AUTHOR/BYLINE: Sanjay Kalra, Leszek Czupryniak, Gary Kilov, Roberta Lamptey, Ajay Kumar, AG Unnikrishnan, Aissa Boudiba, Mohamed Abid, Zhanay A. Akanov, Ali Latheef, Mustafa Araz, Ralph Audehm, Silver Bahendeka, Naby Balde, Sandeep Chaudhary, Chaicharn Deerochanawong, Olufemi Fasanmade, Hinde Iraqi, Tint Swe Latt, Jean Claude Mbanya, Joel Rodriguez-Saldana, Ko Seung Hyun, Zafar A Latif, Maxim Lushchyk, Magdy Megallaa, Mohammed Wali Naseri, Nguyen Quang Bay, Kaushik Ramaiya, Hoosen Randeree, Syed Abbas Raza, Khalid Shaikh, Dina Shrestha, Eugene Sobngwi, Noel Somasundaram, Norlela Sukor, Rima Tan.
Early insulin use has been associated with the reversal of diabetes. To tackle the epidemic of diabetes, various countries are scaling up equitable and affordable access to insulin for improved care. Multiple regimens, formulations, and delivery devices of insulin are increasingly being used to individualise treatment and attain the best possible glycaemic control in people with diabetes.
Available subcutaneous insulins differ in onset, peak, and duration of action and in safety profiles, ranging from ultra-short-acting to ultralong-acting preparations. With a plethora of formulations, which need to be matched with heterogeneous patient profiles, the initiation and intensification of insulin therapy are increasingly becoming challenging.
Adult-onset diabetes has been stratified into subgroups to individualise treatment according to patient characteristics, disease progression, and risk of diabetic complications. These subgroups include insulin-deficient and insulin-resistant diabetes as well as mild obesity- and age-related diabetes.
Guidelines for the non-pharmacologic and pharmacologic management of diabetes have been formulated by the IDF, American Diabetes Association (ADA), and American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE).
The approach to insulin therapy has been described in multiple guidelines for diabetes. The ADA has described an algorithm for the initiation of insulin therapy with basal insulin and the stepwise inclusion of rapid-acting and premixed insulins.
The IDF and AACE/ACE have also described a comprehensive algorithm for adding or intensifying insulin in persons with type 2 diabetes. The AACE/ACE explores factors that should be considered when selecting a formulation for insulin initiation, including age, life expectancy, motivation, presence of complications, overall health status, and cost of formulations.
In these guidelines, the key disease characteristics influencing the choice for initiation and continuation of therapy include the duration and severity of diabetes. Though these guidelines provide elaborate algorithms for insulin therapy, criteria for regimen and formulation selection are inadequately addressed. The guidelines, which largely focused on basal and rapid-acting insulins, do not include directions for use of all available formulations.
The East African Diabetes Study Group (EADSG) Guidelines recommend that insulin therapy in people with diabetes should not be delayed and patients should be educated about insulin regimens, choice of formulations for treatment, and regular monitoring of glycaemic control.
These guidelines together with those of the Research Society for the Study of Diabetes in India (RSSDI) and the Society for Endocrinology, Metabolism and Diabetes of South Africa have explained practical aspects of insulin regimens in detail, providing a patient-centred approach to initiation and intensification of therapy.
There are some guidelines that provide directions for the initiation and intensification of insulin therapy with premixed insulin. However, these guidelines do not compare the premixed insulin preparations with other insulin preparations. In addition, these guidelines do not specifically describe the patient characteristics that prompt a preference for premixed insulins. In this article, we identify the gaps in current practices and build an objective, rational approach to patient selection for premixed insulins. This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.
Premixed insulin: formulations and pharmacokinetics
Premixed insulins are fixed component formulations of rapid or short-acting and intermediate- or long-acting insulins for both fasting and postprandial glycaemic control. These formulations include the conventional premixed formulations with human insulin, premixed analogue formulations, and a premixed coformulation of rapid-acting and ultra-long-acting basal insulin analogues.
Premixed insulins can be dosed once, twice, or thrice daily, depending upon patient requirements. The premixed insulins have pharmacokinetics that favour both 24-hour efficacy and patient convenience. This explains the high adherence rates and better glycaemic control with premixed insulins.
