Laurence Hirsch

Skin and subcutaneous adipose layer thickness in adults with diabetes at sites used for insulin injections: implications for needle length recommendations

Abstract Objective: During subcutaneous insulin therapy, inadvertent intramuscular (IM) injections may increase pain and/or adversely affect glucose control. The most appropriate needle length for patients depends on skin thickness (ST) and the distance to muscle fascia. ST and subcutaneous adipose layer thickness (SCT) were measured in adults with diabetes. Research design and methods: A total of 388 US adults with diabetes (in three BMI subgroups: <25, 25–29.9, and ≥30 kg/m2) with diverse demographic features were evaluated. Each subject had ultrasound measurements of ST and SCT at four injection sites. Results: Subjects had BMI 19.4–64.5 kg/m2, age 18–85 years; 40% Caucasian, 25% Asian, 16% Black, 14% Hispanic; 28% type 1 diabetes. Mean ST (±95% CI) was: arm 2.2 mm (2.2, 2.3), thigh 1.9 mm (1.8, 1.9), abdomen 2.2 mm (2.1, 2.2) and buttocks 2.4 mm (2.4, 2.5). Multivariate analyses showed body site, gender, BMI, and race are statistically significant factors for ST but effects were small. Thigh ST was <0.6 mm thinner than the buttocks. Differences of 10 kg/m2 account for 0.2 mm ST variation. Mean SCT was: arm 10.8 mm (10.2, 11.3), thigh 10.4 mm (9.8, 10.9), abdomen 13.9 mm (13.2, 17.7) and buttocks 15.4 mm (14.7, 16.2). Females had 5.1 mm greater SCT. Differences of 10 kg/m2 account for 4 mm SCT variation. Adverse events: A few mild hypo- or hyperglycemia events, unrelated to study procedure, were detected and treated before subject discharge from study visits. Limitations: Only adults in the US were studied; some measurements could not be obtained on every subject, at every injection site. Conclusions: Injection site ST does not differ by clinically significant degrees in demographically diverse adults with diabetes; SCT has a wider range. Needles ≥8 mm, inserted perpendicularly, may frequently enter muscle in limbs of males and those with BMI <25 kg/m2. With 90° insertion, needles 4–5 mm enter the subcutaneous tissue with minimal risk of IM injection in virtually all adults. These data will assist recommending appropriate length needles for subcutaneous insulin injections in adults.

Comparative glycemic control, safety and patient ratings for a new 4 mm × 32G insulin pen needle in adults with diabetes

Abstract Objective: Pen needles (PN) for subcutaneous insulin therapy have become smaller; 5 mm PNs are now the shortest in use. We evaluated the safety, efficacy and patient ratings of a new 4 mm × 32 gauge (G) PN. Research design and methods: Subjects with type 1 and type 2 diabetes and HbA1c 5.5% to 9.5% participated in a randomized non-inferiority cross-over trial, at four U.S. centers. Subjects used 4 mm × 32G PNs and either 5 mm × 31G PNs (4/5 mm) or 8 mm × 31G PNs (4/8 mm) in two, 3-week treatment periods; order of needle use was controlled. Subjects were either ‘low dose’ or ‘regular dose’ users (highest single insulin dose ≤ 20 units and 21–40 units, respectively). Percent absolute change in serum fructosamine (% |Δ Fru|) was the primary endpoint; unexplained, severe hypo- or hyperglycemia was a secondary measure. Leakage at injection sites and pain measured by visual analog scale were tertiary measures. Equivalent glycemic control was defined á priori as % |Δ Fru| (including 95% CI) within 20%; 40 subjects per subgroup provides 90% power at α = 0.05. Clinical trial registration: The study was registered on clinicaltrials.gov (identifier: NCT00928057). Results: Of 173 subjects randomized, 168 completed the study, and 163 were included in the fructosamine analyses – 83 and 80 in the 4/5 mm and 4/8 mm groups, respectively. Subjects were 56% male, mean 52.6 yrs, 63% type 2. Baseline HbA1c = 7.5 ± 1.0% and fructosamine 301 ± 55.1 μmol/L. Mean % |Δ Fru| was 4.9% (95% CI 3.8, 6.0) and 5.5% (4.5, 6.4), respectively, for the 4/5 mm and 4/8 mm groups, meeting glycemic equivalence criteria; results were similar in both dose groups. The median |Δ Fru| was 11.0 μmol/L (8.0, 13.0) and 13.5 μmol/L (9.8, 18.0) for the 4/5 mm and 4/8 mm groups, respectively. Unexplained, severe hypo- and hyperglycemic episodes were infrequent and not different between PNs. The 4 mm PN was rated significantly less painful and preferred by approximately 2/3 of subjects (p < 0.01). All three PNs had similar reported injection site leakage. Limitations: The study was of relatively short duration, in adults in the U.S. Further trials in other patients (e.g., GLP-1 users, pediatrics, obese) should be performed. Conclusions: The 4 mm × 32G PN provided equivalent glycemic control compared to 31G, 5 mm and 8 mm PNs with reduced pain, no difference in insulin leakage and was preferred by patients.

