Several Types of Diabetes
Diabetes is, in fact, two different diseases, both characterized by improper management of blood sugar levels and problems with the insulin hormone regulating it.
Insulin works by letting the sugar in the blood enter the cells. When functioning properly, insulin production controls and modulates blood sugar.
Source: Warner Orthopedics
Classic symptoms of diabetes include weight loss, blurred vision, and what are often referred to as the ‘4 Ps of Diabetes”. These include,
- Polyuria (excessive urination)
- Polydipsia (excessive thirst)
- Polyphagia (excessive hunger)
- Polyneuropathy (nerve damage)
If left untreated, diabetes can cause cardiovascular problems, as well as damage to the kidney, eyes, nerves, hearing, and foot (including up to requiring amputation). Untreated or poorly treated diabetes accounts for approximately 1.5 million deaths every year. And that’s despite the quality of care and drugs for diabetes to have progressed over the years.
Type-1 Diabetes
Type-1 diabetes is the consequence of the immune system attacking the pancreas, the cells producing insulin. Before the production of insulin by the pharmaceutical industry (first from animals, then from modified bacteria), this was a 100% deadly disease, mostly affecting children.
Source: Diabetologia
As for many auto-immune diseases, the root causes of the disease are not fully known, with genetic factors playing a role, as well as possibly diet, viral infection, and environmental causes. While some lifestyle changes might help, there is no foolproof way to prevent type-1 diabetes.
Source: Danii
Type-1 diabetes affects around 9 million people, most of them in high-income countries, with 2 million in the USA alone.
Type-2 Diabetes
Type-2 diabetes is the consequence of the body’s cells becoming irresponsive to insulin. So, contrary to type-1 diabetes, insulin is still produced by the body but progressively loses its potency. For this reason, it is also called insulin-resistant diabetes.
Source: Danii
While genetics and ethnicity seem to be risk factors, the recent rise in type-2 diabetes is mostly linked to changes in the population’s lifestyle, with excessive consumption of sugar, tobacco, obesity, lack of physical activity, and high blood pressure as major risk factors.
Almost 37 million Americans are type-2 diabetics with 1.2 million new cases per year, and the disease affects 537 million adults in the world, or 10.5% of the adult population. The disease has progressed quickly in recent years, with case growth correlating with economic development and changes in diet.
Source: IDF
Gestational Diabetes
A third type of diabetes, known as gestational diabetes, is induced by pregnancy and tends to be temporary, resulting from the associated hormonal changes.
So, while commonly temporary, it is nonetheless a serious condition that can lead to severe complications for both the mother and baby if untreated.
For this reason, early detection of potential gestational diabetes and monitoring of blood sugar during pregnancy by a medical professional is extremely important.
Curing Diabetes?
Because they are ultimately different diseases, although with similar symptoms, treatments for type-1 and type-2 diabetes will differ, even if some treatment concepts might overlap.
A type-1 diabetes cure would require repairing normal insulin production and either avoiding new auto-immune damages or protecting the new production from the immune system. Meanwhile, a type-2 diabetes cure would need to cancel the insulin resistance in some way.
Better Insulin Chemistry
Insulin is the hormone regulating blood sugar, and while not always a perfect solution, it is still one of the most common therapies prescribed to diabetic patients.
The first insulin commercialized was extracted from the pancreas of an animal. The first treatment was done in 1922 on a 14-year-old boy dying from diabetes, saved in less than 24 hours. The Nobel Prize of Medicine would be given to insulin discoverers in 1923.
Shortage in production, unstable concentration, and impurity risks made the pharmaceutical industry switch to insulin produced by genetically modified bacteria as soon as the technology was commercialized in 1982, kick-starting the birth of the biotech industry.
Since then, many reformulations of basic insulin have been done to help modulate the potency and duration of its effects. This can be done by changing some part of the amino acid chain of the insulin protein or even using a 14-carbon fatty acid chain in the case of insulin detemir.
Source: Healthline
In the future, even more advanced forms of insulin, like, for example, once-weekly insulins, ultrastable insulin (not requiring cold chain), or even monthly insulin treatment (“GELA”- in phase 2 of clinical trials at Novo Nordisk & GE Healthcare)
Better Diabetes Management Devices
For now, insulin is commonly delivered through injection or other medical devices. Blood sugar is monitored through dedicated devices requiring the cumbersome sample of a drop of blood from a patient’s finger.
Source: Healthline
This could change soon. For example, we discussed how insulin could become as easy to take as a pill, and which company might manufacture it in “Insulin-Dependent Diabetics May Soon Benefit From Oral Delivery of Medication”.
Glucometers are also expensive devices, usable only for this specific function. Researchers found that the magnetometer already integrated into smartphones could be repurposed into a glucometer at low costs, as we explored in “In Need of a Glucometer? Your Phone May Soon Be the Solution”.
We also discuss the possibility of glucose monitors being powered with batteries using blood sugar itself in “Could Internal Batteries Power Next-Gen Wearables and Even Battle Cancer?”
