Abstract
Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio > 300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 94-109 |
| Number of pages | 16 |
| Journal | American Journal of Kidney Diseases |
| Volume | 77 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2021 |
Funding
Dr Tuttle is supported by National Institutes of Health (NIH) grants and a Center for Disease Control and Prevention contract and has served as a consultant for Eli Lilly & Co, Boehringer Ingelheim, AstraZeneca, Gilead, Goldfinch Bio, Novo Nordisk, Bayer, and Janssen. Dr Cavender has received research support (nonsalary) from Amgen, AstraZeneca, Bristol Myers Squibb, Chiesi, CSL Behring, GlaxoSmithKline, and Novartis; research support (salary) from Novo-Nordisk; and consulting fees from AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, and Merck. Dr Perreault has received personal fees from speaking and/or consulting from Novo Nordisk, Sanofi, AstraZeneca, Boehringer-Ingelheim, Janssen, Merck, and UpToDate. Dr Vallon reports grants from the NIH and has served as a consultant and received honoraria from Bayer, Boehringer Ingelheim, Eli Lilly & Co, Janssen Pharmaceutical, Merck, and Retrophin and grant support for investigator-initiated research from AstraZeneca, Bayer, Boehringer-Ingelheim, Fresenius, and Janssen Pharmaceutical. Dr Rossing reports having given lectures for AstraZeneca, Bayer, Novo Nordisk, and Boehringer-Ingelheim and has served as a consultant for AbbVie, AstraZeneca, Bayer, Eli Lilly & Co, Boehringer-Ingelheim, Astellas, Gilead, Mundipharma, Vifor, and Novo Nordisk, all fees given to Steno Diabetes Center Copenhagen. Dr Brosius reports grants from the NIH and the Juvenile Diabetes Research Foundation; the University of Michigan has contracted with Gilead for his consulting services. Dr Fioretto reports receiving personal fees for advisory boards or scientific presentations from AstraZeneca, Mundipharma, Boehringer-Ingelheim, Eli Lilly & Co, and Novartis. Mr Fowler is a consultant for Responsum Health, Bayer, Gilead, Chiesi, Talaris, Retrophin, Otsuka, and Veloxis. Dr Heerspink has served as a consultant for Abbvie, AstraZeneca, Boehringer-Ingelheim, Fresenius, Gilead, Janssen, Merck, Mundipharma, Mitsubishi-Tanabe, and Retrophin and received grant support from Abbvie, AstraZeneca, Boehringer-Ingelheim, and Janssen. Dr Mottl has contracts with Aurinia, Boehringer-Ingelheim, Calliditas, Duke Clinical Research Institute, and Pfizer; has been a member of the scientific advisory board for AstraZeneca; and has consultancy agreements with Proteomics Int. Dr Rosas reports grants from the NIH, Bayer, and Ironwood Pharmaceuticals and has participated in advisory boards for Reata and Bayer Healthcare. Dr Molitch reports grants from the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Novartis, and NovoNordisk and consulting fees from Merck, Pfizer, and Janssen. Dr McGuire has received honoraria for clinical trial leadership from AstraZeneca, Sanofi Aventis, Janssen, Boehringer-Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Lexicon, Eisai Inc, GlaxoSmithKline, Lilly USA, and Esperion and honoraria for consultancy from AstraZeneca, Sanofi Aventis, Lilly USA, Boehringer-Ingelheim, Merck & Co, Novo Nordisk, Metavant, Applied Therapeutics, and Afimmune. Dr Wanner has received honoraria from AstraZeneca, Sanofi, Boehringer Ingelheim, Merck, Eli Lilly & Co, and Mundipharma. Mr Manley is employed by the NKF. Dr Perkovic has received fees for advisory boards, steering committee roles, or scientific presentations from Abbvie, Astellas, AstraZeneca, Bayer, Baxter, BMS, Boehringer-Ingelheim, Chinook, Dimerix, Durect, Eli Lilly & Co, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Sanofi, Servier, Vifor, and Tricida. Katherine R. Tuttle, MD, Frank C. Brosius III, MD, Matthew