Intradermal Microneedle Delivery of Insulin Lispro Achieves Faster Insulin Absorption and Insulin Action than Subcutaneous Injection

BACKGROUND This study compared insulin lispro (IL) pharmacokinetics (PK) and pharmacodynamics (PD) delivered via microneedle intradermal (ID) injection with subcutaneous (SC) injection under euglycemic glucose clamp conditions. METHODS Ten healthy male volunteers were administered 10 international units (IU) of IL at 3 microneedle lengths (1.25, 1.50, or 1.75 mm) in a randomized, crossover fashion on Days 1-3 followed by a repetitive ID 1.5-mm microneedle dose (Day 4) and an SC dose (Day 5). RESULTS Microneedle ID delivery resulted in more rapid absorption of IL, with decreased time to maximum insulin concentration (ID vs. SC: 36.0-46.4 vs. 64.3 min, P < 0.05) and higher fractional availability at early postinjection times. ID produced more rapid effects on glucose uptake with shorter times to maximal and early half-maximal glucose infusion rates (GIRs) (ID vs. SC: time to maximum GIR, 106-112 vs. 130 min, P < 0.05; early half-maximal GIR, 29-35 vs. 42 min), increased early GIR area under the curve (AUC), and faster offset of insulin action (shorter time to late half-maximal GIR: 271-287 vs. 309 min). Relative total insulin bioavailability (AUC to 360 min and AUC to infinite measurement) did not significantly differ between administration routes. ID PK/PD parameters showed some variation as a function of needle length. Delivery of ID IL was generally well tolerated, although transient, localized wheal formation and redness were observed at injection sites. CONCLUSIONS Microneedle ID insulin lispro delivery enables more rapid onset and offset of metabolic effect than SC therapy and is safe and well tolerated; further study for insulin therapy is warranted.

Microneedle-Based Intradermal Versus Subcutaneous Administration of Regular Human Insulin or Insulin Lispro: Pharmacokinetics and Postprandial Glycemic Excursions in Patients with Type 1 Diabetes

BACKGROUND This study assessed pharmacokinetics (PK) and pharmacodynamic postprandial glycemia (PPG) in patients with type 1 diabetes mellitus (T1DM) after a standardized liquid meal following insulin lispro (IL) or regular human insulin (RHI) given by microneedle-based intradermal (ID) versus subcutaneous (SC) delivery. RESEARCH DESIGN AND METHODS In this randomized, open-label, five-way crossover study, 29 T1DM patients received IL and RHI (0.125 U/kg) at 2 min and 17 min premeal, respectively, by both the SC and ID routes and also received RHI by the ID route at 2 min premeal. Blood glucose was stabilized at 120 mg/dL prior to a standardized 82-g carbohydrate liquid meal. ID delivery used a 34-gauge 1.5-mm steel microneedle, and SC delivery used a 31-gauge 8-mm syringe needle. RESULTS The 90-min PPG (blood glucose area under the curve for 0-1.5 h) for ID RHI was 14% lower than SC RHI at -17 min (P < 0.0001) and 11% lower than ID RHI at -2 min (P = 0.0006). PPG did not differ between ID RHI and SC IL, both at -2 min (P = 0.8345). ID IL PPG was lower than SC, both at -2 min, but not significantly (P = 0.10). Both ID IL and ID RHI PK data showed significantly faster uptake and time to maximum concentration, higher maximum concentration, and shorter systemic circulating duration versus SC dosing. ID IL and RHI delivery was generally well tolerated. CONCLUSIONS PPG with RHI administered ID via microneedle was improved versus SC delivery when dosed 17 min premeal. ID RHI provided similar control of PPG as SC IL immediately premeal. Further studies of ID insulin delivery via steel microneedles are warranted.

