monofilament testing were abnormal only in those whose vibration perception was less than or equal to 4 seconds. Of 32 patients with vibration perception of 4 seconds or less, 50% had normal monofilament test scores, including 29% of 17 patients with absent vibratory sensation. CONCLUSION: The CTF test is reproducible and accurate. It provides a quantitative assessment of DPN and can document severe neuropathy, even in the presence of a normal result with the 10-g monofilament test. The risk of foot ulcers, which is associated with diminished vibratory sensation, can therefore be detected earlier and more accurately with the CTF test. The CTF test should replace the 10-g monofilament test as the recommended technique for detection of DPN.