The conventional premixed biphasic human insulin is a combination of regular human insulin and neutral protamine Hagedorn (NPH) in ratios of 30/70 or 50/50. These are administered 30 min prior to meals, and the action lasts for about 10–16 hours. The analogue premixed formulations (Lispro 25/75, Lispro 50/50, BIAsp 30/70, BIAsp 50/50) have a quicker onset of action and can be administered up to 15 min prior to meals. When compared with conventional premixed formulations, the analogue formulations are longer acting with a duration of action ranging from 12- to 24-hours.
IDegAsp (70/30) is a combination of the ultra-long-acting insulin degludec (IDeg) and rapid-acting analogue insulin aspart (IAsp) that provides safe and well-tolerated control of both fasting and prandial hyperglycaemia. IDegAsp 70/30 offers advantages of mealtime flexibility with quicker onset (10–20 min) and longer duration of action ([24 h).
Premixed insulin: initiation and intensification
Premixed insulin analogues have efficacy and safety outcomes similar to those of basal or basal-bolus insulin. In a review comparing premixed and basal plus regimens, Downie et al reported similar efficacy and safety with both regimens for both insulin initiation in insulin-naive patients and intensification in patients who have failed on basal insulin.
In a meta-analysis of 13 randomised controlled trials (16–60 weeks, n=5255), comparing the premixed and basal-bolus regimens there were no significant differences in HbA1c levels, rate of hypoglycaemia, weight change, or daily insulin dose with the two regimens despite the greater complexity and number of injections associated with basal-bolus insulin.
Better overall glycaemic control is also reported with premixed insulins (insulin lispro 25/27, BIAsp 70/30) than with the basal insulins (insulin glargine) in insulin-naive as well as pretreated patients. Some researchers report a higher risk of minor nocturnal hypoglycaemia with premixed insulin than with basal insulin regimens.
The Indian National Consensus Group (INCG) has provided guidance for initiation and intensification of therapy with premixed insulin in the management of diabetes in primary care. According to INCG, premixed insulins, preferably analogue formulations, offer a simple, safe, and easy option for the initiation of treatment in diabetes and should be considered for the management of all stages of diabetes.
The Royal Australian College of General Practitioners (RACGP) and RSSDI have provided guidance for the initiation, titration, and intensification of therapy with premixed insulin. According to these guidelines, premixed insulin may be an appropriate and simple option for glycaemic control when fasting and postprandial glucose levels are consistently elevated.
Patients may be switched to premixed insulin if target HbA1c levels are not achieved with basal insulin alone or therapy intensified to basal plus or basal-bolus. It is important to emphasise appropriate nutrition and physical activity at all stages of treatment initiation and intensification.
Treatment with premixed insulin (10 U or 0.1–0.2 U/kg/day immediately before or soon after the largest meal, usually the evening meal) can be started in insulin-naive persons with diabetes. The dose is then titrated once or twice a week depending upon the lowest blood glucose levels (fasting/prandial) over the last three days.
Asians with lower BMI may require a lower dose. The once-daily dose may be equally split into a pre-breakfast and pre-dinner dose if the evening preprandial glucose levels or HbA1c remain high or if dose requirements increase beyond 30 U/day or 0.4 U/kg/day. Some clinicians use the criteria of 50 U/day or 0.5 U/kg/day to guide the twice-daily dosing of premixed insulin. Twice daily dosing can again be titrated to achieve the target fasting and prandial glycaemic control.
A practical approach commonly used for high-mix insulin is to distribute the dose of premixed insulin as two-thirds in the morning and one-third in the evening when the once-daily insulin dose exceeds 20 or 30 U.
Factors influencing the choice of premixed formulations
Patient-centred/subjective factors
Glycaemic control is determined not only by insulin formulations but also by patient characteristics. Few guidelines have elaborated upon patient characteristics to guide the choice for initiation and intensification of therapy with premixed insulin.
The RACGP lists patient characteristics that should be considered for initiating and planning insulin treatment. These include the physical and cognitive capability to administer multiple injections and monitor blood glucose several times a day, support of the family and treating physician, patient preferences, meal patterns, and activity routine.
The key patient characteristics that influence the choice of therapy with premixed insulin include duration and symptoms of hyperglycaemia, overall health and other medical conditions, past and ongoing treatment, lifestyle, and patient preferences.
An appropriate history, detailed physical examination, and required investigations can help to adopt a patient-centred approach in tailoring treatment with premixed insulin.
