Real World Study Suggests Canagliflozin Does Not Increase Risk of Below- Knee Amputation in People with Type 2 Diabetes


Michelle Kirkwood

Orlando, Florida
June 24, 2018

Analysis of more than 700,000 patients comparing canagliflozin to other SGLT2i and anti-hyperglycemic medications also confirms less hospitalizations for heart failure, as shown in prior studies

Canagliflozin does not increase the risk of amputation for the general type 2 diabetes (T2D) population or in patients with established cardiovascular disease, but does reduce a patient’s risk of hospitalization for heart failure, according to the study, “Canagliflozin (CANA) vs. Other Antihyperglycemic Agents on the Risk of Below-Knee Amputation (BKA) for Patients with T2DM—A Real-World Analysis of >700,000 U.S. Patients,” presented today at the American Diabetes Association’s® (ADA’s) 78th Scientific Sessions® at the Orange County Convention Center Convention Center.

Sodium glucose co-transporter 2 inhibitors (SGLT2i), such as canagliflozin, are anti-hyperglycemic medications prescribed for the treatment of T2D. Recent evidence from the CANVAS Program indicated that in addition to positive effects on glycemic levels, canagliflozin also provides significant cardiovascular benefits for people with T2D, reducing the risk of heart attacks and heart failures. However, results also identified an increased risk of leg and foot amputations with canagliflizon, and in 2017, the Food and Drug Administration began requiring a boxed warning to be added to the canagliflozin drug labels to describe this risk.

This new study, known as OBSERVE-4D, examined canagliflozin-associated effects on lower extremity amputation and hospitalization for heart failure compared to other SGLT2i therapies and non-SGLT2is across a broad T2D population of more than 700,000 patients. U.S. claims databases were analyzed using a prespecified protocol to examine canagliflozin-associated effects on below-knee amputations and hospitalization for heart failure, compared to other SGLT2is and non-SGLT2i medications. This retrospective, real-world observational study included 142,000 new users of canagliflozin, 110,000 users of other SGLT2i medicines and 460,000 users of non-SGLT2i anti-hyperglycemic agents in routine clinical practice with on-treatment median exposure of less than six months.

This large comprehensive analysis found no increased risk of below-knee amputation with canagliflozin or any of the SGLT2is across the general T2D population or in patients with established cardiovascular disease. The study detected a reduction in hospitalization for heart failure across the SGLT2i class, consistent with randomized clinical trials and other real-world evidence studies. Similar results were seen in a subgroup of patients with T2D and established cardiovascular disease. Researchers noted that although the results are derived from multiple large datasets reflecting current use in the U.S., the number of patients with long-duration exposure is limited and further study will be required to fully understand the issue.

“Prior to this analysis, no real-world study has shown direct, head-to-head, comparative evidence among individual SGLT2i medicines,” said the study’s lead investigator John Buse, MD, PhD, director of the Diabetes Center, director of the North Carolina Translational and Clinical Sciences Institute and executive associate dean for clinical research at the University of North Carolina School of Medicine in Chapel Hill. “We did not observe an increased risk in amputation with canagliflozin or any of the SGLT2is, and we confirmed they can have an important and positive impact on reducing a patient’s risk of hospitalization for heart failure. Of course, when physicians evaluate the best treatment for their patients, they should consider the factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Our research indicates that the overall benefit-risk profile of SGLT2is is positive, and physicians should feel comfortable and confident in prescribing the class to their patients.”

To speak with Dr. Buse, please contact the ADA Press Office on-site at the Orlando Convention Center on June 22 - 26, by phone at 407-685-4010 or by email at

The American Diabetes Association’s 78th Scientific Sessions, to be held June 22-26, 2018, at the Orange County Convention Center in Orlando, is the world’s largest scientific meeting focused on diabetes research, prevention and care. During the five-day meeting, more than 16,000 health care professionals from around the world will have exclusive access to more than 3,000 original diabetes research presentations, participate in provocative and engaging exchanges with leading diabetes experts, and can earn Continuing Medical Education (CME) or Continuing Education (CE) credits for educational sessions. The program is grouped into eight theme areas: Acute and Chronic Complications; Behavioral Medicine, Clinical Nutrition, Education and Exercise; Clinical Diabetes/Therapeutics; Epidemiology/Genetics; Immunology/Transplantation; Insulin Action/Molecular Metabolism; Integrated Physiology/Obesity; and Islet Biology/Insulin Secretion. Felicia Hill-Briggs, PhD, ABPP, President of Health Care and Education, will deliver her address, “The American Diabetes Association in the Era of Health Care Transformation,” on Saturday, June 23, and Jane E.B. Reusch, MD, President of Medicine and Science, will present her address, “24/7/365 – Lifetime with Diabetes,” on Sunday, June 24. In total, the 2018 Scientific Sessions includes 375 oral presentations; 2,117 poster presentations, including 47 moderated poster discussions; and 297 published-only abstracts. Join the Scientific Sessions conversation on social media using #2018ADA.


4-LB - Canagliflozin (CANA) vs. Other Antihyperglycemic Agents on the Risk of Below-Knee Amputation (BKA) for Patients with T2DM—A Real-World Analysis of >700,000 U.S. Patients

News Briefing: Diabetes & Cardiovascular Disease, Sunday, June 24, 9:00 a.m., ET

Session Title: Evolving Concepts in Clinical Management Strategies

Session Type: Moderated Poster Discussion

Location: Exhibit Hall (ePoster Theater A)

Session Time: Sunday, June 24, 2018, 12:00 - 1:00 pm


Sodium glucose co-transporter 2 inhibitors (SGLT2i) are indicated for treatment of T2DM; some SGLT2i have reported a CV benefit and some reported a risk of BKA. U.S. claims databases were analyzed using a prespecified protocol to examine CANA-associated effects on BKA and hospitalization for heart failure (HHF) vs. other SGLT2i and non-SGLT2i. Analyses used a propensity score adjusted new user design with numerous sensitivity analyses. The 4 databases included 142K new users of CANA, 110K of other SGLT2i, and 460K of non-SGLT2i AHAs. Meta-analysis results are reported when heterogeneity across databases was not substantial (I2

Author Disclosure Block: P. Ryan: Employee; Self; Janssen Research & Development, LLC. J.B. Buse: Other Relationship; Self; ADOCIA, AstraZeneca, Dexcom, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Fractyl Laboratories, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Metavention, NovaTarg, Novo Nordisk A/S, Sanofi, VTV Therapeutics. Research Support; Self; Boehringer Ingelheim GmbH, Johnson & Johnson Services, Inc., Theracos, Inc. Other Relationship; Self; Shenzhen Hightide Biopharmaceutical, Ltd. Research Support; Self; National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences. Other Relationship; Self; National Institute of Diabetes and Digestive and Kidney Diseases, American Diabetes Association. Research Support; Self; Patient-Centered Outcomes Research Institute. Other Relationship; Self; National Institute of Environmental Health Sciences. M. Schuemie: Employee; Self; Janssen Research & Development, LLC. F. Defalco: Employee; Self; Janssen Research & Development, LLC. Z. Yuan: Employee; Self; Janssen Research & Development, LLC. P. Stang: Employee; Self; Janssen Research & Development, LLC. J.A. Berlin: Employee; Self; Johnson & Johnson, LLC. N. Rosenthal: Employee; Self; Janssen Research & Development.

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