A few days ago the results of a potentially game-changing trial on the treatment of type 2 diabetes and cardiovascular disease (EMPA-REG OUTCOME trial) were presented at an international diabetes conference in Stockholm, Sweden and simultaneously published in the New England Journal of Medicine (1). For the first time, a study has found that a drug that lowers blood sugar (glucose) also appears to reduce the risk of death thereby improving survival.
I must admit that I’ve always found it a bit difficult to understand why we treat type 2 diabetes like we do. Of course, I’m not a diabetologist and therefore probably have a somewhat limited understanding of the disease. However, as a cardiologist I see a large number of people with diabetes, type 2 diabetes in particular.
Cardiologists use drugs to treat high blood pressure because randomized controlled trials have shown that such treatment lowers mortality and reduces the risk of future cardiovascular events. For the same reason, patients with established cardiovascular disease are treated with statin drugs and patients with congestive heart failure are treated with ACE – inhibitors and beta blockers.
Having type 2 diabetes increases the risk of cardiovascular disease. However, although we constantly treat patients with the disease with glucose-lowering drugs, it has not been convincingly shown that such treatment reduces the risk of cardiovascular disease or death.
So why do we treat type 2 diabetics with glucose-lowering agents if it isn’t proved that they improve prognosis or reduce the risk of complications?
And, another thing; Why do we recommend high carbohydrate diets to type 2 diabetics if the aim is to lower blood sugar? All of us know that carbohydrates are just chains of sugar molecules.
So, is there a paradigm shift in the treatment of type 2 diabetes? How does the recently published EMPA-REG OUTCOME trial change our approach to the disease?
For those not very well acquainted with the issue, I just want to recapitulate shortly the difference between type 1 and type 2 diabetes as these are two separate diseases that are approached and treated quite differently.
Type 1 vs. Type 2 Diabetes
Type 1 diabetes used to be called juvenile onset or insulin-dependent diabetes because it often presents in childhood and it is characterized by the inability of the pancreas to produce the insulin.
Insulin is necessary for the cells of the body to be able to utilize glucose for energy production. Without insulin, glucose accumulates in the blood leading to hyperglycemia. Due to the absence of insulin, patients with type 1 diabetes need to be treated with insulin.
Conversely, type 2 diabetes, formerly called adult-onset or non-insulin-dependent diabetes, can occur at any age. Although it is most common among adults, the prevalence is rising among children.
Type 2 diabetes is characterized by insulin resistance. Insulin resistance is defined as a diminished response to a given concentration of insulin. Initially, the pancreas responds by producing more insulin. For this reason, people with insulin resistance often have high blood levels of insulin. However, as diabetes develops, the beta cells of the pancreas often become unable to produce more insulin and its blood levels drop.
Type 2 diabetes is commonly associated with obesity or the metabolic syndrome. Many patients with the disorder also have high blood pressure and lipid abnormalities.
Worldwide, approximately 90% of people with diabetes have type 2 diabetes.
The EMPA-REG OUTCOME Trial
Empagliflozin is a selective inhibitor of sodium glucose transporter 2. The drug lowers blood glucose by decreasing the reabsorption of glucose in the kidneys, thereby increasing urinary glucose excretion. Sounds quite simple; lowering blood glucose by throwing out excess glucose with the urine.
The EPMG-REG Outcome Trial was a phase III, international, multicenter, randomized, parallel group, double-blind cardiovascular safety study of empagliflozin, given at an oral dose of 10 mg/day or 25 mg/day compared to the best usual care in patients with type 2 diabetes who were at increased cardiovascular risk due to the presence of established cardiovascular disease. The study was done at 590 sites in 42 countries across six continents and involved more than 7,000 patients observed over a median of 3.1 years.
The study found that cardiovascular death, hospitalizations for heart failure, and all-cause mortality were all reduced by more than a third (relative risk reductions of 38%, 35% and 32% respectively).
The number of patients needed to be treated (NNT) with empagliflozin for 3 years to prevent one cardiovascular death was 39 which is quite impressive compared with many other commonly used drug interventions in cardiovascular medicine.
Is It About Sugar In and Sugar Out or Something Else
Of course, the results of the EPMG-REG Outcome Trial raise some questions.
The first thing that comes to mind is whether the effect of the drug is due to its glucose-lowering effect. If a drug works because it lets patients urinate excess sugar molecules one could assume that putting less sugar into the system, by reducing carbohydrate intake, would be just as beneficial.
Interestingly this may remind us of the discussion with statin drugs. Initially, we believed they worked because they lowered blood cholesterol, LDL cholesterol in particular, but then it later turned out that statins have several other effects that may explain why they are beneficial for people with cardiovascular disease.
Interestingly, empagliflozin may induce weight loss, lower blood pressure, reduce arterial stiffness and visceral obesity. All these effects may potentially explain why the drug is beneficial for patients with type 2 diabetes and cardiovascular disease. So, possibly, the reason the drug works has nothing to do with blood sugar whatsoever.
It is of interest to look at the subgroup analyses from the New England paper. Keep in mind that such analyses are sensitive and should be interpreted carefully.
For example, there was not a statistical difference in the primary endpoint between empagliflozin and placebo among patients with glycated hemoglobin > 8.5% but only among these with levels < 8.5%. Similarly, there was no treatment effect in those with body mass index (BMI) > 30 and only those with BMI < 30.
Interestingly, empagliflozin was associated with small increases in both LDL cholesterol and HDL cholesterol. Thus, lowering of LDL cholesterol does not explain the efficacy of the drug.
The Bottom Line
The EPMG-REG Outcome Trial shows for the first time that a glucose-lowering drug given to patients with type 2 diabetes and established cardiovascular disease may improve prognosis and reduce the risk of death.
Whether the positive effect of the drug is due to its glucose-lowering effect or other mechanisms is still a matter of debate.
The authors believe that the mechanisms behind the cardiovascular benefits of empagliflozin are multidimensional and may involve its glucose-lowering effect as well as changes in arterial stiffness, cardiac function and oxygen demand, protective effects on kidney function and positive effects on body weight, visceral adiposity, and blood pressure.
But, still, I can’t help thinking that putting less sugar into the system by reducing carbohydrate intake might have some of the benefits as has increasing its urinary excretion with a drug.