Insulin Injection Into Lipohypertrophic Tissue: Blunted and More Variable Insulin Absorption and Action and Impaired Postprandial Glucose Control.

OBJECTIVE Lipohypertrophy (LHT) is common in insulin-treated patients but its exact impact on insulin absorption and action is unclear. RESEARCH DESIGN AND METHODS In this crossover study, 13 patients with type 1 diabetes received subcutaneous abdominal injections of 0.15 units/kg insulin lispro into LHT (confirmed by examination and ultrasound) and normal adipose tissue (NAT). On one day, a euglycemic clamp was performed with two injections each into LHT and NAT, and on another day one injection per region was given before a standardized mixed meal (75 g carbohydrates), all in randomized order. RESULTS Compared with NAT, LHT reduced insulin absorption (mean area under the insulin concentration curve [AUCINS0–4h] 131 vs. 165 h * mU/L [LHT vs. NAT]; Cmax 61 vs. 79 mU/L, P < 0.02, respectively) and effect (areas under glucose infusion rate [GIR] curves [AUCGIR0–4h 625 vs. 775 mg/kg, P < 0.05]) but increased intrasubject variability ([coefficient of variation] AUCINS0–4h 52 vs. 11%, Cmax 55 vs. 15%, AUCGIR0–4h 57 vs. 23%, all P < 0.01). Postprandial blood glucose (BG) concentrations were ≥26% higher with LHT (AUCBG0–5h 731 vs. 513 mg * h/dL, BGmax 199 vs. 157 mg/dL, 2-h BG 150 vs. 104 mg/dL, 5-h BG 145 vs. 81 mg/dL, all P < 0.05) and maximum concentrations occurred later. Hypoglycemia (BG ≤50 mg/dL) occurred numerically less frequently with LHT injection (two vs. six patients), whereas profound hyperglycemia (BG ≥300 mg/dL) only occurred with LHT injection (two patients). Tmax-INS did not differ between LHT and NAT in either study. CONCLUSIONS Insulin absorption and action are blunted and considerably more variable with LHT injection, leading to profound deterioration in postprandial glucose control.

Pharmacokinetics and postprandial glycemic excursions following insulin lispro delivered by intradermal microneedle or subcutaneous infusion.

Background: Intradermal (ID) delivery has been shown to accelerate insulin pharmacokinetics (PK). We compared the PK and pharmacodynamic (PD) effects of insulin lispro administered before two daily standardized solid mixed meals (breakfast and lunch), using microneedle-based ID or traditional subcutaneous (SC) delivery. Method: The study included 22 subjects with type 1 diabetes in an eight-arm full crossover block design. One arm established each subjects optimal meal dose. In six additional arms, the optimal, higher, and lower doses (+30%, −30%) were each given ID and SC delivery, in random order. The final arm assessed earlier timing for the ID optimal dose (−12 versus −2 min). The PK/PD data were collected for 6 h following meals. Intravenous basal regular insulin was given throughout, and premeal blood glucose (BG) adjusted to 115 mg/dl. Results: The primary end point, postprandial time in range (70–180 mg/dl), showed no route-based differences with a high level of overall BG control for both SC and ID delivery. Secondary insulin PK end points showed more rapid ID availability versus SC across doses and meals (ΔTmax −16 min, ΔT50rising −7 min, ΔT50falling −30 min, all p < .05). Both intrasubject and intersubject variability for ID Tmax were significantly lower. Intradermal delivery showed modest, statistically significant secondary PD differences across doses and meals, generally within 90–120 min postprandially (Δ12 mg/dl BG at 90 min, Δ7 mg/dl BGmax, Δ7 mg/dl mean BG 0–2 h, all p < .05). Conclusions: This study indicates that ID insulin delivery is superior to SC delivery in speed of systemic availability and PK consistency and may improve postprandial glucose control.

