Statins and Diabetes – Time to Let the Cat out of the Bag

Cholesterol and Diabetes - Time to Let the Cat out of the BagRecently, concerns have been raised about the increased risk of diabetes associated with statin therapy.

However, it has been pointed out that the risk of diabetes is low in absolute terms and when compared with the reduction in cardiovascular events achieved by treatment. In other words, the potential benefits to health are believed to outweigh potential risks. Therefore, expert guidance regarding the use of statins in clinical practice has not changed.

But is this how clinical medicine should be practiced?

From a public health perspective a therapy that increases the risk of one disease at the same time as it reduces the risk of another, may be acceptable, assuming the net effect will be positive in terms of general health risks.

However, from the individual perspective the picture may be different. We may not be willing to accept treatment that might slightly reduce our risk of heart disease but could increase the risk of diabetes?

What if we’re not one of the lucky ones. What if we get diabetes and don’t benefit in terms of cardiovascular risk. It’s a gambling game.

Furthermore, we still don’t know why statins increase the risk of diabetes. There appears to be a complex interplay between cholesterol metabolism, insulin resistance, obesity and diabetes that needs further clarification.

In fact, two recent papers may have cast some light on these issues.

So much is at stake. Millions of people are taking statin drugs; many of them will not derive much benefit, and some will be harmed. It’s time to let the cat out of the bag.

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The Role of LDL Receptors

In 1985, Michael S. Brown and Joseph L. Goldstein were awarded the Nobel Prize in Physiology or Medicine for revolutionizing our knowledge about the regulation of cholesterol metabolism and the treatment of diseases resulting from elevated levels of blood cholesterol.

Brown and Goldstein found receptors on cell surfaces that mediate the uptake of low-density lipoprotein (LDL). LDL is the primary carrier of cholesterol in blood.

The liver plays a key role for the clearance of LDL from the blood stream. LDL receptors on the surface of liver cells bind LDL and remove it from the blood.

After binding to the LDL receptor, the LDL/LDL-receptor complex is moved to endosomes within the cells, where the LDL is released from the complex. The LDL receptor then moves back to the cell surface where it can bind to additional LDL particles. The free LDL left within the cells is transported to lysosomes and degraded into cholesterol ester droplets, free fatty acids, and amino acids.

Cholesterol and Diabetes. Letting the Cat out of the Bag
After binding to the LDL receptor, the LDL/LDL-receptor complex is moved to endosomes within the cells, where the LDL is released from the complex. The LDL receptor then moves back to the cell surface where it can bind to additional LDL particles. The free LDL left within the cells is transported to lysosomes and degraded into cholesterol ester droplets, free fatty acids, and amino acids.

Statins and LDL Receptors

Statin drugs have revolutionized the pharmacological treatment of cardiovascular disease. These drugs effectively lower the levels of LDL cholesterol in blood.

Today, statins are widely used to treat patients with cardiovascular disease and healthy people with high blood levels of LDL cholesterol or other measures of increased risk.

Statins inhibit an enzyme called HMG-CoA reductase. This enzyme converts HMG-CoA into mevalonic acid, a cholesterol precursor.

Inhibition of HMG-CoA reductase by statins impairs cholesterol synthesis by liver cells and reduces circulating levels of LDL cholesterol.

Furthermore, the reduction of cholesterol within cells drives an increase in the expression of LDL receptors. This is believed to be a key step for the lowering of blood levels of LDL cholesterol achieved by statin treatment.

Familial Hypercholestrolemia and Diabetes

Familial hypercholesterolemia is a dominantly inherited disease characterized by high plasma levels of LDL cholesterol. Patients with this disorder are at increased risk for premature cardiovascular disease (1).

Brown and Goldstein discovered that the underlying mechanism to hereditary familial hypercholesterolemia is a partial or complete lack of functional LDL receptors leading to decreased clearance of cholesterol from the circulation and higher levels of blood cholesterol.

Interestingly, this is exactly the opposite to the situation with statins where cellular uptake of cholesterol is improved due to increased availability of LDL-receptors.

A new observational study from the Netherlands studied the risk of diabetes among 25,000 patients with familial hypercholesterolemia and 38,000 unaffected relatives participating in a national screening program between 1994 and 2014 (2).

The study found that the prevalence of type 2 diabetes was significantly lower in patients with familial hypercholesterolemia than their unaffected relatives.

The investigators believe that cellular cholesterol uptake is a common pathway in familial hypercholesterolemia and statin-induced diabetes. They propose that intracellular cholesterol accumulation associated with increased LDL receptor availability may be detrimental to the beta cells of the pancreas.

