For a disease that afflicts 460m people worldwide and kills over 4m every year, there have been relatively few pharmacologic innovations in the last two decades. In fact, the most reliable drug for lowering glucose levels in patients with Type 2 Diabetes and Prediabetes continues to be Metformin which has been around for nearly 4 decades in a synthetic form and for centuries as derived from French Lilac plants. So, it is only natural that when the news broke earlier in 2021 about the success of Semaglutide in achieving weight loss in patients, it was quickly branded as a “miracle” drug. Well, the truth for most patients might not be as miraculous as initially touted by pharma companies and a vast majority of patients are still better off making diet and lifestyle changes to reverse the root cause of their metabolic diseases naturally. Please note that this analysis is meant for informational purposes only and not as a recommendation for any drug or as a substitute for medical advice.
Let us dive in! There are 8 classes of glucose-lowering medications available for Diabetes. We will analyze these below and briefly touch upon bariatric surgery as an option for patients who are morbidly obese. The 8 classes of medications are (generic molecule names in brackets):
Alpha-glucosidase inhibitors (Acarbose)
Dipeptidyl Peptidase 4 Inhibitors (Linagliptin, Vildagliptin, Sitagliptin)
Sodium-Glucose Cotransporter 2 Inhibitors (Empagliflozin, Canagliflozin)
Glucagon-like Peptide 1 Agonists (Semaglutide, Liraglutide)
Biguanides (Metformin): Metformin works by blocking the production of hepatic glucose from glycogen and thus, bringing down the blood glucose levels. It causes minor improvement on insulin resistance as well. Metformin has been the first line of treatment for Type 2 Diabetes and Prediabetes for roughly 4 decades now and has a proven safety profile. It has also recently been shown to have anti-cancer and anti-ageing benefits. It does cause some gastrointestinal issues at high doses and so, needs to be dosed in stages. It is also reported to suppress mitochondrial activity in muscle tissues. Mitochondria are the cellular organelles which produce energy. Hence, their underactivity can cause fatigue and lack of motivation for heavy exercise. Given the points above, it likely only has moderate overall impact on lowering blood glucose levels and on reversing the insulin resistance. It is quite cheap and affordable.
Insulin: In Type 2 Diabetes patients, insulin injections bring down blood glucose levels by overcoming the insulin resistance in cells so they absorb more glucose from the blood stream, essentially mimicking endogenous insulin produced by the pancreas. Unfortunately, this means that the underlying root cause of insulin resistance does not get resolved. It just gets overpowered by the brute force of more exogenous insulin. In fact, with even more insulin in circulation, insulin resistance gets worse which is why patients regularly need to inject more and more insulin to maintain the same glucose levels. High insulin levels can cause cardiovascular disease even after maintaining glucose levels because of the arterial stiffness caused by blocking the production of Nitric Oxide. On high insulin doses, patients may escape the microvascular complications such as kidney, vision and nerve issues caused by high glucose levels, but they are likely to get more lethal macrovascular complications of the heart (heart attack, heart failure) and brain (strokes). It also causes weight gain by storing more energy in the form of fat. This is how Type 2 Diabetics start gaining even more weight as soon as they are put on insulin injections. This is not great for the patient’s health because weight loss is key for controlling diabetes. Insulin also causes increased appetite because it interferes with our satiety signaling in the brain by breaking the feedback loop of the satiety hormone Leptin. Therefore, patients on insulin experience increased hunger pangs which make their diet changes even more difficult. Insulin can also cause hypoglycemia, which can sometimes be quite serious. So, no wonder all medical association guidelines prescribe insulin only after most other pharmacologic options have been exhausted and all diet and lifestyle changes have been tried. Insulin is also expensive. It is an injectable and treatment adherence is often much lower than desired.
Sulfonylureas (Glimepiride): Sulfonylureas work by forcing the beta cells in our pancreas to produce more insulin. More insulin in circulation then works like how exogenous insulin works as explained above. Unfortunately, because of the similar mechanism as insulin, Sulfonylureas also suffer from the same drawbacks as exogenous Insulin.
Alpha-glucosidase inhibitors (Acarbose): These work by slowing the action of certain enzymes that break down starchy foods into simple carbohydrates, thereby delaying the digestion of carbohydrates and hence, slowing down glucose absorption and resulting in lower postprandial glucose levels in blood. Because of this mechanism of action, these are only effective when you eat and are known to bring down post-prandial glucose excursions. Because they blunt the glucose spikes, they also bring down the insulin levels and helps with reducing insulin resistance and in causing post meal glucose crashes. They are quite cheap and affordable, but they can cause some gastro-intestinal and other side-effects that patients should seek advice on.
