Key Points

• Yes, clinical studies and ADA diabetes guidelines recommend the combined use of Invokana (generic name: canagliflozin) with Januvia (generic name: sitagliptin), along with diet and exercise, as one option for patients with type 2 diabetes who are not controlled on their current treatments.
• Type 2 diabetes is a progressive disease, and over time patients may need add-on treatments to help manage their blood sugar levels. Medications are often added in a stepwise fashion to metformin, which is usually the first drug used in treatment.
• Invokana and Januvia work in two different ways: Invokana is classified as an SGLT-2 (sodium-glucose co-transporter-2) inhibitor and Januvia is an incretin-based therapy.
• Choice of medications are selected for patients individually, considering presence or risk of heart or kidney disease, A1C lowering goals, weight concerns, side effects, and cost, among other factors.

Januvia and Invokana are targeted therapies that work in two different ways to help reduce blood sugar. They also provide beneficial effects on important outcomes in type 2 diabetes such as body weight and blood pressure.

If you are not meeting your A1C goals after three months of metformin therapy, your doctor may consider adding additional medications from different classes. Your doctor may recommend combination therapy, such as metformin with Invokana and Januvia if you have an A1C level that is 1.5–2.0% above your target goal.

• Based on the American Diabetes Association (ADA), Standards of Medical Care in Diabetes, 2020 an SGLT2 inhibitor with a proven benefit for your heart, such as Invokana (canagliflozin), can be added to metformin therapy in patients at high risk of heart disease or with established heart disease, chronic kidney disease or heart failure.
• When the combination of Invokana and metformin is no longer adequately allowing you to meet your goals, a DPP-4 inhibitor, such as Januvia (sitagliptin) can be added to your treatment.

There are many options to choose from for type 2 diabetes treatment. You and your doctor will select your treatments based on parameters specific for you, such as how well treatment works, your medical conditions such as heart or kidney disease, concerns for weight gain or other side effects, and medication cost, among other considerations.

How do Invokana and Januvia work together?

For treatment of various illnesses, medications with different mechanisms (how they work) may be combined.

A common example you may be familiar with is the use of an opioid pain medication, such as hydrocodone, with a milder pain reliever such as acetaminophen. These drugs are in two different classes and work in different ways. However, by combining them, greater pain relief can be achieved while using lower doses of medicine and a lower risk for side effects.

The same principle works in type 2 diabetes, achieving a greater lowering of blood sugar levels with a lower risk for side effects due to high doses. Certain medications from different classes can be combined, along with diet and exercise, to help manage blood sugar and possible diabetes complications. Certain diabetes treatments also have established benefits for your heart and kidney health, as well.

Plus, type 2 diabetes and high blood sugar is not caused just by one problem. Loss of cell function in the pancreas, loss of insulin effectiveness, overactive glucagon release from the liver, a reduced incretin effect and increased blood sugar absorption by the kidneys can all aggravate your condition. So it makes sense that use of different types of drugs that target these mechanisms could have an added effect.

Invokana

Invokana is classified as an SGLT-2 (sodium-glucose co-transporter-2) inhibitor. It blocks proteins in the kidney that reabsorb sugar (glucose) back into the bloodstream. Invokana blocks these proteins which results in more glucose being excreted in the urine to help lower blood sugar and improve A1C.

Invokana is approved as an oral prescription tablet used to help manage blood sugar (glucose) in adults with type 2 diabetes. It is used in addition to an appropriate diet and exercise regimen.

• Invokana is also used to lower your risk of heart attack, stroke, or death if you have type 2 diabetes and known heart or blood vessel disease.
• If you have diabetic kidney disease (nephropathy) with a certain amount of protein in your urine, Invokana can also reduce the risk of end-stage kidney disease, heart-related death, and hospitalization for heart failure.

Other FDA-approved medications in the SGLT-2 inhibitor class include empagliflozin (Jardiance), dapagliflozin (Farxiga), and ertugliflozin (Steglatro). These medicines come as single agents and can also be combined with metformin.

