**3. Skin thickness**

intradermal (ID) delivery be avoided since the pharmacokinetics (PK) and pharmacodynamics (PD) of insulin are significantly altered in these tissue spaces. Optimal delivery also requires that sites of injection or infusion be rotated systematically in order to avoid the most common complication of insulin therapy, lipohypertrophy (LH). Insulin delivered into LH also has significantly altered PK and PD, which can lead to unexpected hypoglycemic episodes and glycemic variability. The latter are associated with worsened overall glucose control, increased

Recently, new recommendations have been published as a consensus document from international diabetes experts [1]. This publication was the collective output of 183 experts from 54 countries who wrote and vetted a practical, evidence-based roadmap for optimal insulin delivery at the FITTER (Forum for Injection Technique and Therapy: Expert Recommendations) workshop from October 23 to 24, 2015, in Rome. FITTER was the fourth in a sequence of workshops on optimal insulin delivery [2–4]. The FITTER recommendations were also based on the results of the fourth Injection Technique Questionnaire (ITQ) survey conducted from 2014 to 2015. In total, 13,289 insulin-injecting patients from 42 countries participated [5].

Each recommendation is followed by a grade (e.g., A2). The letter indicates the strength of each recommendation: A. Strongly recommended; B. Recommended; C. Unresolved issue. The number indicates the degree of scientific support for each recommendation: 1. At least one rigorously performed study which is peer-reviewed and published; 2. At least one observational, epidemiologic, or population-based study which is peer-reviewed and published; 3. Consensus expert opinion based on patient experience. Since FITTER, many diabetes groups from countries around the world have adapted and adopted these recommendations as local guidelines. We draw on certain of these recommendations in the review that follows as well as summarize studies that have been performed since FITTER and will follow a thematic format,

A large survey of current insulin delivery has shown that there are many aspects of injection practice which are suboptimal [5, 6]. For decades, professionals had been advising patients to use insulin needles which, we now know, were too long for them, with no scientific rationale. However, after the shortest pen needles (4 mm) became available and studies on injection site anatomy and needle performance began to be published, starting in 2010 [7, 8], showing the safety and efficacy of these needles, the recommendations of experts changed. It was recognized that 4-mm pen needles were the optimal choice for nearly all injecting patients, whether adults or children: thin, normal-weight or obese, male or female, and of all ethnicities. These needles were felt to be a key step toward reducing the risk of IM injections. As a result, the use of the 8-mm needle, the dominant size in 2010, has decreased dramatically since then, with a

short- and long-term complications, and higher costs.

58 Ultimate Guide to Insulin

beginning with the anatomy of injection sites.

**2. Current insulin delivery practice**

corresponding increase in the use of the 4-mm needle.

The skin is the main obstacle the needle must overcome. Needles must be at least long enough to traverse the skin and reach the SC tissue. Adult skin, according to a number of studies using imaging techniques ranging from ultrasound (US) to computer tomography (CT), has yielded remarkably similar results across genders, ethnicities, age groups, and body mass index (BMI) categories. The skin averages approximately 2–2.5-mm thick and varies in its 95% confidence interval (CI) between 1.25 and 3.25 mm. These studies included patients with type 2 diabetes (T2DM) from the Philippines [9], Korea [10], China [11], and India [12]; both type 1 diabetes (T1DM) and T2DM adults from the USA (including four different ethnic groups) [7]; and children from South Africa [13] and Italy [14].

The skin in children is slightly thinner than in adults, but these differences are largely irrelevant for insulin infusions and injections. Skin thickness increases during adolescence and reaches adult size in the late teens.

Babies have more SC tissue than preschool children. Children from 2 to 6 years have very little SC tissue regardless of gender. Children from 7 to 13 years gain SC tissue slowly but SC tissue thickness is almost the same in both genders until puberty. At puberty, girls increase their SC

Optimal Insulin Delivery

61

http://dx.doi.org/10.5772/intechopen.76232

SC tissue thickness when combined with the currently available needle lengths yields a relatively clear indication of the risk of IM injection. **Tables 1** and **2** show the risks for adult and pediatric persons with diabetes, respectively. It is clear from these data that the shorter the

IM-injected insulins have a much greater variability in absorption and effect (PK and PD) compared to SC-injected. This variability is influenced by both exercise and the properties of the individual insulins. Human insulins and the new analogs also differ as to their PK when injected IM. In general, IM insulin is often associated with a more rapid absorption and unexplained hypoglycemia [17–19]. Because of the difficulty of predicting the impact of IM injections on PK and PD, various measures can be taken to avoid injecting IM: using of shorter needles, lifting of a skin fold into which one injects the insulin, or choosing injection sites with thicker layers of SC fat. A combination of the above techniques can also be

In the last decade, insulin needle lengths have decreased dramatically. Previously, adults were given needles that were ≥ 8 mm long and children ≥6 mm. As shown in **Tables 1** and **2**, these lengths are now universally recognized as too long. They make IM injections more likely, and on the whole, the length of the needle has little or nothing to do with glucose control, according to a multitude of studies [8, 21–28]. Longer needles also tend to have larger

Hirsch [8] compared the 4-mm pen needle to 5- and 8-mm needles and showed the former to be safe and efficacious in adults (i.e., comparable glucose control); leakage from the skin was equivalent and both pain scores and overall preference were better with the 4 mm. In Japan, Miwa [29] compared the 4-mm needle with 6 mm and showed equivalent results, as did Nagai [30] when comparing 4-to 5-mm pen needles. Hirose [31] found equivalent modeled PK/PD results for the 4 mm compared to the 6- and the 8-mm needles, in young non-diabetics. Birkebaek [32] found a reduced IM risk with 4 versus 6-mm PNs in children and lean adults. Lo Presti [14] measured the skin and SC in children and adolescents with diabetes (ages 2–17)

In obese adults, Bergenstal [33] recently showed that the 4-mm pen needles deliver equivalent glycemic control (HbA1c) to both 8- and 12.7-mm pen needles. These obese patients were taking

diameters (smaller G or gauge), which correlates with a greater injection pain.

and concluded that the safest needle length for all ages is the 4 mm.

tissue more rapidly than boys as a result of hormonal differences.

needle, the lower the risk of IM injection.

**5. IM insulin**

used [20].

**6. Needle length**