In the long run, Artificial Pancreas Systems (APS) could be bionic implants fully replacing both the insulin production role of the pancreas and insulin injections, with smart patches with micro-needles and monitoring blood sugar levels as an intermediary option.
Diabetes Drugs
Currently Approved Drugs
Beyond insulin, many drugs can be taken to reduce the severity of diabetes or even try to prevent it. Most diabetes drugs are designed for type-2 diabetes, both the most common type and also the one for which insulin injections are often insufficient.
- Alpha-Glucosidase Inhibitors: This class of drugs blocks the intestines from breaking down starch (a main component of grains) into sugar, reducing the rise of blood sugar from food.
- Biguanides & Thiazolidinediones : this class includes metformin, a common diabetes drug. It reduces the amount of sugar released into the blood by the liver, and also helps muscles absorb glucose, both effects resulting in lower blood sugar levels.
- Bile acid sequestrants (BASs): mostly a cholesterol drug, it also reduces sugar through a still unclear mechanism.
- Meglitinides & Sulfonylureas: they stimulate the release of insulin by the pancreas (obviously not a drug useful for type-1 diabetes).
- SGLT2 inhibitors: this class increases the evacuation of glucose via the kidney in the urine.
- Dopamine-2 agonists: a Parkinson’s disease drug, it has also been shown to reduce blood sugar and reset the circadian rhythm.
- DPP-4 inhibitors/gliptins: this drug class increases the lifespan of GLP-1, a naturally produced hormone regulating blood sugar.
- GLP-1 Agonists: these drugs activate the receptors sensitive to GLP-1. Recently they have gained a reputation as a “miracle drug” against obesity and for weight loss after approval by the FDA for this application, with a massive commercial success we discussed in “The New Blockbuster Drug: Wegovy”.
All of these drugs mostly worked by trying to force the body to ignore insulin resistance or modify blood sugar levels despite the insulin resistance. However, one drug in particular deserves its own section: Tzield (Teplizumab), a monoclonal antibody.
What makes it remarkable is that this drug approved in 2022 might help delay or prevent stage 3 of type-1 diabetes (when damage to the pancreas becomes severe). Tzield was developed by Provention Bio, which was acquired by Sanofi for $2.9B in March 2023.
Other similar treatments are in development, notably from Novo Nordisk, with DNA immunotherapy to preserve the function of pancreas cells.
While not solving the underlying problem, some drugs can help limit the damage caused by diabetes. For example, a drug targeting the S100A9 molecule in the body can reduce the risk of dangerous ketogenesis.
Drugs that reduce the risks of heart attack or damage to other organs can also help.
Anti-Obesity drugs
Because type-2 diabetes is tightly linked to metabolic syndrome and obesity, reducing this factor could have a large impact on diabetes as well.
GLP-1 agonists and other related drugs seem to have a strong impact on obesity but also got later on an indication for reducing cardiovascular risks. So it is not yet confirmed, but they might one day help manage diabetes directly, especially with furthermore advanced iterations of the GLP-1-focused therapies
Gene Therapy
Type-1 Diabetes
The first target for gene therapy to end diabetes is type-1 diabetes. The ideas are varied, ranging from protecting the pancreas’ cells in the first place (preventive treatment) to curing this type of diabetes by either regenerating the insulin production capacity and/or modulating the immune system activity.
A leading candidate for this technology is CRISPR Therapeutics, through collaboration with ViaCyte (purchased by Vertex in July 2022)
The idea is to gene edit stem cells, incorporate them in a medical device that will shield them from the immune system, and implant the device in the patient, re-creating the lost functions of the pancreas.
Source: CRISPR Therapeutics
Phase 1 of clinical trials of this drug started in February 2022. The relation between CRISPR Therapeutics and Vertex is a complex one, with the 2 companies already partners for the first ever approved gene editing therapy for rare blood disease.
In January 2024, Vertex “has chosen to opt out of the diabetes gene-edited stem cell therapy it gained through the acquisition of ViaCyte, leaving CRISPR to take the clinical-phase program forward itself”.
It is unclear what motivated this decision, and it has definitely through some cold water on investor enthusiasm for the company. Still, the strategy to recreate insulin production AND protect it from the immune system is probably the general right direction.
You can also read more in the systematic review titled “Gene Therapy – Can it Cure Type 1 Diabetes?” about other research efforts done to use gene editing to cure type-1 diabetes
Type-2 Diabetes
While less straightforward than “regrowing the missing cells,” gene editing can also be useful for treating insulin-resistance diabetes.
One possibility is, for example, to target the liver for gene therapy, by reducing the activity of the DPP-4 enzyme, already targeted by some drugs.
Another option is to target the PAX5 gene, which could restore normal PAX5 levels in individuals with type 2 diabetes. Many other genes are potential targets (more than 15 so far), as they have been linked to increased chances of developing type-2 diabetes.
Source: Biotechnology & Biotechnological Equipment
Diabetes Companies
1. CRISPR Therapeutics
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a recently discovered tool for genetic editing. It allows for very precise and directed gene editing, and its discoverers have won the 2020 Nobel Prize.
