Insulin delivery devices (British National Formulary, section 126.96.36.199)
Most UK patients use insulin pens and insulin cartridges, rather than syringes and 10-mL vials, which are still used by the majority of patients in the USA. Many devices are available, and new ones are frequently introduced. While the concept is the same, the details differ, and some are important when discussing the choice of pen device with patients, for example whether they deliver insulin in 0.5, 1- or 2-unit increments, the maximum number of units they deliver (which varies between 40 and 78) and the pressure required to inject the insulin. Specialist teams are usually up to date with delivery devices: ask their advice if you or the patient is uncertain about the precise name. Refillable pens are designed to have a long life, and patients who have not had their injection devices reviewed may be using fully reliable but less convenient devices. There are two basic types: refillable and prefilled disposable pens. (The Monthly Index of Medical Specialities, or MIMS, issued monthly to all GPs in the UK, contains a useful visual guide to all current diabetes devices, including lancets and blood glucose meters.)
NovoNordisk: NovoPen 4, NovoPen Demi (delivers in 0.5-unit increments, useful for children, and adults with low insulin requirements).
- Lilly: HumaPen Luxura, HumaPen Memoir (digital display of the details of the last 16 doses dispensed: date, time and units), Luxura HD (0.5-unit pen).
- Sanofi-Aventis: ClikSTAR.
- Owen Mumford: Autopen 24 (Sanofi-Aventis cartridges), available in 2-unit increment (2–42) and 1-unit increment (1–21) versions. Autopen Classic for Lilly and Wockhardt (animal insulin) cartridges.
Prefilled disposable pens
Increasingly used, these are convenient, and highly suitable for older people and those with dexterity problems.
- NovoNordisk: FlexPen
- Lilly: KwikPen
- Sanofi-Aventis: SoloStar
Errors in prescribing insulin are very common, are frequently more than trivial and are potentially lethal. If there is any doubt, try to corroborate with others, especially GPs and community nurses, and use the expertise of pharmacists before prescribing.
- Generic insulin is not available in most countries; insulin preparations must be prescribed by brand name. Older insulin preparations often had similar-sounding names, but newer insulins are now required to have unique names that are unlikely to be confused. Half-remembered names are dangerous; older patients are apt to recall correctly the names of insulins they used for many years, but which they may not be currently using.
- Analogue (modified human) insulins, on the other hand, also have approved names (see below) based on the amino-acid changes in the molecule, for example insulin glargine is Lantus, insulin aspart is NovoRapid. They are still best prescribed by brand name.
- Write ‘units’ in full. Do not abbreviate to ‘U’, which can be misread as ‘0’, or ‘IU’ (international units), which can be misread as ’10’.
- Inpatients: the priority is to prescribe the insulin preparation correctly. If you know the precise name of the device, then it can be added, but it is not critical (compare inhalers). Where protocols are in place, patients should administer their own insulin using their own device.
- Inpatients: indicate the time of administration in relation to meals, as well as by clock time, where necessary. Twice-daily biphasic insulin should not be prescribed in the middle of the day or at bedtime, an alarmingly common practice.
Insulin Preparations (Table 4.1)
Since the first clinical use of insulin in 1922, prolonging the short-lived effect of native hexameric insulin to provide consistent basal insulin levels, especially overnight, has been a pharmaceutical challenge. The first preparation, still widely used, was NPH (Neutral Protamine Hagedorn, 1946). Longer-acting forms with zinc (e.g. lente and PZI) are still manufactured but very little used. Two long-acting human analogue insulins have been introduced over the past decade: glargine (Lantus, Sanofi-Aventis) forms crystals at neutral tissue pH that are slowly absorbed, while detemir (Levemir, NovoNordisk) has a long-chain myristic fatty acid attached to the modified insulin molecule which delays transfer from the subcutaneous tissue and from the circulation by attaching to plasma albumin. It should probably not be used in patients with profound hypoalbuminemia. Both long-acting analogues are often described as ‘peakless’, but they are better thought of as having a gentle onset and offset of action that lasts 22–24 hours. This contrasts with the definite peak action of NPH which occurs at about 4–6 hours and which is responsible for its increased risk of nocturnal hypoglycemia. All are often better given twice daily. Reduction in (but not abolition of) nocturnal hypoglycemia is the most important effect of the long-acting analogues; any reductions in HbA1c are usually clinically not important. The relative hepatoselectivity of detemir, resulting in less peripheral lipogenesis, may be responsible for the smaller weight gain seen with this insulin compared with NPH and glargine, although the difference is relatively small (e.g. up to 1.5 kg). Very long-acting analogues are in development (see below).
Progressive shortening of the time of onset and offset of short-acting mealtime insulins was achieved initially by changing from beef to highly purified monocomponent pork (1970s), then to biosynthetic human insulin (1980s), and most recently to the rapid-acting human analogue preparations, of which there are currently three. The first, insulin lispro, was introduced in 1997. Various changes to pairs of amino acids in the insulin molecule decrease the tendency to hexamer formation, thereby increasing the speed of absorption from subcutaneous tissue. When given 15 minutes before (though not when given after) meals, they reduce postprandial hyperglycemia more than soluble/regular insulin or rapid-acting analogue given at the start of a meal, but comparative trials have not shown consistent improvements in HbA1c.
Their benefits vary in different patients: the lower rate of late-morning hypoglycemia is important to some patients, as is their value in patients who take supplementary doses with snacks between main meals, but their relatively rapid offset of action can lead to pre-meal hyperglycemia if the interval between meals is more than 4–5 hours, and some patients prefer the longer action of soluble insulin for breakfast and lunch, while using a rapid-acting analogue with a very late evening meal, where a longer-acting soluble insulin might overlap with a long-acting bedtime insulin.
The overall advantages or otherwise of both long- and rapid-acting analogues over their human equivalents continue to be debated; analogue regimens have higher ratings for treatment satisfaction and quality of life measures, but it would be unwise to abandon wholesale a group of insulin preparations that served several generations, including the DCCT cohort, perfectly well.