Intramuscular risk at insulin injection sites--measurement of the distance from skin to muscle and rationale for shorter-length needles for subcutaneous insulin therapy.

BACKGROUND Intramuscular (IM) injection can increase insulin absorption, causing hypoglycemia. Available needle lengths today are 4-12.7 mm for pens and 6-12.7 mm for syringes. We describe the distance (D) from skin surface to muscle fascia at injection sites for subcutaneous (SC) insulin therapy and recommend needle lengths to reduce IM injection risk. MATERIALS AND METHODS At two locations in the United States, skin and SC fat thicknesses were measured by ultrasound at the abdomen, arm, thigh, and buttock in diverse adults (body mass index [BMI] range, approximately 19-65 kg/m²) with diabetes (n=341 with one or more paired skin and SC measurement, permitting calculation of D). The natural log of D by body site, BMI, and gender were analyzed using a mixed model to estimate IM risk. RESULTS D varied significantly by body site, BMI, and gender (each P<0.001), increasing with higher BMI and in women. Median D ranged from 10.9 mm (95% confidence interval, 10.3, 11.6) at the thigh to 16.9 mm (15.9, 18.1) at the buttock. Minimum D was <3 mm at the thigh and <5 mm elsewhere. When inserted 90° without pinch-up, the most commonly used needle worldwide (8 mm) has estimated IM risks of 25% and 9.7%, respectively, in the thigh and abdomen, versus 1.6% and 0.1%, respectively, with a 4 mm needle. A 45° insertion reduces, but does not eliminate, IM risk with longer needles. CONCLUSIONS Gender, BMI, and body site affect D; when combined with needle length and insertion angle, these factors permit detailed estimates of IM insulin injection risk. Such risk varies across sites, appears greatest at the thigh, is unnecessarily increased with 8 mm and 12.7 mm needles, and is greatly reduced with shorter-length needles and good injection technique.

Reduced Silent Occlusions with a Novel Catheter Infusion Set (BD FlowSmart): Results from Two Open-Label Comparative Studies

Abstract Background: Insulin pump users experience periods of unexplained hyperglycemia. In some cases these may be due to insulin flow interruptions termed “silent occlusions,” which occur without activating the pump alarm and may require set replacement. Materials and Methods: In-line pressure profiles of a novel infusion set with a 6-mm, 28-gauge polymer, dual-ported catheter (BD FlowSmart™; Becton Dickinson and Co., Franklin Lakes, NJ) were compared with those of an existing infusion set (Quick-set®; Medtronic MiniMed, Northridge, CA) in two separate studies involving insulin diluent infusions over 2.5–4.5-h periods in healthy adults without diabetes. Study 1, a pilot study (n = 25), compared the occurrence of flow interruption events (silent occlusions and/or occlusion alarms) between the two infusion sets and between manual or device-assisted insertion methods. Study 2 (n = 60) was designed to show ≥50% reduction in flow interruption events with the BD set after manual insertions. (Silent occlusions were defined by a continuous pressure rise for ≥30 min.) Results: In Study 1, significantly fewer silent occlusions were seen with BD FlowSmart versus Quick-set infusion sets for both manual (three of 22 [13.6%] vs. 12 of 24 [50%]; P = 0.012) and mechanical (two of 24 [8.3%] vs. nine of 25 [36%]; P = 0.037) insertions, yielding risk reductions of 73% (95% confidence interval [CI], 25–91%) and 77% (95% CI, 17–94%), respectively. In Study 2, flow interruption events occurred in three of 117 (2.6%) and 12 of 118 (10.2%) BD FlowSmart and Quick-set infusion sets, respectively, yielding a 75% risk reduction (95% CI, 20–92%; P = 0.030). Percentage of time with flow interruption was significantly lower with BD sets in both studies (P < 0.02). Leakage (>0.5 IU or 5 μL) occurred infrequently and did not differ between sets. Conclusions: A novel side-ported insulin infusion set demonstrated significant reductions in flow interruptions, including silent occlusions, versus a leading marketed set, which may improve insulin delivery.

Safety and efficacy of insulin therapy delivered via a 4mm pen needle in obese patients with diabetes.