Januvia

Januvia works differently than Invokana. Januvia is in a class of drugs known as dipeptidyl peptidase 4 (DPP-4) inhibitors, which work by blocking the deactivation of incretin hormones. By increasing and prolonging active incretin levels, Januvia increases insulin release from the pancreas and decreases glucose (sugar) overproduction from the liver. Januvia works in response to your differing blood sugar levels.

Januvia is approved as a prescription oral diabetes tablet taken once daily, along with diet and exercise, to help to lower blood sugar levels (glucose) in adults living with type 2 diabetes. DPP-4 inhibitors do not have a proven cardiovascular benefit like the SGLT2 inhibitors.

Other FDA approved medications in the DPP-4 inhibitor class include saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina). These medicines come as single-ingredient products or combined with other diabetes medicines such as metformin.

How will using Invokana and Januvia together help my diabetes?

Large, comparative studies suggest that each new class of diabetes medicine added to initial therapy with metformin will generally lower your A1C by about 0.7–1.0%, as noted by ADA guidelines.

If you don’t reach your goal A1C after 3 months with metformin, it can be combined with any of six other classes of type 2 diabetes medications: sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, or basal insulin.

If you have heart disease or are at high risk of heart disease, an SGLT-2 inhibitor with demonstrated cardiovascular (heart and vessel) and kidney benefit, such as Invokana may be recommended as part of your medication regimen. Other SGLT-2 inhibitors, such as empagliflozin (Jardiance) and dapagliflozin (Farxiga) have also been shown to lead to statistically significant reductions in cardiovascular events like heart attack and stroke and improve kidney function.

If you have type 2 diabetes but don’t have established heart disease, heart failure or chronic kidney disease, the choice of additional agents will be guided by your doctor’s choices, considering your specific needs. Avoiding side effects including low blood sugar and weight gain, drug cost, and use of oral or injectable therapy will all be considered.

Related questions

• What is Januvia used for and how does it work?
• When is the best time to take Januvia?
• How long does it take for Januvia to work?

Studies on combined use

A randomized, controlled, 26-week study evaluated canagliflozin (Invokana) and placebo when added on to metformin and sitagliptin (Januvia) treatment in patients who were inadequately controlled on metformin and sitagliptin alone.

Canagliflozin treatment was started using a step‐wise titration from 100 to 300 mg. Canagliflozin significantly improved A1C measures, fasting plasma glucose, body weight and systolic blood pressure, and was well-tolerated. The greatest reductions in A1C measurements were seen after 12 weeks of therapy. Canagliflozin was associated with an increased incidence of genital yeast infections (5/108 women, 1/108 men).

Is it safe to use Invokana and Januvia together?

In general, combining SGLT2 inhibitors like Invokana with DPP-4 inhibitors such as Januvia has been found to be safe and is recommended in treatment guidelines. However, each drug is associated with a unique set of side effects to consider (see Table 1).

In studies looking at the use of canagliflozin added on to metformin and sitagliptin, the number of patients who stopped treatment due to side effects was low. For example, when compared to placebo, 11.1% of patients stopped treatment with canagliflozin compared to 8.3% with placebo. The incidence of serious adverse events in both groups was the same, 1.9%.

Table 1. Selected Safety Considerations with Invokana and Januvia

	Invokana (canagliflozin)	Januvia (sitagliptin)
Boxed Warning	Yes; risk of amputation in lower limbs	No
Hypoglycemia (low blood sugar)	Low or no risk	Low or no risk
Ketoacidosis	Yes (rare)	No
Acute kidney injury or kidney failure	Yes	Yes
Weight change	Weight loss	Weight neutral
Low blood pressure, volume depletion events	Yes	No
Serious allergic reactions	Yes	Yes
Dose adjustments needed	Yes, in kidney disease; with UGT inducers (i.e., rifampin) - canagliflozin exposure is reduced. Use not recommended in patients with severe hepatic impairment.	Yes, in kidney disease; no clinical experience in patients with severe hepatic impairment.
Bone fractures	Yes	No
Genital yeast infections	Yes	No
Acute pancreatitis	No	Yes

Kidney and liver function

You must have adequate kidney function to use Invokana and Januvia, either alone or together. Your doctor will regularly monitor your kidney function to be sure it is safe for you to remain on your medications and your specific doses.

