Keeping Blood Sugar Under Control: How Do Oral Semaglutide and Empagliflozin Stack Up for Treating Type 2 Diabetes?

For the over 37 million people in the United States living with type 2 diabetes, keeping blood sugar levels in a healthy range can feel like a never-ending battle. 

No matter how motivated someone may be to follow their doctor’s recommendations for diet, exercise, and lifestyle changes, most patients eventually need the help of medication to properly control their glycemic levels. 

The consequences of prolonged high blood sugar are severe, from cardiovascular disease, kidney damage, vision loss, and much more. That’s why finding an effective and well-tolerated treatment regimen is so critical.

Fortunately, the past decade has brought several exciting new drug classes to the type 2 diabetes arena. Two of the most promising are oral semaglutide and empagliflozin, offering new mechanisms of action compared to older medications like metformin. 

But with so many options now available, how do healthcare providers and patients know which medication might be the best fit for their individual needs? 

Let’s take a detailed look at how these two newer medications stack up against each other.

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What Are Oral Semaglutide and Empagliflozin and How Do They Work?

To understand how these two drugs compare, it’s important to first understand how each one works to lower blood sugar in the body.

Oral semaglutide is classified as a GLP-1 receptor agonist, part of the incretin mimetic class of diabetic medications. It mimics the effects of GLP-1, a hormone produced in the gut that stimulates the release of insulin from the pancreas. 

The pill form provides similar efficacy to the injected semaglutide products like Ozempic, but with easier administration. The convenience of the oral format has made it a popular option since being approved by the FDA in 2019.

Empagliflozin belongs to a class known as SGLT2 inhibitors, which work by blocking reabsorption of glucose in the kidneys, leading to excretion of excess sugar through the urine. It was approved by the FDA in 2014 and sold under the brand names Jardiance and Synjardy.

Both medication classes have become preferred options recommended by the American Diabetes Association for many type 2 patients, especially those struggling to reach their target A1c with lifestyle changes and metformin alone. But how do they compare head-to-head?

What Differences in Efficacy Have Clinical Trials Shown Between Oral Semaglutide and Empagliflozin?

Several large clinical trials have directly compared the efficacy of oral semaglutide and empagliflozin, looking at key metrics like A1c reduction, weight loss, blood pressure control, and need for additional medications.

The PIONEER 2 trial enrolled 1,203 patients inadequately controlled on metformin with baseline A1c between 7-10.5%. Participants were randomized to receive either oral semaglutide (3mg, 7mg, or 14mg) or empagliflozin 25mg daily in addition to metformin. 

After 26 weeks, semaglutide demonstrated superior reductions in A1c and body weight at all doses compared to empagliflozin. Those on the highest 14mg semaglutide dose saw A1c drops of 1.3% on average and weight loss of 4.4kg. With empagliflozin, A1c fell 0.8% and weight went down 2.5kg. Blood pressure decreases were also greater with semaglutide.

Another trial, SUSTAIN 9, compared semaglutide injected weekly to empagliflozin 25mg over 30 weeks in 302 patients on metformin background therapy. Average A1c decrease was 1.5% in the semaglutide group compared to 0.7% with empagliflozin. Weight reduction was 6.5kg with semaglutide vs 3.8kg with empagliflozin.

The key results of these clinical trials comparing oral semaglutide and empagliflozin can be summarized as follows:

Drug	Trial	Patients	Baseline A1c	A1c Reduction	Weight Loss
Oral Semaglutide 14mg	PIONEER 2	1,203	7-10.5%	1.3%	4.4 kg
Empagliflozin 25mg	PIONEER 2	1,203	7-10.5%	0.8%	2.5 kg
Semaglutide Injected	SUSTAIN 9	302	7-10.5%	1.5%	6.5 kg
Empagliflozin 25mg	SUSTAIN 9	302	7-10.5%	0.7%	3.8 kg

Based on these and other randomized controlled trials, semaglutide appears to provide greater improvements in glucose control and weight loss compared to empagliflozin when added to metformin. 

However, empagliflozin has been associated with meaningful reductions in blood pressure and cardiovascular events in patients with type 2 diabetes based on findings from the large EMPA-REG OUTCOME trial. The choice between these two effective therapies may come down to individual patient priorities and needs.

What Do We Know About the Safety Profiles of These Two Medications?

As newer drugs, extensive data has now accumulated on the safety profiles of both oral semaglutide and empagliflozin through widespread clinical use and ongoing collection of real-world evidence. This allows patients and providers to make informed choices weighing risks and benefits.

The most common side effects of semaglutide are gastrointestinal in nature, including nausea, vomiting, diarrhea, and abdominal discomfort. These tend to be transient, but lead to discontinuation rates of up to 12% in trials. Like other GLP-1 drugs, semaglutide may increase risk of diabetic retinopathy complications and has been rarely associated with thyroid C-cell tumors in rodents. No medullary thyroid carcinoma risk has been observed in humans to date.

Empagliflozin is generally well-tolerated, with less than 5% discontinuing treatment due to adverse events in clinical trials. However, it does come with increased risk of genital mycotic infections, urinary tract infections, and hypotension. 

How Are These Medications Prescribed and Monitored in Clinical Practice?

Oral semaglutide and empagliflozin have similar starting doses, usually prescribed as a once daily pill, with or without food. The maintenance dose of semaglutide is typically 7-14mg, while empagliflozin is taken consistently at 25mg per day. Some key considerations for healthcare providers when prescribing these medications include:

• What is the patient’s baseline A1c, blood pressure, weight, kidney function? This helps determine efficacy goals and parameters to monitor.
• What other medications is the patient taking? Look for drug interactions.
• Does the patient have any complications like retinopathy that may influence medication choice?
• Counsel patients on potential side effects and when to follow up if experienced.
• Emphasize the importance of routine monitoring of A1c, kidney function, blood pressure, weight, etc.
• Remind patients of ongoing lifestyle interventions like diet, exercise and glucose self-monitoring that complement medication use.

Following initiation, providers follow up within 2-3 months to assess response and tolerability. This allows adjustment of dosage if needed. Continued regular monitoring helps ensure the medication results in sustained improvements in glycemic control and other parameters.

What Are the Costs and Accessibility Considerations for These Treatments?

For many patients, out-of-pocket costs can be a significant factor in diabetes treatment decisions. Some key considerations around medication expenses include:

• Oral semaglutide is available as a brand name only, Rybelsus, with a monthly wholesale price around $850.
• Empagliflozin is sold as the brand Jardiance for approximately $550 per month, or as the generic for $10-50 per month.
• Both are covered by most commercial insurance and Medicare plans, but may require prior authorization or higher cost-sharing tier.
• Eligible patients can receive manufacturer savings cards to reduce copays, sometimes to $0-10. State assistance programs are also available.
• Taking the pills on a daily basis provides convenience compared to injectable options.

Overall, empagliflozin is likely to be the more affordable option, but many patients can access semaglutide through insurance coverage or patient assistance programs. Discussing costs with providers and insurance helps patients understand their options.

The Bottom Line

Shared decision-making between patients and their healthcare providers allows the unique benefits, risks, costs, and accessibility of these medications to be weighed. 

With newer agent classes like SGLT2 inhibitors and GLP-1 receptor agonists, people living with type 2 diabetes have more choices than ever to take control of their health. By selecting the optimal therapy for each individual, patients can successfully manage their blood sugar, prevent frightening complications, and thrive with diabetes.

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