Statins are one of the most frequently prescribed medications in the world to treat conditions related to high blood cholesterol level, high triglyceride level, high level of low-density lipoprotein (LDL) and low level of high-density lipoprotein (HDL), all of which are linked to an increased mortality rate among people. There are a few conditions that can be caused by the biochemical changes stated earlier but most of them contribute to an increased in cardiovascular incidents if left untreated. When my mom was still alive, she was prescribed with a cocktail of medications tailored to her heart condition along with a prescription of statin as a precautionary measure, in case her blood cholesterol level shoot up high. I'm not entirely sure whether the prescription of statins in patients with a normal reading of blood cholesterol was appropriate or not but in my opinion, it is not. There are a few reasons for that and one of them is, most of the patients are not educated enough to determine (by themselves) when to or not to take statins. Eventually, most of the time, these patients will gobble up everything that is prescribed to them by their doctors for the sake of recovering from whatever diseases they were diagnosed with, without even knowing the consequences that might have ensued if their blood cholesterol were to reduced below the normal parameter.
Sure, a few studies conducted in the past have concluded that a high reading of blood cholesterol is associated with high mortality rates but so does a low reading of blood cholesterol. Cholesterol is an essential component of cell membranes and has been the key substrate for the production of a few hormones that make up a healthy individual such as testosterone, oestrogen and a few adrenal hormones. Cholesterol is also important for fat digestion as it is one of the components of bile acids that are responsible for digesting fat to aid its absorption; in other words, cholesterol has its own merits but people can't seem to appreciate that. Apart from cholesterol, the level of low-density and high-density lipoprotein can also affect mortality and morbidity rates in some ways. People have been calling LDL the "bad cholesterol" and HDL the "good cholesterol" which could have stemmed from the fact that an increased in LDL level are associated with a high risk of getting an atherosclerotic-related cardiovascular complication. Nevertheless, both LDL and HDL act as an important "vehicle" for cholesterol to move about so that they can either be used by the cell or be excreted from it; LDL will be providing cells with cholesterol and if the level of cholesterol exceeded a certain reading, HDL will act as a cleanup crew, transporting "bad" cholesterol from various cells to the liver for excretion, thus being branded as the good cholesterol (more like good lipoprotein).
Statins are designed to disrupt the function of a specific enzyme called HMG-CoA reductase (rate-limiting enzyme) in the liver which is responsible for producing cholesterol. The words "rate-limiting" here means it will basically become the sole determinant for the rate of cholesterol production; either it will go faster, slower or stop altogether. When the level of cholesterol being produced decline, we can expect a reduction in the concentration of LDL as well; as the number of cholesterol available which require transportation reduces, there is no point in keeping the number of LDL up. HDL on the hand would have remained constant as the role of transporting bad cholesterol or any worn out cholesterol to the liver for excretion would never stop but some statins could increase the expression of HDL thus reducing their risk of getting cardiovascular-related diseases (Source). This can be due to the fact that HDL removes cholesterol and exhibits antioxidant and anti-inflammatory properties that could have been beneficial for patients' health.
How Statins Could Have Caused Diabetes?
Diabetes Mellitus (particularly the type II variant) is one of the most common chronic diseases among elderly people, globally. Currently, the incidence of childhood obesity is on the rise and if we let it be without proper interventions, they (children) would be diagnosed with diabetes before they can reach 30 years old. Although some variant of diabetes can be caused by autoimmune diseases or genetics, most of them were affected due to individualised sedentary lifestyles coupled with problematic eating habits (those are factors which can be controlled). The symptoms and consequences caused by diabetes might seem mild to others but it is actually a debilitating disease if we consider it in the long run. I can't seem to remember how many times did patient came to the Orthopaedic clinic and being counselled by their doctors regarding some options to treat diabetic foot ulcers which include amputation. What would you do if you were in the shoe of someone who tries to decide whether to or not to cut your own foot due to extensive, non-healing and probably infected wounds, all of which caused by poorly controlled diabetes? I'm sure it would be more difficult than it seems.
