My dad has diabetes* - that's why, very often, I remind him that he should eat sensibly and exercise regularly. I also drop the occasional passive-aggressive line telling him to take his medications so that his diabetes is kept under control. He never listens. He is the outright typical diabetic patient - non-compliant with treatment, always annoyed and irritated when people ask about their health, and generally having a 'que sera, sera' attitude. Fear no more, since recently a study published on New England Journal of Medicine brings good news - a new insulin formulation which only requires patients to administer it (on their own) once weekly rather than daily (as per current guidelines) [1]. We need to appreciate that a lot of the times, patients do want to make changes to their lives - however, the crux of the issue lies not in blind obstinacy, but the uphill struggle of making these changes in the first place. As the study aptly put, it is 'clinical inertia'. The lack of clinical improvement due to one's diminishing determination in the course of treatment. However, before I begin elucidating on the features of the study, I have to address several questions: (1) What is diabetes and what are the differences between Type 1 and Type 2 diabetes? (2) What is insulin and is this the only treatment modality for those afflicted by the disease? To answer these questions, we have to be thrown back to basics. Let's take a look at our lovely friend, the pancreas.
Diagram showing the Pancreas and the Duodenum, as well as the cells present in an Islet of Langerhans (extracted from https://www.brainkart.com/media/article/article-Anatomy-and-Function-LZs.jpg)
Battle of St Pancreas
(For those of you who don't get it, St Pancras is the name of a train station in London)
First of all, the pancreas is an organ tucked at the posterior part of the abdominal cavity, right behind (as shown above) a segment of the small bowel known as the duodenum. The pancreas is normally, upon examination, impossible to palpate and any chronic pathology over there is likely not to be attributed to the pancreas upon first presentation. For instance, pancreatic cancer has a mean diagnostic interval (the time period from the emergence of the first symptom to the time of diagnosis) of 117 days (mean), where the symptoms are mostly non-specific. Indigestion, decreased appetite and changed bowel habits are the three most common symptoms reported. [2] The pancreas is responsible for a wide variety of functions, including the production and release of digestive enzymes and hormones. We can divide the pancreas, functionally thus, into two parts: exocrine (for digestive purposes) and endocrine (hormone production). Exocrine, in essence, means dealing with things outside the body. If you think really closely, food particles have never actually entered our body. They go through a particular tract (the gastrointestinal, or alimentary tract) and get chucked out after all the nutrients are sucked out. Endocrine has an opposite connotation - everything internal. Nevertheless, we must not be misled by the terms. After all, this sort of division is only 'functional', not 'anatomical'. The exocrine and endocrine parts of the pancreas are arranged together, so that there are no strict boundaries demarcating the two. Back to the diagram, the centre features the Islet of Langerhans, which is the fancy name for a cluster of cells responsible for producing different hormones.
There are different types of cells present in the Islet of Langerhans, respectively being the alpha-cells, beta-cells, gamma-cells, delta-cells, PP cells and epsilon-cells. These cells produce the following hormones and they execute the following functions [3]:
Alpha-cells: glucagon (generally the antagonist, aka arch-nemesis, of insulin; increasing blood glucose levels by encouraging the conversion from glycogen into glucose);
Beta-cells: The man of the hour (or men; I used plural) - production of insulin which is crucial for the encouragement of reduction in blood glucose levels and increase in glucose absorption by body cells;
Gamma-cells: Arbitrator between the alpha- and beta-cells; controlling their populations;
Delta-cells: Troublemaker who produces a hormone called somatostatin which can shut many physiological processes in the body down. In endocrine diseases such as acromegaly (increased production and release of growth hormone from the pituitary gland), drugs that mimic the activity of somatostatin are used (not somatostatin directly since the naturally-occurring hormone acts for a very brief period of time in the body);
Epsilon-cells: Hunger Trigger - producing ghrelin, the hunger hormone;
PP Cells: The ultimate cynic who beats the pancreas up whenever it feels insecure - essentially reducing the production and release of pancreatic enzymes and hormones; it also encourages gastric juice secretion. The hormone released is called the pancreatic polypeptide.
