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Inhibitors to release and agonists to block: the janus face of the newest antidiabetics

Chronic kidney disease (CKD) is a common long-term complication of type 2 diabetes and represents a major public health problem in the U.S. The two leading causes of chronic kidney disease are type 2 diabetes and hypertension. There are 26 million people in the U.S. diagnosed with diabetes and an additional 9.45 million are undiagnosed. In the U.S., 108 million (45%) adults have hypertension or are taking blood pressure medications. This is why the America Heart Association (AHA) insists on high blood pressure prevention to reduce heart and kidney disease. An estimated 37 million American adults have kidney disease. Most patients with end stage kidney disease have type 2 diabetes; and people with type 2 diabetes, on the other hand, are at increased risk for high blood pressure, cardiovascular diseases (CVDs) including heart attacks or heart failure, and stroke. Although there are established standards of care, a disproportionately high burden of kidney and cardiovascular disease exists in this population, leading to concerning levels of avoidable death, illness and health care costs, as well as poor quality of life.

Two newer groups of medications prescribed primarily for Type 2 diabetes treatment (SGLT2 inhibitors and GLP-1 receptor agonists) could significantly reduce risks associated with chronic kidney disease (CKD) and heart disease. Based on analyses of the clinical trials through March 2020, a group of leading experts in diabetes, heart failure, kidney disease and cardiometabolic disease believe the medicines should be considered for people with CKD and Type 2 diabetes to protect against heart and kidney disease and their serious complications, according to a new Scientific Statement from the AHA “Cardiorenal Protection With the Newer Antidiabetic Agents in Patients With Diabetes and Chronic Kidney Disease” published in the journal Circulation. The statement reviews evidence from multiple, large, international, randomized controlled trials of two classes of blood sugar control medications, SGLT2 inhibitors and glucagon like peptide-1 receptor agonists (GLP-1 RAs), in patients with type 2 diabetes, chronic kidney disease and those who were either at risk for or already had cardiovascular disease.

Analysis of the clinical trials results yielded these recommendations:

  • Early and ongoing assessment of risks for kidney and heart disease can help identify patients who may benefit from the protective and preventive effects of these medicines.
  • Tailor medication choices to meet the needs of each individual patient.
  • Monitoring and control of high blood pressure.
  • Identify risks for hypoglycemia (low-blood sugar) and educate patients on the signs so they can seek treatment quickly.
  • Adjust all medications in tandem with these medicines and consider the burden of “polypharmacy” – meaning taking 5 or more medications daily for multiple conditions.
  • Patients should be counseled about the risks and symptoms of “euglycemic” diabetic ketoacidosis (DKA), when taking SGLT2 inhibitors as well as “classic” DKA, which is serious and can be fatal.
  • The health care professional team should regularly screen and counsel patients about regular foot care to prevent foot ulcers or blisters that can quickly become infected and lead to amputation.

The composite results of the trials found that SGLT2 inhibitors and GLP-1 RAs can safely and significantly reduce the risk of cardiovascular events and death, reduce hospitalization and slow the progression of chronic to end-stage kidney disease including the risks of dialysis, transplantation or death. The scientific statement provides detailed, practical guidance for health care professionals to recognize and treat patients who may benefit from SGLT2 inhibitor and GLP-1 RA medications.  The writing group identified two additional patient subgroups who may benefit from SGLT2 inhibitors and GLP-1 RAs: people with heart failure with reduced ejection fraction (HFrEF) with or without Type 2 diabetes; and people with chronic kidney disease who do not have Type 2 diabetes. The writing group anticipates more data emerging to validate the use of SGLT2 inhibitors and GLP-1 RA medications for these at-risk patients. GLP-1 RAs received initial FDA approval for use in glycemic control in 2005, and SGLT2 inhibitors were approved in 2013, and they were approved for treating people with Type 2 diabetes.

Medications within the two classes work in different ways: SGLT2 inhibitors decrease blood sugar by causing the kidneys to remove sugar from the body through the urine. Research on this class of drigs have shown they also can reduce the risk of heart failure, slow the progression of chronic kidney disease and reduce risk of cardiovascular death. GLP-1 RAs work by simulating the functions of the body’s natural incretin hormones that help lower post-meal blood sugar levels. The medicines in this group have been shown to reduce the risks of heart attack, ischemic stroke and/or cardiovascular death. Recent studies show these newer medications are not widely prescribed, especially among patients with higher risks for cardiovascular disease and chronic kidney disease. Metformin and insulin enhancers like repaglinide remain preferred, perhaps because of their known clinical profiles. A recent nationwide study of over one million commercially insured and Medicare Advantage adult beneficiaries, showed that 7% of patients with Type 2 diabetes were treated with an SGLT2 inhibitor medication.

Scientists deem that the most important question that needs to be addressed in the future is the actual implementation of these medicines in clinical practice. When multidisciplinary teams can identify high-risk patients and ensure targeted delivery of these therapies, as appropriate, clinicians could greatly reduce the burden of heart and kidney disease for millions of people with Type 2 diabetes. Improving the cardiovascular and kidney health of as many people as possible – reducing morbidity, mortality and health care expenditures – are the primary goals.

  • edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Rangaswami J et al. Circulation 2020 Sep 28:CIR0000000000000920. 

Birkeland KI, Bodegard J et al. Diabetes Obes Metab. 2020 Sep 7. 

Qiu M, Ding LL, Zhang M et al. Pharmacol Res. 2020 Aug;161:105175. 

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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