A. Cavender, MD, MPH, Paola Fioretto, MD, Kevin J. Fowler, BS, BA, Hiddo J.L. Heerspink, PhD, Tom Manley, RN, Darren K. McGuire, MD, MHSc, Mark E. Molitch, MD, Amy K. Mottl, MD, MPH, Leigh Perreault, MD, Sylvia E. Rosas, MD, MSC, Peter Rossing, MD, DMSc, Laura Sola, MD, Volker Vallon, MD, Christoph Wanner, MD, and Vlado Perkovic, MBBS, PhD. The following companies provided a grant to the NKF to support the planning and conduct of the workshop: AstraZeneca, Boehringer Ingelheim, Janssen, Sanofi, Merck, and Metavant. The workshop sponsors had no role in the development of the workshop agenda or objectives. The sponsors were restricted from viewing any part of the workshop report manuscript until it was accepted for publication and therefore had no role in the content developed for this report. Dr Tuttle is supported by National Institutes of Health (NIH) grants and a Center for Disease Control and Prevention contract and has served as a consultant for Eli Lilly & Co, Boehringer Ingelheim, AstraZeneca, Gilead, Goldfinch Bio, Novo Nordisk, Bayer, and Janssen. Dr Cavender has received research support (nonsalary) from Amgen, AstraZeneca, Bristol Myers Squibb, Chiesi, CSL Behring, GlaxoSmithKline, and Novartis; research support (salary) from Novo-Nordisk; and consulting fees from AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, and Merck. Dr Perreault has received personal fees from speaking and/or consulting from Novo Nordisk, Sanofi, AstraZeneca, Boehringer-Ingelheim, Janssen, Merck, and UpToDate. Dr Vallon reports grants from the NIH and has served as a consultant and received honoraria from Bayer, Boehringer Ingelheim, Eli Lilly & Co, Janssen Pharmaceutical, Merck, and Retrophin and grant support for investigator-initiated research from AstraZeneca, Bayer, Boehringer-Ingelheim, Fresenius, and Janssen Pharmaceutical. Dr Rossing reports having given lectures for AstraZeneca, Bayer, Novo Nordisk, and Boehringer-Ingelheim and has served as a consultant for AbbVie, AstraZeneca, Bayer, Eli Lilly & Co, Boehringer-Ingelheim, Astellas, Gilead, Mundipharma, Vifor, and Novo Nordisk, all fees given to Steno Diabetes Center Copenhagen. Dr Brosius reports grants from the NIH and the Juvenile Diabetes Research Foundation; the University of Michigan has contracted with Gilead for his consulting services. Dr Fioretto reports receiving personal fees for advisory boards or scientific presentations from AstraZeneca, Mundipharma, Boehringer-Ingelheim, Eli Lilly & Co, and Novartis. Mr Fowler is a consultant for Responsum Health, Bayer, Gilead, Chiesi, Talaris, Retrophin, Otsuka, and Veloxis. Dr Heerspink has served as a consultant for Abbvie, AstraZeneca, Boehringer-Ingelheim, Fresenius, Gilead, Janssen, Merck, Mundipharma, Mitsubishi-Tanabe, and Retrophin and received grant support from Abbvie, AstraZeneca, Boehringer-Ingelheim, and Janssen. Dr Mottl has contracts with Aurinia, Boehringer-Ingelheim, Calliditas, Duke Clinical Research Institute, and Pfizer; has been a member of the scientific advisory board for AstraZeneca; and has consultancy agreements with Proteomics Int. Dr Rosas reports grants from the NIH, Bayer, and Ironwood Pharmaceuticals and has participated in advisory boards for Reata and Bayer Healthcare. Dr Molitch reports grants from the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Novartis, and NovoNordisk and consulting fees from Merck, Pfizer, and Janssen. Dr McGuire has received honoraria for clinical trial leadership from AstraZeneca, Sanofi Aventis, Janssen, Boehringer-Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Lexicon, Eisai Inc, GlaxoSmithKline, Lilly USA, and Esperion and honoraria for consultancy from AstraZeneca, Sanofi Aventis, Lilly USA, Boehringer-Ingelheim, Merck & Co, Novo Nordisk, Metavant, Applied Therapeutics, and Afimmune. Dr Wanner has received