Patients should be engaged in decision making when selecting an insulin formulation for glycaemic control. Patients should be encouraged to adopt consistent meal timings and components. They should also be asked for a preference regarding injection frequency and blood glucose monitoring. In addition, costs should be discussed to make the therapy affordable in the long term.
Continuous support and guidance from the treating physician can help combat patient fears and doubts and reduce the possibility of ‘psychological insulin resistance’. Initial and continued therapy with premixed insulin should be guided by patient attributes and tailored to patient needs instead of trying to find a ‘one-size-fits-all’ regimen. Initiation of a small dose of insulin (2 IU) in the clinic helps to overcome needle phobia.
Dietary factors
Dietary patterns and preferences influence glycaemic control and are an important factor to be considered in the selection of insulin formulations for treatment.
Dietary composition: premixed insulins are best used in persons who consume meals of balanced and uniform dietary composition. The EADSG Guidelines emphasise the importance of matching the dose of insulin to carbohydrate intake. The INCG recommends only premixed insulin at initiation as high glycaemic levels in response to a meal are more common in ethnic Asian communities. There may also be racial variations in the physiologic glycaemic response to meals. Asians have relatively higher post-prandial glucose levels due to the consumption of carbohydrate-rich diets. The diets of West Africans are rich in carbohydrates, and hence post-prandial glucose levels tend to be high. Premixed insulins are the preferred preparation in the Southeast Asian and African countries and are included in the National List of Essential Medicines of various countries.
Dietary patterns: regularity in meals is key in the achievement of glycaemic goals. However, dietary patterns may vary according to professional lifestyles and religious practices. Cultural practices such as Ramadan influence the glycaemic control and use of insulin in people with diabetes. Premixed insulin analogues with established efficacy and safety profile and lower rates of hypoglycaemia are preferred over premixed human insulins in people with diabetes during periods of religious fasting. IDegAsp may be considered as the preferred premixed insulin for people with diabetes who fast during Ramadan. Risk stratification and counselling are important in these individuals. Persons with erratic dietary patterns may benefit from IDeg Asp as it does not need to be injected at the same meal-time(s) each day.
Lifestyle
In patients with busy/stressful lifestyles and erratic meal patterns, the flexibility to match insulin administration with the major meal of the day offers convenience and improves compliance. According to a multinational consensus group, IDegAsp is good preparation for initiation of insulin therapy in the following: drug-naive patients with symptoms of hyperglycaemia, patients on a high carbohydrate diet, patients with high HbA1c levels, and postprandial excursions. It can also be used to initiate therapy following failure of (single, dual, or triple) oral anti-diabetic agents.
Overall health status
The overall health of the patient is a key determinant for the choice of the insulin formulation. Analogues have an advantage over human insulins due to the lower risk of hypoglycaemia associated with their use.
Metabolic health
Another important determinant of glycaemic goals and control is the metabolic health of the patient. This includes non-glycemic parameters related to renal, hepatic, endocrine, and metabolic parameters. The Metabolic Quartet, HbA1c, blood pressure, weight, and lipids, describes the four vascular-metabolic targets in diabetic patients. The pathology of postprandial hyperglycaemia may include impaired glucagon suppression in addition to reduced secretion of insulin.
Number of injections per day
A number-based insulin taxonomic model has been developed to offer more patient-centric care for diabetes. This model, based on variables such as the number of injections per day and the pharmacokinetic and pharmacodynamic characteristics of insulin preparations, helps inform the choice of therapy with available formulations of insulin. This model reflects the versatility of insulin in the management of diabetes and enables the physician to choose a formulation according to patient needs. The model assigns a code based on the frequency of injections and simplifies the classification of regimens used for insulin therapy including the premixed insulins. Based upon the patterns of an individual’s glycaemic levels, motivation level, psychosocial limitations, ease of use, and acceptance of insulin, premixed insulin can be used once, twice, or thrice daily.
Patient preferences
Premixed insulin is the best option in patients who are unwilling or unable to adhere to the increased injections and monitoring required with basal plus/basal-bolus regimens. As a patient-centred approach to the management of diabetes, patient-reported outcomes (PROs) should be measured before and during treatment. Quality of life is a common measurable target that can be used to determine the outcomes of insulin regimens. Other potential PROs include patient satisfaction, diabetes distress, anxiety and depression, coping skills, and communication.
Patient satisfaction and convenience
Patient satisfaction is important for the initiation and continuation of insulin therapy. Patients on basal-bolus or basal plus insulin may show dissatisfaction with therapy due to the excessive variability in glycaemic levels, frequent episodes of nocturnal hypoglycaemia, and multiple injections.
