Diabetes Meds Go Beyond Blood Sugar Control

For decades, treatment of diabetes was largely disconnected from the treatment of heart disease, even though a person with diabetes is twice as likely to die from cardiovascular causes as someone without diabetes.

Recently, though, the paradigm has shifted treatment. Gone are the days when diabetes drugs were judged simply on their ability to lower blood sugar. Glucose control is not unimportant, but today’s treatments for Type 2 diabetes, the most common variety by far, are expected to do much more, thanks to changes that forced the FDA to examine how diabetes drugs work.

These innovative drugs that launched within the past decade include sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, which are powerful on their own but typically work alongside familiar drugs, including insulin.

“While SGLT2 inhibitors have been in use for years, they are increasingly being used in combination with other anti-diabetic medications like metformin and/or dipeptidyl peptidase-4 (DPP-4) inhibitors,” says Matthew Sussman, vice president of modeling and strategy services at Panalgo (formerly Boston Health Economics), a health analytics company. “Additionally, innovations have been applied to GLP-1 receptor agonists, including one with an oral formulation — most others are injectable — and another for use in pediatric patients with (Type 2 diabetes).” The action hasn’t been limited to pharmaceuticals. Sussman also notes an increased focus on diet and exercise to reduce blood glucose.

Clinical trial results of several current therapies for Type 2 diabetes — including selected SGLT2 inhibitors and GLP-1 agonists — have found that the medications have a protective effect against cardiovascular disease.

For example, evidence for the clinical benefits of Jardiance (empagliflozin), an SGLT2 inhibitor, has shown that it is not only effective in treating Type 2 diabetes but also in protecting patients from future cardiovascular events.

Crisis begets opportunity

In 2006, GlaxoSmithKline’s Avandia (rosiglitazone maleate) was a blockbuster drug with annual sales of $2.5 billion. But the next year, results reported in the New England Journal of Medicine linked the drug to heart attacks, and Congress told the FDA to respond. Some scientists had long complained that pharma companies should be forced to study whether glucose-lowering drugs caused heart attacks, strokes or vascular problems. Just lowering blood sugar wasn’t enough, they argued.

The Avandia crisis gave scientists their chance. They convinced the FDA to require “cardiovascular outcomes trials,” which would take years and involve thousands of patients.

The pharma companies balked at the cost at first. But in 2015, their investment paid off. A randomized, placebo-controlled trial of Jardiance showed it had protective effects against cardiovascular disease. Companies with competing SGLT2 inhibitors then tweaked their study designs to see what their drugs could do against cardiovascular disease.

Evidence from trials of the GLP-1 receptor agonists showed that they were also cardiovascular-and-diabetes twofers.

Heart failure surprise

SGLT2 inhibitors work by targeting a receptor that normally causes the body to retain blood sugar. Evidence about how they might also be protective against cardiovascular
disease points in several directions. The possibilities include that they lower blood pressure, have anti-inflammatory effects and improve energy metabolism of heart tissue. After the positive results for Jardiance, studies of other SGLT2 inhibitors — namely, Invokana (canagliflozin) and Farxiga (dapagliflozin) — were also shown to treat diabetes and protect patients from future cardiovascular disease events.

The big (and pleasant) surprise has been that SGLT2 inhibitors can slow down heart failure and keep patients out of the hospital. This matters to health systems because they are judged on Medicare readmissions for heart failure under the ACA.

In addition to studying the cardiovascular benefits of SGLT2 inhibitors in people with diabetes, drugmakers have also done studies to find out if these drugs worked equally well in heart failure even when patients don’t have diabetes. Stephanie Redmond, Pharm.D., CDE, founder of DiabetesDoctor.com, notes that Farxiga is now approved for treating heart failure in patients without diabetes.Recent clinical trial results mean that Jardiance is likely to get a similar sort of approval.

“The reason this is so important is that forever we have worked hard to lower blood sugars because they help reduce the risk of microvascular complications (eye disease, kidney damage, nerve damage),” says Redmond. But there is not a strong correlation that blood sugar control alone reduces your risk of heart events, she continues. “So, while controlling blood sugars helps quality of life, two-thirds of our diabetic patients die from a heart event. Now we finally have drugs that we are seeing reduce the risk of dying from a heart event in a way (that’s) different than the way they lower sugars.”

More in the pipeline

According to DelveInsight, a life science market research and business consulting firm, the diabetes market features more potential competitors to the SGLT2 inhibitors and GLP-1 receptor agonists. Consider the following:

• DWP16001 is an oral SGLT2 inhibitor under development by Daewoong Pharmaceutical Co. Ltd., a Korean company, and is currently in a phase 2 clinical trial.
• Efpeglenatide is a GLP-1 receptor agonist under development by Sanofi and in a phase 3 clinical study that’s expected to be completed by next year.

Vinita Rakheja, an editor at DelveInsight, says the Sanofi entrant uses long-acting protein technology known to be effective in Type 2 diabetes treatment. “The GLP-1 (receptor agonists) have the ability to suppress the release of glucagon and enhance insulin secretion in a glucose-dependent manner by binding to the GLP-1 receptor on the beta cells of the pancreas. Unfortunately, endogenous GLP-1 is degraded within one to two minutes. However, efpeglenatide has been synthetically modified for a potential once-a-month injection.”

Tirzepatide is a dual agonist to activate two receptors, the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor. Eli Lilly has a trial underway that compares the investigational drug with its GLP-1 receptor agonist, Trulicity (dulaglutide). Redmond says tirzepatide is unique. Although there are several GLP-1 receptor agonists— including Trulicity, Novo Nordisk’s Victoza (liraglutide) and Ozempic (semaglutide) — tirzepatide is the only dual agonist. The addition of the GIP agonist produces additional effects on glucose and body weight and has beneficial effects on functionality of pancreatic beta cells that produce insulin.

The DelveInsight analysis predicts that tirzepatide will be successful because of its novel mechanism of action. Reviews on the drug’s effects on weight loss have also been positive. Results presented at last year’s American Diabetes Association annual meeting raised concerns about side effects. Lilly has reportedly worked on the dosing to address this.

The SGLT2 inhibitors may also get some competition from similar drugs with an added mechanism of action. Lexicon Pharmaceuticals has launched four phase 3 studies on sotagliflozin, a dual inhibitor of both SGLT1 and SGLT2 now sold in Europe as Zynquista. While targeting the SGLT2 receptor addresses most of the blood sugar normally retained in the body, adding the SGLT1 receptor as a target addresses the remaining glucose. But there is this bump in the road: The FDA previously reviewed this drug as a treatment for Type 1 diabetes along with insulin, but it wasn’t approved after a split vote by an advisory panel. Redmond says a risk of diabetic ketoacidosis — a serious condition that can be fatal — was seen in trials. In late July, Lexicon officials said they will not seek FDA approval unless they find a new marketing partner.

Keith Loria is a regular contributor who is based in the Washington, D.C., area.