• Invokana doses need to be adjusted in patients with an eGFR less than 60 mL/min/1.73 m². Do not use Invokana in patients on dialysis or in patients with severe liver disease.
• Januvia doses need to be adjusted in patients with an eGFR less than 45 mL/min/1.73 m². Januvia may be administered without regard to the timing of dialysis. There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score >9).

Invokana can also raise potassium levels (known as hyperkalemia).

Genital yeast infections

The use of Invokana is linked with a risk for genital yeast infections, in both women and men, although women may be at greater risk. This is one of the most common side effects with Invokana, reported in 11% to 12% of women (11-12 out of 100) and 4% to 5% of men in clinical studies.

Generally, genital yeast infections are mild, treatable with oral or topical antifungal therapy, and do not lead to treatment discontinuation.

Volume depletion, dehydration

Adding canagliflozin to metformin and sitagliptin therapy increased the incidence of osmotic diuretic events (6/108 patients, 5.6%) compared to placebo + metformin/sitagliptin (4/108 patients, 3.7%). These events may include: increased dry mouth, increased thirst, urgent need to urinate, excessive urination, urination at night.

Hypoglycemia (low blood sugar)

In one smaller study looking at the use of canagliflozin (or placebo) added on to metformin and sitagliptin, hypoglycemia (low blood sugar) occurred in 2 out of 108 patients (1.9%) receiving placebo compared to 4 of 108 patients (3.7%) receiving canagliflozin. The overall risk for hypoglycemia with this triple therapy was low.

There is an increased risk of hypoglycemia (low blood sugar) when Januvia or Invokana are added to an insulin secretagogue (such as sulfonylurea like glipizide or glimepiride) or insulin therapy. Your doctor may need to lower your dose of the sulfonylurea or insulin to reduce the risk of low blood sugar.

Bottom Line

• Januvia and Invokana can be used together, and are often combined with metformin as a triple therapy in patients who require additional options for meeting their A1C goals. These treatments are typically well-tolerated by most patients.
• Invokana and Januvia target two different mechanisms involved with type 2 diabetes to have a positive effect on blood glucose lowering. Invokana is associated with beneficial heart and kidney outcomes, weight loss and blood pressure control, too.
• Overall, the use of Januvia and Invokana together has been found to be safe, with a low incidence of hypoglycemia (low blood sugar). However, patients with kidney impairment will need to have their doses adjusted or avoid Invokana use.

Review the full set of side effects associated with these medications with your doctor prior to treatment. Always follow your doctor’s recommendations for drug treatment, diet and exercise while receiving care for type 2 diabetes.

This is not all the information you need to know about Invokana and Januvia for safe and effective use. Review the full product information and speak to your health care provider if you have questions or concerns.

References

• Pratley RE, Cersosimo E. Use of Canagliflozin in Combination With and Compared to Incretin-Based Therapies in Type 2 Diabetes. Clin Diabetes. 2017;35(3):141‐153. doi:10.2337/cd16-0063.
• Rodbard HW, Seufert J, Aggarwal N, et al. Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately controlled on metformin and sitagliptin. Diabetes Obes Metab. 2016;18(8):812‐819. doi:10.1111/dom.12684
• Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2020. American Diabetes Association Diabetes Care 2020 Jan; 43(Supplement 1): S98-S110. https://doi.org/10.2337/dc20-S009
• Fulcher G, Matthews DR, Perkovic V, et al. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18(1):82‐91. doi:10.1111/dom.12589
• Invokana [package insert]. Janssen Pharmaceutical Companies. Titusville, NJ. Accessed May 26, 2020 at https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/INVOKANA-pi.pdf
• Januvia [package insert]. Merck and Co. Whitehouse Station, NJ. Accessed May 15, 2020 at https://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf

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