Severe Hypoglycemia Risk With Long-Acting Insulin Analogs vs Neutral Protamine Hagedorn Insulin.

Importance: Previous studies have found that the risk of severe hypoglycemia does not differ between long-acting insulin analogs and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes. However, these studies did not focus on patients 65 years or older, who are at an increased risk for hypoglycemia, or did not include patients with concomitant prandial insulin use. Objective: To examine the risk of emergency department (ED) visits or hospitalizations for hypoglycemia among older community-residing patients with type 2 diabetes who initiated long-acting insulin or NPH insulin in real-world settings. Design, Setting, and Participants: This retrospective, new-user cohort study assessed Medicare beneficiaries 65 years or older who initiated insulin glargine (n = 407 018), insulin detemir (n = 141 588), or NPH insulin (n = 26 402) from January 1, 2007, to July 31, 2019. Exposures: Insulin glargine, insulin detemir, and NPH insulin. Main Outcomes and Measures: The primary outcome was time to first ED visit or hospitalization for hypoglycemia, defined using a modified validated algorithm. Propensity score-weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs. The risk of recurring hypoglycemia events was estimated using the Andersen-Gill model. Post hoc analyses were conducted investigating possible effect modification by age. Results: Of the 575 008 patients initiating use of insulin (mean [SD] age 74.9 [6.7] years; 53% female), 407 018 used glargine, 141 588 used detemir, and 26 402 used NPH insulin. The study included 7347 ED visits or hospitalizations for hypoglycemia (5194 for glargine, 1693 for detemir, and 460 for NPH insulin, with a median follow-up across the 3 cohorts of 0.37 years (interquartile range, 0.20-0.76 years). Initiation of glargine and detemir use was associated with a reduced risk of hypoglycemia compared with NPH insulin use (HR for glargine vs NPH insulin, 0.71; 95% CI, 0.63-0.80; HR, detemir vs NPH insulin, 0.72; 95% CI, 0.63-0.82). The HRs were similar for the recurrent event analysis. The protective association of long-acting insulin analogs varied by age and was not seen with concomitant prandial insulin use. Conclusions and Relevance: In this cohort study, initiation of long-acting analogs was associated with a lower risk of ED visits or hospitalizations for hypoglycemia compared with NPH insulin in older patients with type 2 diabetes in Medicare. However, this association was not seen with concomitant prandial insulin use.

Nondestructive Quantitative Inspection of Drug Products Using Benchtop NMR Relaxometry-the Case of NovoMix® 30.

Batch-level inference-based quality control is the standard practice for drug products. However, rare drug product defects may be missed by batch-level statistical sampling, where a subset of vials in a batch is tested quantitatively but destructively. In 2013, a suspension insulin product, NovoLog® Mix 70/30 was recalled due to a manufacturing error, which resulted in insulin strength deviations up to 50% from the labeled value. This study analyzed currently marketed FlexPen® devices by the water proton transverse relaxation rate using a benchtop nuclear magnetic resonance relaxometer. The water proton transverse relaxation rate was found to be sensitive to detecting concentration changes of the FlexPen® product. These findings support the development of vial-level verification-based quality control for drug products where every vial in a batch is inspected quantitatively but nondestructively.

Different insulin concentrations in resuspended vs. unsuspended NPH insulin: Practical aspects of subcutaneous injection in patients with diabetes.

AIMS: This study measured the insulin concentration (Ins[C]) of NPH insulin in vials and cartridges from different companies after either resuspension (R+) or not (R-; in the clear/cloudy phases of unsuspended NPH). METHODS: Measurements included Ins[C] in NPH(R+) and in the clear/cloudy phases of NPH(R-), and the time needed to resuspend NPH and time for NPH(R+) to separate again into clear/cloudy parts. RESULTS: In vials of NPH(R+) (assumed to be 100%), Ins[C] in the clear phase of NPH(R-) was<1%, but 230±41% and 234±54% in the cloudy phases of Novo Nordisk and Eli Lilly NPH, respectively. Likewise, in pen cartridges, Ins[C] in the clear phase of NPH(R-) was<1%, but 182±33%, 204±22% and 229±62% in the cloudy phases of Novo, Lilly and Sanofi NPH. Time needed to resuspend NPH (spent in tipping) in vials was brief with both Novo (5±1s) and Lilly NPH (6±1s), but longer with all pen cartridges (50±8s, 40±6s and 30±4s from Novo, Lilly and Sanofi, respectively; P=0.022). Time required for 50% separation into cloudy and clear parts of NPH was longer with Novo (60±7min) vs. Lilly (18±3min) in vials (P=0.021), and affected by temperature, but not by the different diameter sizes of the vials. With pen cartridges, separation into clear and cloudy parts was significantly faster than in vials (P<0.01). CONCLUSION: Ins[C] in NPH preparations varies depending on their resuspension or not. Thus, subcutaneous injection of the same number of units of NPH in patients with diabetes may deliver different amounts of insulin depending on its prior NPH resuspension.