OBJECTIVE To determine whether insulin delivered via a 4-mm × 32-gauge pen needle (PN) provides equivalent glycemic control as 8-mm × 31-gauge and 12.7-mm × 29-gauge PNs in obese (body mass index ≥30) patients with diabetes. PATIENTS AND METHODS This prospective, multicenter, randomized, open-label, 2-period, crossover, equivalence, home-based study was conducted from October 26, 2010, through May 31, 2012. After a 3-week wash-in period, eligible patients aged 18 to 80 years with a hemoglobin A1c (HbA1c) level of 5.5% to 9.5% (37-80 mmol/mol) were randomized to compare either 4- vs 8-mm PNs or 4- vs 12.7-mm PNs, using each of the 2 assigned PNs for 12 weeks in random order. The primary outcome was change in HbA1c level, with equivalence limits of ±0.4%. RESULTS The 274 patients randomized (mean ± SD age, 56.7±11.0 years) had a mean ± SD body mass index of 37.0±6.1 (range, 29.1-59.9) and took up to 350 U of insulin daily; 226 patients were included in the modified intention-to-treat analysis. Mean (95% CI) changes in HbA1c levels with the 4-mm PN were -0.08% (-0.21 to 0.06) and -0.10% (-0.19 to 0.00) vs the 8- and 12.7-mm PNs, respectively, within equivalence margins. The 4-mm PN was less painful than the larger PNs (P<.05), with similar leakage rates reported (4.1%-4.3%). Patients preferred the 4-mm PN over the 12.7-mm PN (P<.05) but not significantly vs the 8-mm PN. There were no differences between PNs in insulin doses and hypoglycemic or hyperglycemic adverse event rates. CONCLUSION The 4-mm × 32-gauge PN provides equivalent glycemic control as 8- and 12.7-mm PNs in obese patients with diabetes, with less pain and no increase in leakage. Shorter PNs should be considered in all insulin-requiring patients with diabetes, including those who are obese. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01231984.

Glycemic control, reported pain and leakage with a 4 mm × 32 G pen needle in obese and non-obese adults with diabetes: a post hoc analysis.

Abstract Objective: The shortest pen needle (PN) for subcutaneous insulin therapy is 4 mm. Clinicians may hesitate to use it in obese patients. We report a post hoc analysis of a previously published study of the 4 mm × 32 G PN, evaluating responses in obese (≥30 kg/m2) and non-obese (<30 kg/m2). Methods: Subjects (BMI 20 to 49 kg/m2, 52% obese) with diabetes used 4 mm × 32 G PNs and either 5 mm or 8 mm PNs (both 31 G) in two, 3-week treatment periods in a randomized noninferiority cross-over trial. Percentage absolute change in fructosamine (%│Δ Fru│) was the primary endpoint. Equivalent glycemic control was defined as %│Δ Fru│ within 20% (including 95% CI). The impact of obesity on change in fructosamine, pain and reported insulin leakage from the skin is described. Clinical trial registration: Clinicaltrials.gov – identifier: NCT00928057. Limitations: This report is a post hoc analysis of two BMI subgroups resulting in smaller sample sizes. Results: Of 168 who completed the study, 163 were included in the fructosamine analyses − 83 and 80 in the 4/5 mm and 4/8 mm groups, respectively. For the 4/5 mm group, mean BMI ± SD in non-obese and obese groups were 25.9 ± 2.3 and 35.0 ± 4.9 kg/m2, respectively; 4/8 mm group 25.2 ± 2.6 and 35.6 ± 4.2 kg/m2. BMI group was not significant for %│Δ Fru│ for either 4/5 mm or 4/8 mm. Between BMI groups, the difference of the means in %│Δ Fru│ was 0.4% (4/5 mm) and 0.3% (4/8 mm). The 4 mm PN was significantly less painful in all subject groups, except non-obese in 4/5 mm. Regardless of needle size, obese subjects reported more leakage events. For both BMI groups, there were fewer total reported leakage events when using the 4 mm vs 5 mm and 8 mm needles. Conclusions: The 4 mm pen needle provided equivalent glycemic control in both obese and non-obese patients compared to 5 mm and 8 mm needles with no increase in reports of skin leakage, in this post-hoc analysis. These findings should be confirmed in a prospective randomized controlled trial.