Where fewer injections are required, flexibility in the time of administration, and reduction of the injection-meal time gap, IDegAsp insulin offers more convenience to patients. Twice daily premixed insulin regimens protect the privacy of a patient and allow freedom of choice in self-disclosure of medical status. The flexibility in the timing of administration makes this premixed co-formulation a preferred choice, particularly for people with busy lifestyles and variable meal patterns.
Insulin distress
Defined as the emotional response to the suggestion of insulin use, insulin distress is a common deterrent in the attainment of glycaemic control. Premixed insulins having a lower index of intrusion and flexibility help to reduce insulin distress. Patient distress, apprehension, and anxiety associated with insulin use are reduced if such formulations are used. The pharmacokinetics of premixed insulin allows a more patient-friendly approach to initiation and continuation of therapy.
Laws of Parsimony
Premixed insulins enable the adoption of the Law of Therapeutic Parsimony in diabetes care. According to this law, the least number, quantity, and frequency of administration of a drug should be prescribed to achieve desired therapeutic outcomes without compromising the safety and well-being of patients. With control of both fasting and prandial glucose levels and HbA1c, premixed insulins are an appropriate choice for achieving glycaemic targets and reducing complications in persons with diabetes. The use of premixed formulations has allowed a reduction in the number of required injections. The flexibility offered by premixed analogues is associated with a reduction in injection-meal time gaps and improved compliance. These formulations have reduced the requirement for frequent glucose monitoring.
Glucocentric/objective parameters
Many subjective parameters guide the choice of formulation and regimen in therapy with premixed insulins. There is a need to include more objective parameters of patient characteristics to enable the selection of the ‘right insulin for the right person.’ Premixed insulin formulations can be combined with bolus insulins to customise the insulin regimens to suit individual glycaemic profiles and patient needs in diabetics. In patients with severe insulin deficiency or resistance, IDegAsp may be administered with the main meal and IAsp may be administered with the other two meals to build a three-dose intensive regimen for achieving glycaemic targets.
Glycaemic status
In individuals with diabetes, the glycaemic status is influenced by several clinical and biochemical factors. Changes in glycaemic status, determined by history, clinical examination, and glucometric indices, help to determine the aetiology and pathogenesis of dysglycaemia and plan the appropriate therapeutic strategies. Glycaemic status may be classified as predominant insulin deficiency or insulin resistance and predominant fasting, prandial, or combined hyperglycaemia. Obesity and other modifiable factors may impact the glycaemic status of an individual. Reinforcing the patient-centred approach suggested by guidelines, the determination and monitoring of glycaemic status can help to translate glycaemic management into better patient outcomes.
Glycaemic variations
Glycaemic variations including predominant fasting hyperglycaemia, predominant postprandial hyperglycaemia, overall hyperglycaemia, risk of hypoglycaemia, and comorbidities should be determined to guide the choice of therapy in diabetics. The quantity, composition, and patterns of dietary intake are key determinants of glycaemic variations in individuals with diabetes. Another equally important factor is a lifestyle, which includes the duration, intensity, and patterns of physical activity. Persons on premixed insulin should be counselled not to indulge in unaccustomed vigorous physical activity within two to three hours of taking the injection. Comorbid conditions such as rheumatoid arthritis, asthma, acromegaly, hyperthyroidism, and Cushing’s syndrome may worsen hyperglycaemia, while diseases such as hypothyroidism, Addison’s disease, renal and hepatic impairment, and malabsorption syndromes, such as celiac disease, may precipitate hypoglycaemia.
Further, complications associated with diabetes may amplify challenges in glycaemic control. Variability in glucose levels may be seen in conditions such as diabetic gastroparesis. These factors necessitate glycaemic monitoring in people with diabetes to achieve glycaemic targets while reducing glucose variability and hypoglycaemia.
There are some situations in which a basal-bolus regimen may be preferred. Usually, these are persons with type 1 diabetes or life-, organ-, or limb-threatening complications. These include persons with LADA, pancreatic diabetes, brittle diabetes, gestational diabetes mellitus, and new-onset diabetes after transplant (NODAT). These situations also include persons with diseases such as tuberculosis, extensive foot ulcer, or other severe infections.