Diagram showing the state of the Islet of Langerhans in a healthy pancreas and in a diseased pancreas (afflicted by Diabetes Mellitus Type 1). Here, we can see beta-cells being destroyed in the diseased pancreas. (Extracted from: http://www.exosome-rna.com/wp-content/uploads/2017/01/islets.jpg)
In diabetes, beta cells are affected. Type 1 and Type 2 diabetes differ in many respects, but principally in pathophysiology (referring to what went wrong in the process). Type 1 diabetes accounts for five to ten per cent of all diabetes cases. Cutting a very long story short (and I'm not exaggerating here, since even The Lancet has a specialty journal specifically addressing current research needs in diabetes and hormone medicine in general), Type 1 diabetes involves the death or destruction of beta cells from a young age. The production of insulin is grossly affected by the reduction in normal functioning of these cells. The destruction can be attributed to the rise of autoantibodies (which can be heavily associated with genetic factors), where they can be directed to beta-cells or insulin. We are seeing patients with much younger onset, accounting for equal to or over 85 per cent of all cases of diabetes in the youth (under 20 years old). The peak incidence is at 10-14 years of age. While for type 2 diabetes, the mean age of diagnosis is often higher. In the US, for instance, it stood at 52 years from 1988 to 1994. However, in recent years, there is a general decrease in the figure. American statistics showed that the mean age of diagnosis dropped to 46 years in 1999 to 2000. In the UK, the percentage of patients aged 40 or below at the time of diagnosis increased continuously from 5.9 per cent in 1991-1995 to 12.4 per cent in 2006-2010. Type 2 diabetes operates through two veins in general: (a) insulin resistance, and (b) insulin secretion deficit. Insulin resistance is the primary and foremost mechanism, where the hormone has 'lost its charm'. It simply cannot ask others to do anything anymore. An analogy from the university of life would be an attractive, young male model being able to command as much female attention as he wanted when he was still in his golden years. However, the moment he got married, he lost his charm although in terms of structure and build, he remained roughly the same. In the case of Type 2 diabetes, the liver doesn't listen to insulin. Liver cells are less prone to converting glucose into glycogen, the form of sugar for storage purposes. Body cells don't listen to insulin. That's why they also absorb less glucose into their corpuses. Even fat cells (constituents of adipose tissues) don't bat an eyelid when the old, charming insulin prince comes to visit. They are totally nonchalant. This leads to the decrease in production of fatty tissue. The concentration of fatty acids increases in the blood as more of them are released, flowing all the way to the liver and skeletal muscles. Also, as insulin doesn't work as well as it used to, there is higher concentration of LDL (so-called 'bad cholesterol') synthesised from blood triglycerides. LDL is bad since it deposits more cholesterol (lipids) to the vessel wall, increasing the risk of atherosclerosis. The nightmare doesn't stop here. Since there is insulin resistance, the pancreas produces more insulin. At first, this might help. However, this cannot last for long. Eventually, beta cells experience damage and this leads to relative insulin deficiency. It is a vicious cycle, until everything breaks down in the end leading to overtly high blood glucose levels. [4-7, 13]
Diabetes doesn't stop here. With such profound metabolic consequences, it can lead to a wide variety of complications, including stroke, coronary heart disease, lower limb ulceration and eye changes (diabetic retinopathy). Its systemic nature demands sincere medical attention and regular follow-up of the diabetic patient after diagnosis to make sure their condition does not get worse through time.
