With the growing incidence of obesity around the world, more patients than ever are faced with the task of raising insulin doses to reach glycaemic targets.² Increased insulin injections, greater injection sizes, and more regular insulin pen shifts are among the obstacles.¹ To make matters worse, a large subcutaneous insulin depot may cause pain and irritation at the injection site.² Patients with these medication problems can find it more difficult to adhere to their insulin therapy, resulting in low glycaemic control.²

If dietary improvements and antihyperglycemic medications (oral or injectable) aren't enough to reach glycaemic objectives, diabetic patients frequently switch to insulin therapy.³ In most patients with type 2 diabetes, the introduction of insulin begins with long-acting insulin (basal only) and progresses to prandial insulin (basal-bolus therapy).³ A basal-bolus regimen is always required for people with type 1 diabetes.³ Older age and a higher body mass index (BMI) with central obesity are causes that increase insulin resistance in people with diabetes, necessitating higher insulin doses to sustain near-euglycemia.¹

TREATMENT FAILURE

A complex diabetes regimen, polypharmacy, side effects, therapeutic inertia, and non-adherence are all causes that could contribute to insulin therapy failure.⁴ In addition, in patients who undergo several regular doses, improper insulin administration procedures and pen misuse may have a major effect on metabolic function.⁴ Insulin has a complex effect on metabolism, cell growth and differentiation.⁵ Insulin receptors are present in nearly all mammalian cells, and they react to insulin.⁵ Muscle, adipose tissue, the brain, and nerves are among the main tissues targeted by insulin's metabolic effects.⁷

Macrophages, endothelial cells, and insulin-producing pancreatic cells are among the most prominent insulin target cells with a metabolic role.⁷ In addition, PI3K and AKT, some of the key mediators of insulin signalling, are activated downstream of other growth factor receptors.⁷ Insulin stimulates several mitogenic pathways, such as growth factor receptor-bound protein 2 (GRB2) and ERK, resulting in a network of interconnected signalling pathways.⁷

Several concentrated insulins with various concentration levels have become available in recent years.¹ A non-exhaustive list would include the following:⁷

• Decreased injection volume
• Fewer injections
• Less pain at injection site
• Less frequent pen changes
• Easier delivery of larger doses.

As a result, concentrated insulins offer several advantages and more opportunities to provide personalised insulin therapy to patients who need it.² Concentrated insulins are obvious good options for obese and extreme insulin-resistant patients who need comparatively larger doses of insulin.¹ It's important to reach optimum glycaemic regulation early in the course of diabetes to prevent long-term complications.¹

DANGERS OF INSULIN USE

In the last 20 years, numerous studies have been conducted to see whether intensive blood glucose control will reduce the risk of major adverse cardiac events (MACE) in diabetic patients.⁷ The results of these studies showed that despite good glycaemic control, MACE did not decrease significantly, and in some cases, MACE increased.⁷ Hypoglycaemia has been suggested as a possible reason for the detrimental effects on heart events observed in these studies due to the use of many antidiabetic drugs, including insulin, to achieve better blood glucose control.⁷

Hypoglycaemia is the most common anti-diabetic medication side effect, particularly in people who take insulin or insulinotropic agents.⁷ Although mild hypoglycaemia is common and normally responds to patient self-treatment, severe hypoglycaemia (SH), which occurs infrequently, can be fatal to the cardiovascular (CV) system.⁷ Although the exact mechanism causing the negative CV outcomes associated with hypoglycaemia has yet to be established, a variety of negative CV outcomes have been proposed, including activation of myocardial ischaemia and injury, myocardial infarction, and changes in cardiac repolarisation, all of which can lead to an electrophysiological state conducive to cardiac arrhythmia.⁷