Source:
Source: Lab Associates
What sets CRISPR Therapeutics apart is the all-star team of founders, including Dr. Emmanuelle Charpentier, one of the co-discoverers of CRISPR-Cas9 technology.
CRISPR Therapeutics is developing an efficient and versatile CRISPR/Cas9 gene-editing platform for therapies to treat hemoglobinopathies, cancer, diabetes, and other diseases.
The first therapy that they were advancing was targeting the blood diseases β-thalassemia and sickle cell disease.
They have now been approved under the commercial name of Casgevy for both applications, making it the first-ever approved CRISPR gene therapy. Sickle cell and beta-thalassemia are major rare diseases, and the treatment comes with a $2.2M per therapy price tag.
In the long run, they are working on making this gene therapy doable in-vivo (instead of the current ex-vivo approach, requiring expensive and complex extraction of the patient marrow cells first).
Another major potential for CRISPR Therapeutics, although not about rare diseases, is in curing type-1 diabetes. We already discussed above and in more detail CRISPR Therapeutics’ gene therapy for this application
The company is also working on several other rare diseases, notably:
- Duchene’s Muscular Dystrophy (DMD): IND-enabling stage (Investigational New Drug)
- Acute hepatic porphyria: IND-enabling stage.
- Myotonic Dystrophy Type-1 (DM1): preclinical
- Cystic Fibrosis: Pre-clinical
- 2 other undisclosed rare disease programs.
The company’s first allogeneic CAR-T program targeting B-cell malignancies (cancer) is also in clinical trials.
You can also read more about CRISPR Therapeutic in our article “Gene Editing: CRISPR Therapeutics vs. Beam Therapeutics.”
Overall, despite the separation with Vertex regarding the diabetes program, CRISPR Therapeutics is still at the forefront of a potential cure for type-1 diabetes, making it a risky, but potentially very profitable biotech innovator.
2. Novo Nordisk A/S
Novo Nordisk is mostly known for its diabetes therapies, representing 79% of its current revenues.
It is a company we already covered in “Top 5 Blue Chip Pharmaceutical Companies”
Source: Novo Nordisk
A smaller part of its activity is obesity, with just 9% of sales. But an important part is the astonishing growth rate of 84% in 2022. This is entirely based on the launch of Wegovy, an injectable weight-loss medicine. Wegovy mimics a weight-related hormone called GLP-1 (glucagon-like peptide-1).
It had a stellar start, to the point where some manufacturing issues have led to a global drug shortage. The success of Wegovy has boosted Novo Nordisk’s sales growth expectation for 2023 from 13-19% to 24-30%, as the production is now high enough to satisfy demand.
In the US, they recruited US rapper Queen Latifah for a campaign about the stigma surrounding obesity treatments. The success is global, notably in China:
Young girls crowded into the endocrine and metabolism department of the hospital, regardless of whether they were thin or fat, just to get a dose of semaglutide.
In the doctor’s hospital, they only prescribed just over 100 doses of semaglutide in June, but now the number has risen to 1500-2000 doses, which is the average sales volume of semaglutide in most tertiary hospitals in Shanghai.
When Wegovy disappeared from inventory, the other Novo Nordisk treatment for type 2 diabetes drug Ozempic, using the same molecule, was often used as a substitute. Even Elon Musk referred to Wegovy as a way for him to lose unwanted weight.
The GLP-1-inspired drug has been a hit, even larger than Novo Nordisk expected. It might also be something that will need to be taken continuously to keep its benefit, making a long-term treatment and cash cow for Novo Nordisk.
“Using tirzepatide might be a lifetime decision.” Fierce Pharma – Dr. Dan Skovronsky, Eli Lilly’s chief scientific and medical officer,
It must nevertheless be emphasized that potential side effects are no joke, including thyroid cancer, pancreas inflammation, kidney problems, and gallstones. So it is highly recommended to get medical advice first and use it only for severe obesity, and NOT for small weight losses like the young Chinese girls mentioned above.
These issues are related to the whole metabolism, so competitors’ products will likely carry the same risks. This is something investors will want to keep in mind.
We discussed in detail the success of Wegovy in our articles “The New Blockbuster Drug: Wegovy” and what comes next in “Will Amycretin Be the Next Big Thing for Novo Nordisk?”.
When it comes to diabetes, Novo Nordisk is working on weekly and monthly insulins, better insulin pumps/implants, and DNA immunotherapy.
Novo Nordisk’s R&D pipeline also includes other diseases, notably MASH (metabolic dysfunction-associated steatohepatitis) with 4 candidate drugs.
A long-time leader in diabetes, Novo Nordisk’s history has been shaped by the improvement in diabetes therapies and the spread of the disease. It is now becoming an equally important company in treating the quickly growing obesity epidemic.
As a type-2 diabetes permanent cure seems out of reach for several years at the very least, it is likely that Novonordisk will keep benefiting strongly from obesity and diabetes, both brought by an increasingly sedentary lifestyle and unhealthy diets.