Using Insulin
Insulin is the first-line treatment for patients with Type 1 diabetes, since right on the outset, the beta cells are damaged. There is no way (unless you're talking about very imaginative ways such as stem cell regeneration) that the body can make enough insulin anymore. However, for type 2 diabetes, there are many more classes of drugs since insulin resistance is the foremost mechanism, not insulin deficiency. One key example is metformin, which operates by lowering blood glucose levels through decreasing absorption by the intestine (into the bloodstream) and the conversion of glycogen into glucose by the liver. Moreover, metformin improves insulin sensitivity - an attempt to recovery some of the charm it has lost. Other drugs aim at improving the situation by increasing the release of insulin from beta cells, such as sulphonylureas, incretin mimetics (stimulating a substance called GLP-1 which promotes the release of insulin) and DPP-4 antagonists/inhibitors (whereby DPP-4 is a substance which reduces the concentration of incretin). [8-10]
In certain patients, however, the diabetes is said to be 'uncontrolled'. Therefore, desperate times call for desperate measures. Insulin has to be injected to effectively control the situation. There are different types of insulin formulations, each bearing different action times, thus necessitating variant administration regimes. They can be summarised by the figures below.
Diagram showing the durations of action of multiple categories of insulin (extracted from: https://i0.wp.com/images-prod.healthline.com/hlcmsresource/images/topic_centers/2019-3/11371-types-of-insulin-1296x960-body.jpg?w=1155&h=2016)
Table showing different types of insulin formulations (extracted from Medscape) (Note that Insulin Lente is no longer available to humans and NPH Insulin is preferred) (elaborating on the table, Insulin Glargine is a long-acting insulin; NPH Insulin is an intermediate-acting insulin; Regular Insulin is also known as Humulin, where it is extracted from humans; Insulin Lispro is a rapid-acting insulin; Not mentioned above, Insulin Aspart is also rapid-acting)
There are several major adverse events associated with the subcutaneous administration of insulin in subjects with uncontrolled diabetes mellitus. These will be elaborated as we scrutinise the NEJM Study on the new type of insulin formulation (the one which only requires the patient to inject it once a week). However, to give an overview, insulin use can lead to the rise of hypoglycaemic events. Insulin can be overly effective and if the user does not observe timings as well as they should, it can lead to an increase in insulin action - thus, body cells absorb glucose from blood and liver cells convert more glucose into glycogen at greater rates. The glucose level in blood drops very quickly, leading to symptoms such as dizziness, anxiety and agitation. Patients may also present with sweating and tremors. There is also an established association, as reported by American Diabetes Association, between hypoglycaemia and seizures. [11] Furthermore, a condition called lipodystrophy can occur upon subcutaneous injection of insulin. Lipodystrophy, when broken down, means the aberration in adipose tissue structure. There are two variants involved - lipoatrophy and lipohypertrophy. In short, atrophy means regression and diminished structure, while hypertrophy is the opposite - cells growing bigger and bigger.** This has severe ramifications. Apart from bruising which might arise simultaneously, there is also reduced uptake of insulin. Less insulin takes effect in the body if the subcutaneous tissue experiences setbacks. Therefore, one's glycaemic control (the fancy term for the control of levels of blood glucose) is impaired. It is advised that patients inject insulin at different sites, rather than do so at the same location repeatedly.
What does the NEJM Study say?
[1] As mentioned earlier, it's saying that there's a new insulin formulation (Insulin Icodec) that requires patients to administer it once weekly rather than, per current protocol, once daily. This is expected to reduce the number of injections per year from 365 to 52. It is a double-blind, randomised-controlled trial, currently at phase 2 (meaning that they're testing on patients and checking the efficacy of the drug) which covers a total of 33 weeks (2 weeks: screening; 26 weeks: treatment, 5 weeks: follow-up).
Two Groups: (1) Once-weekly dose of Insulin Icodec and placebo*** (once-daily), (2) Once-daily dose of Insulin Glargine and placebo (once-weekly).
Selection Criteria:
Age Range: 18-75 years;
Diabetes Diagnosis made at least 180 days prior (meaning that it is a sustained issue and reflects current clinical practice for diabetes type 2, where metformin and other drugs are trialled before considering insulin injections);
Not previously done insulin injections;
Receiving metformin with or without DPP-4 inhibitor (as seen earlier, the latter is used for increasing the level of GLP-1, thus promoting the release of insulin);
HbA1C (glycated haemoglobin, long-term measure of diabetes mellitus): 7.0 to 9.5 per cent; normal individuals have a measure of lower than 6 per cent. Diabetic patients usually have a percentage exceeding 6.5.