Their conclusion is supported by findings showing that addition of LDL cholesterol to isolated rat islet beta cells resulted in cell death (3). Another study found decreased glucose-stimulated insulin secretion in rodent pancreatic islets that were incubated with LDL-cholesterol (4).

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Statins and Diabetes

A meta-analysis published 2010 that combined information from 13 individual studies (involving a total of 91,140 patients) showed that treating 255 patients with statins for four years led to one extra case of diabetes, whereas 5.4 cardiovascular events were prevented (5). Statin therapy was associated with a nine percent increased risk of diabetes.

Randomized clinical trials suggest that the risk of diabetes increases in a dose-dependent fashion (6).

Observational studies have also reported a higher risk of type 2 diabetes with statin treatment compared with individuals not taking statins (7).

8748152_sThe mechanisms by which statins increase the risk of diabetes is not entirely clear.

It has been suggested that statins may affect insulin secretion and insulin sensitivity. One study has shown that statins may increase body weight which may be important for the risk of diabetes (8) .

A recent Finnish study of men with metabolic syndrome suggests that the risk of statin-induced diabetes may be higher than previously reported (9).

In this study, the investigators studied the effects of statin treatment on blood sugar and the risk for type 2 diabetes in 8,749 nondiabetic men age 45 to 73 years in a 6-year follow-up of the population-based Metabolic Syndrome in Men (METSIM) trial, based in Kuopio, Finland.

The mechanisms of statin-induced diabetes were addressed by evaluating changes in insulin resistance and insulin secretion.

Statin treatment was associated with an increased risk for type 2 diabetes even after adjustment for age, body mass index, waist circumference, physical activity, smoking, alcohol intake, family history of diabetes, and beta-blocker and diuretic treatment The hazard ratio (HR) was 1.46.

Thus, statin therapy appears to increase the risk for type 2 diabetes by 46% in men with metabolic syndrome.

Statin therapy was also associated with a significant increase in fasting blood sugar. Furthermore, individuals taking statins had a 24% decrease in insulin sensitivity and a 12% reduction in insulin secretion compared with those not receiving the drugs.

These new findings may have several implications.

Firstly, the results suggest that previous studies may have underestimated the risk of statin-induced diabetes.

Secondly, the findings demonstrate for the first time that increased insulin resistance is one of the mechanisms leading to diabetes in people receiving statins.

Thirdly, statins were found to affect insulin secretion from the pancreas. The authors suggest that impaired ability of the beta cells of the pancreas to respond to increased insulin resistance may be an important mechanism underlying statin-induced diabetes.

The Bottom Line

The increased risk diabetes associated with statin therapy is a concern although expert guidance regarding the use of these drugs in clinical practice hasn’t changed.

Two recently published papers have added important pieces to our understanding of statin-induced diabetes.

A study from the Netherlands shows that the risk of diabetes among patients with familial hypercholesterolemia is lower than in the general population

The study adds support to the theory that the expression and function of LDL-receptors may be important for glucose metabolism.

Improving LDL receptor function by statins may increase the risk of diabetes because intracellular accumulation of cholesterol may harm the beta cells of the pancreas, limiting their ability to produce insulin.

The ongoing trials on the new PCSK9 inhibitors will hopefully clarify some of the questions regarding LDL receptor function, glucose metabolism, and diabetes.

A recent Finnish study suggests that statin-induced diabetes may be more common than previously reported. This assumption is based on findings from a large observational study of men with metabolic syndrome.

It is likely that the prevalence of diabetes among statin users varies according to the population being studied. Individuals with metabolic syndrome usually have insulin resistance and are at increased risk of developing diabetes. Thus, their risk of statin-induced diabetes might be higher than in the general population.

It is estimated that around 70 million people in the US have metabolic syndrome or about one-third of all adults in the country (10). Many of these individuals are receiving statin treatment due to lipid abnormalities and increased risk for cardiovascular disease.

The study findings suggest that impaired ability of the beta cells of the pancreas to respond to increased insulin resistance may be an important mechanism underlying statin-induced diabetes.

According to a recent JAMA editorial, the recent evidence on the relationship between statin therapy and diabetes risk should not alter guidance regarding the use of statins in patients with elevated cardiovascular risk (11).

The evidence for the use of statins in secondary prevention is strong. Results of randomized clinical trials show that these drugs reduce the risk of future cardiovascular events and lower mortality in people with established cardiovascular disease.

However, the recently observed association between statin use and diabetes risk underscores the lack of knowledge about a a class of drugs prescribed to millions of people worldwide.

In my opinion, until we know more, a conservative approach is warranted when it comes to the use of statins in for healthy individuals without established cardiovascular disease.

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