GLYCAEMIC CONTROL

To avoid long-term complications, it's important to achieve maximum glycaemic control early in the course of diabetes.² Overall glycemic control can be considered as a dual outcome of lowering mean glucose, while minimizing exposure to hypoglycemia.²For most diabetics, intra-patient variability in insulin action, which can impede glycaemic control, is a source of frustration.³Variability in dosing accuracy, variability in insulin absorption due to temperature changes, insufficient priming before injection, injection procedure, and injection site selection are all potential triggers.³

The focus should not only be on the duration of insulin action, meal planning, and accurate insulin dose calculation, but also on giving the right dose to achieve optimal glycaemic control and a higher quality of life.³ Insulin pens are suitable for diabetics that need strict glycaemic regulation because they provide more reliable and precise doses.³

It is important to reach optimum glycaemic lowering early in the course of diabetes to prevent long-term complications.² Insulins that reduce the frequency of hyperglycaemia and hypoglycaemia while also reducing the burden of daily therapy (fewer injections, improved delivery systems) are required, especially in insulin-resistant patients who are on high insulin doses.² Insulin with a higher concentration has been regarded as a possibility.¹

People who have higher insulin requirements will use more pens or cartridges.⁸ People that need higher doses of insulin can also be candidates for new higher concentrated insulin formulations, which are usually only available in a prefilled, dedicated pen/cartridge.⁸

INSULIN LISPRO

Except for the penultimate lysine and proline residues on the C-terminal end of the B-chain at B28 and B29, which are reversed, insulin lispro (rDNA origin) is like human insulin.⁹ This shift has no effect on insulin receptor binding, but it does result in a faster onset of action for this analogue insulin.⁹ Insulin lispro is associated with fewer hypoglycaemic events than normal human insulin in patients with T1DM who undergo multiple daily injections.⁹

The receptor-binding domain of the molecule and its affinity for the insulin receptor are unaffected by structural changes at these locations.⁹ While insulin lispro has a slightly higher affinity for the insulin-like growth factor-1 (IGF-1) receptor than normal human insulin (RHI), the difference in affinity isn't important enough to cause a difference in cell-growth-stimulating activity.⁵Insulin lispro has basically the same effect on lipogenesis as RHI.⁵ Insulin lispro is one of the most studied and widely used rapid-acting insulins.⁵

Insulin lispro significantly improves postprandial blood glucose levels compared with regular human insulin when administered as prandial insulin in conjunction with basal insulin, leading to a lower rate of hypoglycemic events. This was observed even when insulin lispro was administered immediately before meals and the RHI was injected 30-45 min before meals. However, as opposed to RHI, the benefits of insulin lispro on postprandial blood glucose levels and the occurrence of hypoglycaemic cases were not always followed by improvements in glycosylated haemoglobin (HbA1c).⁵

The most plausible reason for this is that the long-acting insulins used in insulin lispro and RHI were insufficient to have true basal coverage, resulting in elevated pre-prandial blood glucose concentrations in insulin lispro patients.⁵ Insulin lispro was used in combination with two or three frequent doses (instead of one) of neutral protamine Hagedorn (NPH) insulin, which resulted in a clinically and statistically important drop in HbA1c levels.⁵ The only rapid-acting analogue with a 200 U/mL dosage is insulin lispro.¹ The PK/PD, effectiveness, and safety profiles of insulin lispro 200 U/mL (IL200) are similar to those of lispro 100 U/mL, but the 200 U/mL pen has a lower glide force and is favoured by patients.¹⁰ More than half of the meal-time insulin patients were prescribed IL200 in a new survey study conducted by a group of German physicians specialising in treating diabetes and administering insulin therapies.¹

Roughly 40% of their patients were on IL200 for more than a year.¹ Since converting from a 100 unit/ml pen, the majority of the surveyed physicians felt IL200 was easy to use and dose/administer.¹ They were optimistic that when on IL200, their patients would hold to an MTI treatment plan.¹