Outcomes:
There are two categories of outcomes, as with every clinical trial- the primary outcome as the main measure to be evaluated, and the secondary outcomes which are ancillary correlations and goals pertinent to the study.
Primary Outcome: Change in HbA1C from start to finish of the treatment period (26 weeks) and between-group differences in this change;
Secondary Outcomes:
Change in fasting blood glucose levels (reflective of short-term changes as relative to HbA1C);
Body Weight;
Mean of 9-point patient-measured blood glucose level (to demonstrate the effects of the drugs throughout the day);
Mean of weekly insulin dose (in the final two weeks of the 26-week treatment period);
The amount of time where the optimal range of blood glucose level is met (i.e. 3.9-7.8 mmol/L) (associated with better clinical outcomes the longer the time) - however, this remains exploratory as only patients where flash glucose monitoring can be done are included.
Safety Outcomes:
These are in place in assessment of adverse events associated with the use of the insulin formulation in question. If the new formulation led to significantly more side effects, then we would hesitate in introducing it to the patient population since it would contravene with our maxim 'do no harm' - rather use a safer drug than a more aggressive one.
Total numbers of any, serious and severe adverse events;
Injection-site events;
Hypersensitivity events (allergies);
Hypoglycaemic events - any (grades 1-3), clinically significant (grade 2) or severe, and severe (grade 3).
Grade 1 hypoglycaemic events are those where the blood glucose level is between 3.0 and 3.9 mmol/L. Clinically significant hypoglycaemic events are defined as those where, as confirmed by measurement, the patient's blood glucose drops to below 3.0 mmol/L. Severe hypoglycaemia is judged by the emergence of cognitive dysfunction, such as confusion.
Results and Discussion:
Graphs showing comparisons between Insulin Icodec and Insulin Glargine by various parameters during the treatment period [1].
Table showing demographic features of the cohort [1].
Comments on anthropometric factors of the cohort:
The cohort remains relatively small: 125 in Insulin Icodec subgroup and 122 in Insulin Glargine subgroup. Larger, randomised-controlled trials performed preferably in multiple centres are required to verify the results produced in this study;
There is considerable disparity in the duration of diabetes - as evidenced by the wide standard deviations. This can be attributed to the recruitment criteria, where chronic diabetes is not essentially required (although only those with a minimum period of 180-days of diabetic history fall within the criteria);
The majority of patients are obese, as evidenced by the mean BMI across both subgroups (thus also the total);
Around 1/5 of the cohort have experienced complications associated with diabetes mellitus, indicating that their disease might be poorly controlled. Microvascular complications assume the majority of such complications across both subgroups.
Comments on Results:
Insulin Glargine and Insulin Icodec both exhibit the same degrees of decrease in HbA1C for the first four weeks, before the rift becomes bigger and bigger. Insulin Icodec reports greater change in HbA1C until the difference stabilises in 20-26 weeks. The resultant HbA1C after administration of Insulin Icodec is lower (6.69% as compared to 6.87%);
Over 2/3 of both subgroups have met their HbA1C targets after the treatment period, with the group of Insulin Icodec reporting a slightly higher percentage (72% as compared to 68%);
Both subgroups report similar blood glucose concentrations throughout the day, although the group taking Insulin Icodec have consistently lower blood glucose concentration. The difference is minimised from 4 am to breakfast next morning;
Insulin dose remains the same for both subgroups until the 4th week, where the differences start to become obvious. The weekly dose of the Insulin Icodec subgroup is consistently lower than its counterpart afterwards.
Reduction in fasting blood glucose is greater (difference: -3.9) in Insulin Icodec subgroup than Insulin Glargine subgroup;
Insulin Icodec subgroup also reports greater reduction in mean 9-point patient-measured blood glucose level, lower body weight and greater percentage of time where the target, normal blood glucose range is met.