Even though statins have been proven to be the most effective medication in controlling and reducing atherosclerotic cardiovascular event, most of the patients (those who were taking statins) were predisposed to get diabetes mellitus in the long run. In a study called the JUPITER trial which was conducted in 2008, they found that the usage of statins (rosuvastatin) has been linked to a 25% chances of getting diabetes mellitus over the median period of 2 years. Previously there are some studies which suggested the possibility of statins to cause an increased risk of developing cancer but they found that people were more likely to get diabetes instead. It is quite baffling to think how medications which reduce "bad" cholesterol and exhibit anti-inflammatory properties could be causing diabetes. In the largest meta-analysis which has been conducted by Navarese et al in 2013 has found that, even though the risk of developing diabetes for each statin were quite different, the data were not statistically significant; it means, if we want to compare the risk of developing diabetes between patients who received a statin with the lowest risk possible to develop diabetes with patients who were receiving placebo, the risk is still significant.
There are a few theories which have been proposed to explain how statins could have caused diabetes. Even though a study conducted by Water DD et al in 2011 has found that most of the people who require statins presented with pre-diabetes features, which means the baseline taken might indicate patients are at a greater risk of developing diabetes even without statins, there are other studies which have proven that an intensive statin treatment could lead to a greater risk of developing diabetes even if patients were having a normal baseline (Preiss et al., Carter et al., Dormuth et al). The reduction of HMG-CoA Reductase activity was thought to disrupt the synthesis of a compound called ubiquinone (CoQ 10) which would lead to mitochondrial oxidative stresses, pancreatic beta-cell apoptosis and thus reduction in insulin secretion. Insulin has been an important hormone which acts as a key to allow the entry of glucose into the cell so that it can be used as an energy source. If the capability for a pancreas to produced insulin is compromised, the concentration of glucose remains in the blood would increase and trust me, glucose would do a lot of damage if they were allowed to interact with circulating proteins in the blood circulation.
Even though statins exhibit an anti-inflammatory property, according to a study conducted in 2014, in some condition, statins would be able to activate a protein called inflammasome which is usually involved in the activation of an inflammatory cascade, leading to insulin resistance caused by the action of interleukin-1β. The unusual interaction between inflammasome and statins could have been achieved by the presence of endotoxin possibly released by gut bacteria due to the alteration of the gut microbiome in people who are obese or people who have any related metabolic diseases. The effect of inflammasome activation can usually be compensated by producing lots of insulin so if statins could impaired insulin secretion by rendering pancreatic beta cell non-functional, it would cause a devastating effect towards patients' general well-being. However, it is worth noting that all of the mechanisms mentioned are highly theoretical. Some studies concluded that even though the incident of hyperglycemia among people who were taking statins are quite significant, the risk for them to develop diabetic-related complications is quite low. It's clear that more research is needed to study the exact mechanism of why people who were taking statins were having a hyperglycaemic episode while having a lower risk of developing microvascular complications. It's quite contradictory don't you think?
Doctors will still prescribe you with statins even if they were well-informed of the possible side effect that can be caused by the said, medication. It's understood that the benefits provided by statins outweigh the risk of developing diabetes in some patients. It's important for doctors to know when to prescribe and when they should not to. Regular monitoring should be imposed on patients who were taking statins and more importantly, patients should have been encouraged to live an active lifestyle instead of a sedentary one. It's good for the heart and certainly, it is a factor that could have prevented us from getting diabetes in the first place. Prevention is always the best alternative.
Sources
- The Healthy Geezer: All About Statins
- Statin-induced diabetes: incidence, mechanisms, and implications
- Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.
- Risk of incident diabetes among patients treated with statins: population based study.
- Higher potency statins and the risk of new diabetes: multicentre, observational study of administrative databases.
- Fluvastatin causes NLRP3 inflammasome-mediated adipose insulin resistance.
- Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
- Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database
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