Dipeptidyl Peptidase (DPP) 4 Inhibitors (Linagliptin, Vildagliptin, Sitagliptin): These are usually recommended as dual therapy with Metformin. They are part of incretin-based therapies which work by stimulating Glucagon-like peptide 1 secretion leading to insulin release. The other medications within this therapy class are GLP-1 Receptor Agonists (discussed below). For all-cause and cardiovascular mortality, SGLT2 inhibitors are considered to be the best, GLP-1 Receptor Agonists next, and DPP-4 inhibitors rank the lowest. DPP 4 inhibitors were associated with increased risk of acute pancreatitis. Costs have come down and are considered affordable for most patients due to the availability of generic versions.
Thiazolidiones (Pioglitazone): TZDs are known to improve insulin sensitivity by promoting glucose uptake in muscle tissue. TZDs and in particular pioglitazone have been shown to improve endothelial function in diabetes, thereby reducing atherosclerosis risks which are linked with cardiovascular diseases. Mechanisms of action are still not fully understood.
SGLT2 inhibitors (Empagliflozin, Canagliflozin): These work by stopping the reabsorption of glucose by the kidneys allowing excess glucose to be sent out of the body through urination. They are effective in bringing down both glucose and insulin levels and, hence, are a good drug from the perspective of improving insulin resistance. By reducing the insulin levels, they are known to also cause weight loss and are associated with additional cardiovascular benefits. But, they do require a certain level of kidney functioning as a prerequisite. Several Diabetes patients have nephropathy and may not be able to use these drugs. They can also cause genital infections such as fungal infections because of high glucose content in urine. So, strict hygiene must be maintained. Costs have come down but are still relatively high for most patients in emerging markets paying out-of-pocket.
GLP-1 Receptor Agonists (Semaglutide, Liraglutide): Coming to the so-called “miracle” weight loss drugs such as Semaglutide, these are also part of the incretin-based therapies and work by decreasing glucagon concentrations, improving insulin sensitivity and increasing satiety signaling in the brain. They are associated with significant weight loss in obese patients and thus improve their glucose levels. But they are also known to cause severe nausea and diarrhea to the extent that 50% patients stop taking the drug before they experience any positive effects. Wegovy (Semaglutide) will also come with a warning about potential thyroid cancer risks. At 0.5 to 1 mg, patients are likely to see clinically significant weight loss and glycemic improvements but, unfortunately, nearly half of the patients drop off at 0.25 mg dosage which is the initial dose just to check for side-effects. For the lucky few patients who can tolerate the side-effects at 0.5 mg and up, they can see 15% weight loss. But they will need to continue the drug for over 6 months to sometimes over a year for their body to adjust to a lower appetite level. These are also weekly injectables and that can also be a problem for some patients. Cost is the major impediment here at USD 1,350 (US prices) per month. So, it could cost over USD 15,000 a year which is clearly out of reach for most patients paying out of pocket. In fact, most insurance plans will likely not cover this drug.
Surgery: Surgery is often considered an option for patients who have tried all diet and lifestyle changes unsuccessfully and for whom other pharmacologic options are not working and are morbidly obese. It is known to cause rapid weight loss and reduction in glucose levels. But surgery is linked to complications in nearly 30% of the patients. Other side effects including recurring hunger pangs every hour because of tiny portion sizes due to reduced gastric size. Needless to mention, surgery is expensive and out of reach for a vast majority of patients.
In summary, none of the options above is a silver bullet for Type 2 Diabetes. There are good medications above which bring down glucose levels and insulin levels and thus reduce the risks of both microvascular and macrovascular complications and should be preferred over other medications. But diet and lifestyle changes to reverse the root cause of insulin resistance should always be the first step for every patient because medications can only go so far. Once again, please treat this article for information only and for assisting you with your discussion with your doctor.
Source: Based on discussions with doctors as well as the following research papers:
Mechanistic Links between Obesity, Insulin, and Cancer (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214048/)
Sugar, Uric Acid, and the Etiology of Diabetes and Obesity (https://diabetes.diabetesjournals.org/content/62/10/3307)
Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis (10.1001/jama.2018.3024)
Comparison of Clinical Outcomes and Adverse Events Associated with Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis
A review of thiazolidinediones and metformin in the treatment of type 2 diabetes with focus on cardiovascular complications