There are more adverse events in Insulin Icodec subgroup than Insulin Glargine subgroup, although the difference is minimal (respectively 229 vs 158 events); However, the latter experiences more severe and serious adverse events;
In terms of hypoglycaemic events, Insulin Icodec subgroup presents with higher percentage of afflicted patients in all grades of hypoglycaemia. The differences are also remarkable: 368 vs 148 events (Insulin Icodec vs Insulin Glargine) for any hypoglycaemic event and 38 vs 32 clinically significant or severe events.
In light of the results, it is very hard to suggest anything other than that Insulin Icodec presents us with a wonderful opportunity. It is a new insulin formulation which has a significantly longer acting duration and half-life, necessitating only a once-weekly regimen rather than a once-daily regimen as dictated by current best practice guidelines. All parameters suggest that Insulin Icodec perform as good as Insulin Glargine at least, outperforming it in many areas. The one worrying part of the picture is the number of hypoglycaemic events experienced by Insulin Icodec subgroup. Such significant differences suggest that further trials are necessary to see if this can be replicated in other centres and larger patient populations. If so, then appropriate ways of management and follow-up are required, such as more frequent home blood-glucose monitoring by the patient and the prompt intake of carbohydrates to rectify the situation. This being said, where the frequency of insulin administration is decreased, the risk of lipodystrophy correspondingly falls. This reduces the risk of impaired insulin uptake. Moreover, in a world where convenience is valued more than ever, I ardently believe Insulin Icodec can be a game-changer in the management of diabetes. It creates an incentive to tackle this morbid illness greater than ever.
*There are two types of diabetes - diabetes mellitus and diabetes insipidus. The former points towards a blood sugar problem, where the latter, a problem with the waterworks (regulating water excretion). I wish to clear this up before I proceed. For purposes of simplicity, I'll refer to diabetes mellitus as only 'diabetes' in this article.
**A distinction should be drawn between hypertrophy and hyperplasia. Hypertrophy refers to the increase in cell volume and size, while hyperplasia, cell number.
***Placebo is often called 'sugar pill', meaning that it has no demonstrable clinical effect. However, it's crucial in randomised controlled trials since it demonstrates the psychological effects of pill-taking and how this affects the disease course. The gross effect of the new drug is deduced from removing the placebo effect from its calculated effect.
[1] Rosenstock J, Bajaj H, Janež A, et al. (2020). Once-Weekly Insulin for Type 2 Diabetes without Previous Insulin Treatment. New England Journal Of Medicine, 383(22), 2107-2116. https://doi.org/10.1056/nejmoa2022474.
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[3] Piro S, Urbano F, Folli F, Finzi G, Marselli L, Marchetti P. (2018) The Endocrine Pancreas. In: Belfiore A, LeRoith D. (eds) Principles of Endocrinology and Hormone Action. Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-319-44675-2_31.
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[7] Yki-Järvinen H. (2011). Pathophysiology of type 2 diabetes mellitus. Oxford Textbook Of Endocrinology And Diabetes, 1740-1748. https://doi.org/10.1093/med/9780199235292.003.1336.
[8] Diabetes treatments. Diabetes UK. (2020). Retrieved 29 November 2020, from https://www.diabetes.org.uk/diabetes-the-basics/diabetes-treatments.
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[11] Brennan M, Whitehouse F. (2012). Case Study: Seizures and Hypoglycemia. Clinical Diabetes, 30(1), 23-24. https://doi.org/10.2337/diaclin.30.1.23.
[12] Gentile S, Strollo F, Ceriello A, & AMD-OSDI Injection Technique Study Group (2016). Lipodystrophy in Insulin-Treated Subjects and Other Injection-Site Skin Reactions: Are We Sure Everything is Clear?. Diabetes therapy : research, treatment and education of diabetes and related disorders, 7(3), 401–409. https://doi.org/10.1007/s13300-016-0187-6.
[13] Holden SE, Barnett AH, Peters JR, et al. (2013), The incidence of type 2 diabetes in the United Kingdom from 1991 to 2010. Diabetes Obes Metab, 15: 844-852. https://doi.org/10.1111/dom.12123.
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