This survey indicated that IL200 was administered to patients with a wide variety of insulin criteria, which is consistent with an overall measurement of concentrated insulins.¹ The majority of patients taking IL200 had T2DM and were likely to be severely insulin resistant.¹ The majority of patients were on a lot of insulin and had to cope with a lot of injections from both basal and bolus therapies.¹

IMPORTANCE OF GLIDE FORCE

Diabetes patients often also have concomitant hand impairments, which can make injecting insulin complicated.¹⁰ As diabetes progresses, the risk of decreased flexibility and limited hand joint mobility increases.¹⁰ Increased insulin doses and reduced hand joint strength and dexterity are only two of the many reasons affecting insulin pen creativity.¹⁰

The injection mechanism design, the inner needle diameter, temperature, and injection speed both affect glide power, which is the amount of effort needed to depress the pen's injection handle (hydraulic flow through the needle).¹⁰ When injecting a big dose of insulin, a pen with a lower glide force that requires less patient effort can be useful.¹⁰ The IL200 pen had slightly lower glide force and less glide force variability in a recently released analysis of glide force characteristics between two prefilled insulin lispro pens.¹⁰ The insulin lispro 200 units/mL pen reduced overall glide force by 53% with the TW needle and 30% with the XTW needle when used at 30 units.¹⁰ The injection speed of nine units per second, which is considered a representative injection speed for patients, is equivalent to that used in previous research.¹⁰ The insulin lispro 200 units/mL pen's glide force characteristics can be useful for patients who need more than 20 units of mealtime insulin a day, with a special advantage for those with hand impairments.¹⁰

CONCLUSION

Many of the most pressing dangers associated with long-term insulin use can be minimised with precision dosing and adherence strategies. A promising strategy to achieve and maintain glycaemic control among diabetics is the use of insulin pens, which are available in several formulations.

The use of concentrated insulins results in reduced injection volume, fewer injections, and fewer split doses. The use of particular insulin pens is also significant since there is a marked difference in glide force between some pens and others.

REFERENCES:

1. Chen, J, et al, 2020. An assessment of physician reasons for prescribing Insulin Lispro 200 units/ml in Germany. Postgraduate Medicine 2020, Vol. 132, No. 8, 727–736.
2. Davies, J, et al, 2018. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018 Dec; 41(12): 2669-2701.
3. Aanstoot, HJ, et al, 2020. Precision Dosing of Rapid-Acting Insulin Matters. Diabetes Technology & Therapeutics, Volume 22, Number 5, 2020
4. Mamza, J, et al, 2019. Clinical characteristics and patient treatment satisfaction with Humalog U-200 in patients with type 2 diabetes mellitus: an observational study. Journal of Drug Assessment, Vol. 9, No. 1, 8–12.
5. Candido, R, et al, 2018. A Review of Basal-Bolus Therapy Using Insulin Glargine and Insulin Lispro in the Management of Diabetes Mellitus. Diabetes Therapy volume 9, pages 927–949.
6. Haeusler, RA, et al, 2018. Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol. 2018 Jan; 19(1): 31–44.
7. Deedwania, P, 2018. Dangers of Hypoglycemia in Cardiac Patients with Diabetes: Time to Switch to Safer, Newer Drugs. J Am Coll Cardiol. 2018 Oct, 72 (15) 1787–1789.
8. Schloot, NC, et al, 2020. Patient characteristics of insulin lispro 200 units/ mL users in real world setting in Germany. Current Medical Research and Opinion, 2020, Vol. 36, No. 10, 1611–1617.
9. Thrasher, J, et al, 2018. Safety of Insulin Lispro and a Biosimilar Insulin Lispro When Administered Through an Insulin Pump. Journal of Diabetes Science and Technology, Vol 12, Issue 3, 2018.
10. Rees, TM, et al, 2015. A Comparison of Glide Force Characteristics Between 2 Prefilled Insulin Lispro Pens. Journal of Diabetes Science and Technology, Vol 9, Issue 2, 2015.