Recently Introduced Diabetes Medications Offer Additional Health Benefits

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By Mahnaz Mellati, MD

By Mahnaz Mellati, MD

The last decade has been very exciting in the world of diabetes care. As the result of much effort, time and money dedicated to research, many new diabetes medications have made it out to market. The medications can be grouped into two major new categories that have rather exotic chemical names: glucagon-like-peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors.

The GLPs include exenatide (Byetta® and Bydureon®), albiglutide (Tanzeum®), dulaglutide (Trulicity®), and liraglutide (Victoza®), while the SGLT-2s include canagliflozin (Invokana®), dapagliflozin (Farxiga®) and empagliflozin (Jardiance®). So why is there so much excitement surrounding the introduction of these drugs?

The GLP-1s lower blood sugar (and, delightedly, often also weight) through a few different mechanisms. GLP-1 is a hormone normally produced in the gut when we eat. The medication class mimics the work of the gut hormone, although in a more longlasting way. The medication decreases calorie intake by making you feel full faster by slowing how fast your stomach empties and through effects that we do not fully understand on the satiety (fullness) center of the brain. The medication class also helps the pancreas produce more insulin (a hormone that lowers blood sugar) but decreases glucagon, another hormone made in the pancreas. Less glucagon is important as glucagon can act against insulin. So, the less glucagon, the better the insulin action.

GLP-1 medication requires injection (with a pre-filled pen and a very small and short needle). There is ongoing research into making a pill form, but currently only the injectable versions are available. GLP-1s can cause some abdominal fullness, abdominal discomfort, or nausea when initially started and when the dose is increased from the baseline dosage, but these side effects, if present, usually decrease after a few days and can even go away completely.

More serious concerns are that GLP-1s can also increase the risk of pancreatitis, an inflammation of the pancreas which usually causes severe abdominal pain with nausea. Individuals with type 2 diabetes (the diabetes in which the insulin does not work as well as it should, plus less insulin being produced over time) are at higher risk of pancreatitis than individuals who do not have diabetes, even if they are not taking the GLP-1s, so it has been confusing to researchers as to whether it is the diabetes or the drug group that is at fault.

In rats and mice (but not monkeys or humans), there are receptors (areas of attachment) on thyroid cells for the GLP-1s. So, in rats and mice, GLP-1s have been shown to increase the risk of a rare type of thyroid cancer called medullary thyroid cancer. The GLP-1s have not been shown to cause this cancer in humans, but to be cautious, if there is any history in the family or personal history of having medullary thyroid cancer, it is recommended this drug class not be used.

SGLT2 inhibitors work through effects on the kidneys. SGLT2s removes sugar from the body via urine. This results in less sugar in your blood and body. Often there is also a bit of weight loss from the loss of the sugar calories in the urine, but there is also a water loss with the elimination of sugar through the kidney, so the medication also has an effect on lowering blood pressure.

Potential side effects most commonly come from the increased sugar in the urine, specifically creating a more hospitable environment for bacteria and yeast infections of the urinary tract and genital areas. If you have any symptoms such as pain or burning sensation at the time of urination or in the genital area, or feel like you have to urinate more frequently than usual or cannot hold your urine, it is recommended you contact your healthcare team.

Another potential side effect of SGLT-2s that has come to attention over the past few years is ketoacidosis. Ketoacidosis is a very serious complication of diabetes typically seen in patients with very high blood sugars. With the SGLT-2s, the diagnosis can be confused by blood sugar levels that are not high. Ketoacidosis symptoms usually include nausea and vomiting, so it is recommended that if you are taking an SGLT-2 and feel sick or nauseated, or become in any way dehydrated, check for ketones in your urine. And if they are present when you test for the ketones, call your healthcare team immediately!

A major question about all these medications is whether they offer other benefits beyond controlling blood sugar, such as positively affecting the heart or kidneys? For example, could they decrease the risk of heart attack or kidney damage in ways that might not be directly connected to blood sugar control? Some recent and very exciting studies suggest this is the case.

An FDA-mandated cardiovascular safety study called LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long-Term Evaluation) compared the use of liraglutide (Victoza) versus no liraglutide in participants with diabetes, evaluating the drug’s ability to lower death from heart and other blood vessel disease causes. Over 9,000 individuals with diabetes and documented heart disease or at high risk for heart disease were involved with the study and were followed by researchers for about four years. Results showed that those taking liraglutide had less overall death from cardiovascular causes and fewer non-fatal heart attacks, non-fatal strokes, coronary surgery and hospitalizations for unstable angina (a type of chest pain caused by reduced blood flow to the heart) or heart failure. Also, less kidney disease progression was seen in those taking liraglutide. Participants taking liraglutide did report more nausea and abdominal symptoms, but interestingly also had a lower incidence of pancreatitis.

In a similar study using semaglutide (another GLP-1 awaiting FDA approval at this time), benefits again were seen. This study showed less death from all causes, as well as fewer hospitalizations for unstable angina or heart failure in those participants using the drug. Additional benefit was seen in less diabetes-related eye damage and less kidney disease.

Data also have been collected on the SGLT-2s. From a study of over 7,000 participants with type 2 diabetes who were at high risk of developing cardiovascular diseases, and who were given either empagliflozin or a placebo, empagliflozin was associated with lower death due to cardiovascular causes, non-fatal heart attacks and non-fatal strokes. Participants who took the empagliflozin were also less likely to be hospitalized for heart failure. And kidney function, followed over the course of three-and-a-half years, was better in those receiving empagliflozin. However, and not surprisingly, genital infections were more common in those taking empagliflozin.

In summary, two relatively new groups of diabetes medications, GLP-1s and SGLT-2 s, have now been shown to have beneficial health effects beyond controlling blood glucose. They can help weight control, blood pressure, can positively impact the development of heart and blood vessel disease and, depending on the specific agent, can even lead to fewer eye and kidney diabetes-associated complications!