In patients with both fasting and postprandial high glucose levels, it may be useful to determine the predominant hyperglycaemia. A person with predominant fasting hyperglycaemia may require either basal insulin at bedtime or one premixed injection before dinner, while another with postprandial hyperglycaemia will respond to a breakfast dose.
High glycaemic levels throughout the day will warrant a two- or three-dose premixed regimen. Dietary patterns influence the glycaemic variations and prescription of a number of doses of premixed insulin. Persons who consume very high carbohydrate meals will respond better to high-mix formulations, while those who are at high risk of hypoglycaemia may prefer low-mix formulations, especially analogues.
Glucometric indices
The evolution of objective glucometric indices has provided a better understanding of glycaemic control. Both fasting and postprandial levels of glycemia are components in determining the HbA1c levels. The most common indices for glycaemic control include fasting and postprandial glucose levels and HbA1c. These together make the glycaemic triad. These parameters together with minimum glycaemic variability and minimum hypoglycaemia make the glycaemic tetrad and pentad, respectively.
Various glucometric indices such as postprandial glucose excursions (PPGE) and the prandial fasting index (PFI) have been suggested to bring objectivity to the choice of therapy. These indices help to determine the relative contribution of fasting and postprandial glucose levels to hyperglycaemia. While these indices are not validated, they serve as a useful therapeutic framework to allow the use of insulin in a rational manner. High PPGE and PFI suggest a higher postprandial glycaemic burden.
Another validated index calculated as the ratio of the fasting blood glucose levels and HbA1c index serves as an indicator of the contribution of fasting hyperglycaemia to the glycaemic burden. When compared with the ratio of fasting blood glucose levels and HbA1c, PPGE and PFI are cheaper alternatives and are more affordable.
These indices can serve as useful clinical decision-making tools in diabetes care. The indices should be validated in clinical studies for informed and widespread application in diabetes management.
Summary
Premixed insulins have unique pharmacokinetic profiles and established efficacy for glycaemic control, which enables multiple and safe dosing in persons with diabetes. However, there is insufficient guidance on how to choose one insulin formulation over another. Patient characteristics are key in selecting the right formulation of premixed insulin in the management of diabetes. Dietary patterns, overall and glycaemic health, comorbid conditions, and any antidiabetic and other concomitant medications influence the selection and continuation of premixed insulin therapy. Insulin stewardship programs in healthcare settings can help make a pragmatic choice of formulation, initiate, and manage appropriate dosing, provide guidance on handling, storage, and disposal of insulin preparations, enable periodic monitoring, and formulate policies for physician and patient education.
When compared with premixed human insulin, premixed analogue insulins offer better mealtime flexibility, postprandial glycaemic control, hypoglycaemic profile, weight management, and comparable fasting glucose control. IDegAsp may be preferred over premixed insulin analogues because of the potentially lower incidence of overall and nocturnal hypoglycaemia and superior fasting glycaemic control. However, the cost may be a limiting factor, and some countries may not have access to IDegAsp.
Most guidelines suggest an intensification of insulin regimens with basal-bolus or premixed analogues. However, these guidelines do not provide guidance for the choice of ratio in premixed formulations (30/70, 50/50, or 70/30). The choice of a premixed formulation should be individualised based upon glycaemic patterns.
Different formulations may be used together, for example, a mid mix (50/50) formulation may be given before breakfast and a low-mix (30/70) formulation may be given before dinner to provide more overnight basal insulin. Low-mix formulations may be switched to mid-mix formulations for dosing before a meal that routinely has the highest carbohydrate content or one that has high ([10 mmol/l) two-hour postprandial glucose levels.
When compared with low-mix formulations, mid-mix insulins offer better control of postprandial glycaemia, lesser glucose excursions, and less intense self-monitoring of blood glucose levels. However, few studies have reported significant reductions in HbA1c with the initiation and intensification of therapy with mid-mix formulations compared with low-mix formulations.
Individuals with diabetes have heterogeneous patient characteristics and glycaemic profiles. The current article describes a rational approach to patient selection for premixed insulin therapy. It is concordant with the classic hierarchy (history, clinical examination, and investigations) followed in medical practice.
This article reinforces the importance of glycaemic status and its variations and reviews the glucometric indices that can be used to objectively plan and execute treatment with premixed insulins. Objectivity in glycaemic monitoring can help to select the right formulation of premixed insulin for the right patient.
REFERENCES:
Originally published in Diabetes Ther (2018) 9:2185–2199. https://doi.org/10.1007/s13300-018-0521-2