honoraria from AstraZeneca, Sanofi, Boehringer Ingelheim, Merck, Eli Lilly & Co, and Mundipharma. Mr Manley is employed by the NKF. Dr Perkovic has received fees for advisory boards, steering committee roles, or scientific presentations from Abbvie, Astellas, AstraZeneca, Bayer, Baxter, BMS, Boehringer-Ingelheim, Chinook, Dimerix, Durect, Eli Lilly & Co, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Sanofi, Servier, Vifor, and Tricida. We thank the conference participants, who aside from the authors of this article included: Amanda Adler, MD, PhD, Oxford, UK; Maryam Afkarian, MD, PhD, Sacramento, CA; Radica Alicic, MD, Spokane, WA; Meaghan Allain, Falls Church, VA; Pamela Anderson, MBA, Titusville, NJ; George Bakris, MD, Chicago, IL; Petter Bjornstad, MD, Aurora, CO; Jaime Blais, PhD, Titusville, NJ; Glenn Chertow, MD, MPH, Palo Alto, CA; Alfred Cheung, MD, Salt Lake City, UT; Mihye (Mia) Cmiel, PharmD, Philadelphia, PA; Stephanie Cogan, New York, NY; Mark Cooper, MBBS, PhD, Melbourne, Australia; Kerry Cooper, MD, Gaithersburg, MD; Ian de Boer, MD, MS, Seattle, WA; Luca De Nicola, MD, PhD, Naples, Italy; Ralph Defronzo, MD, San Antonio, TX; Tony Deluzio, Bridgewater, NJ; Barbara Gillespie, MD, MMS, Chapel Hill, NC; Anthony Gucciardo, New York, NY; Michelle Hangey, BBA, MBA, Philadelphia, PA; Raymond Harris, MD, Nashville, TN; Sibylle Hauske, MD, MBA, Ridgefield, CT; Richard Haynes, DM, MRCP, Oxford, UK; Will Herrington, MA, MBBS, MD, Oxford, UK; Donna Hodge, Titusville, NJ; Diana Jalal, MD, Iowa City, IA; Meg Jardine, MBBS, PhD, Sydney, Australia; Nichole Jefferson, Dallas, TX; Steven Kahn, MBChB, Seattle, WA; Mikhail Kosiborod, MD, Kansas City, MO; Liz Leff, New York, NY; Kerry Leigh, RN, Washington DC; Helen Looker, MBBS, MRCP, Phoenix, AZ; Julie Lovshin, MD, PhD, Ontario, Canada; Sally Marshall, MD, Tyne, UK; Julie Maurey, PharmD, Philadelphia, PA; Peter McCullough, MD, MPH, Dallas, TX; Jim McDermott, PhD, Gaithersburg, MD; Ciaran McMullan, MB BCh, MMSc, Philadelphia, PA; Elizabeth Montgomery, New York, NY; Marcel H. Muskiet, MD, Amsterdam, the Netherlands; Robert Nelson, MD, PhD, Phoenix, AZ; Joshua Neumiller, PharmD, Pullman, WA; Susanne Nicholas, MD, MPH, PhD, Los Angeles, CA; Gregorio Obrador, MD, MPH, Mexico City, Mexico; Milton Packer, MD, Dallas, TX; Sachin Paranjape, PhD, Bridgewater, NJ; Meda Pavkov, MD, PhD, Atlanta, GA; Pablo Pergola, MD, PhD, San Antonio, TX; Michaela Petrini, PA-C, MHS, Ridgefield, CT; Glenda Roberts, Seattle, WA; Motoaki Sano, MD, PhD, Tokyo, Japan; Jay Shubrook, DO, Vallejo, CA; Anna Solini, MD, PhD, Pisa, Italy; Christopher Sorli, MD, PhD, Bridgewater, NJ; Paul Strumph, MD, Durham, NC; Merlin Thomas, MBChB, PhD, Melbourne, Australia; Aliza Thompson, MD, Silver Spring, MD; Marcello Tonelli, MD, Edmonton, Alberta, Canada; Robert Toto, MD, Dallas, TX; Daniel van Raalte, MD, PhD, Amsterdam, the Netherlands; Joseph Vassalotti, MD, New York, NY; Mark West, PharmD, Pittsburgh, PA; Ernest W. Wright, PhD, DSci, FRS, Los Angeles, CA; Jason Wright, PharmD, Gaithersburg, MD; and Helen Yeh, PhD, Gaithersburg, MD. We thank Emily J. Cox, PhD (Providence Health Care, Providence Medical Research Center, Spokane, WA) who assisted in the development of Figure 3. Received April 28, 2020, at Diabetes and AJKD. Evaluated by 3 external peer reviewers, with direct editorial input from the Diabetes Editor-in-Chief and an AJKD Associate Editor and Deputy Editor. Accepted in revised form by both journals August 4, 2020.
Keywords
- Hyperglycemia
- SGLT2 inhibitor
- atherosclerotic cardiovascular disease (ASCVD)
- diabetic kidney disease (DKD)
- heart failure (HF)
- kidney protection
- major adverse cardiovascular events (MACE)
- renal function preservation
- research priorities
- review
- sodium/glucose cotransporter 2 (SGLT2)
ASJC Scopus subject areas
- Nephrology
