Ask the Experts: Dr Barrie Weinstein

Barrie Weinstein, MD

Expert Perspectives
Barrie Weinstein, MD

 

SGLT2 Inhibitors in the Treatment of Type 2 Diabetes

Headshot
Hospital and Institutional Affiliations
Assistant Professor, Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai
Practice Niche
Endocrinology

Question

How do you approach risk-benefit discussions regarding sodium-glucose cotransporter2 (SGLT2) inhibitor use in patients who have type 2 diabetes?

Answer

Whenever I’m starting a patient on a new medication, I make sure to have an extensive discussion with the patient about the risks and benefits. SGLT2 inhibitors are an attractive option for patients with type 2 diabetes. In addition to lowering hemoglobin A1c and fasting plasma glucose, they have also been associated with weight loss, blood pressure lowering, and reduction in progression of albuminuria. In addition, there have been positive cardiovascular outcomes that have been seen in the EMPA-REG and CANVAS trials, which were designed specifically to look at the cardiovascular safety of empagliflozin and canagliflozin, respectively (ClinicalTrials.gov identifiers: NCT01131676, NCT01032629). It is very exciting to start a patient on a new medication and be able to tell the patient that he or she may have reduced cardiovascular risk, reduced admissions to the hospital because of heart failure, or reduced overall mortality resulting from cardiovascular disease by starting these medications.

There have been a lot of positive noteworthy data about SGLT2 inhibitors. However, it is important to discuss the risks. These medications can be very dehydrating, and is very important to talk to patients about staying hydrated with water throughout the day. If a patient becomes dehydrated while taking these medications, this potentially can lead to deleterious effects on the kidneys, although they can be reversible, or to the development of diabetic ketoacidosis.

In patients who have a predisposition for genitourinary yeast infections or urinary tract infections, it is important to emphasize that these patients may be at higher risk of developing those conditions when taking SGLT2 inhibitors. There have been data showing that these medications may lead to increased fractures and amputations, specifically with canagliflozin, although more data are needed to substantiate these findings.

Question

What SGLT2 inhibitor treatment initiation strategies have you employed in the past, particularly with regard to titrating baseline diabetes medication?

Answer

I think it is important to emphasize that the initial therapy for patients with type 2 diabetes should begin with a discussion about diet, exercise, weight loss, and metformin. SGLT2 inhibitors play a role as add-on therapy for patients receiving lifestyle management and metformin who have not achieved optimal glycemic control, with or without insulin. There is also a role for SGLT2-inhibitor therapy in patients you are trying to transition away from insulin or sulfonylureas, especially patients for whom we’d like to promote weight loss.

The overall risk for hypoglycemia is low with these medications, especially when used with metformin therapy. However, in patients who are taking insulin or sulfonylureas, there is an increased risk for hypoglycemia. Therefore, when initiating SGLT2 therapy in these patients who are taking insulin or insulin secretagogues such as sulfonylureas or glinides, it is important to reduce the dose of the medications or completely stop them when starting SGLT2 inhibitors.

In addition, these medications can be very dehydrating. Therefore, in patients who are taking medications such as diuretics, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, or angiotensin-II receptor blockers, it may be important to either reduce the dose of these medications or completely stop them.

Question

What are the long-term benefits of SGLT2 inhibitor treatment you discuss with your patients when considering SGLT2 inhibitor therapy?

Answer

Patients with type 2 diabetes are at an increased risk for cardiovascular disease. Strategies used to lower this risk include blood pressure and lipid lowering employed at each diabetes visit. SGLT2 inhibitors have been shown to have positive cardiovascular outcomes, independent of glycemic control. This was seen in patients with cardiovascular disease, as in the EMPA-REG trial, as well as in patients with cardiovascular disease and without cardiovascular disease, as in the CANVAS trial.

These medications have shown reduced mortality from cardiovascular disease and reduced incidence of hospitalizations resulting from heart failure. This is, therefore, a good class of medications to add on for diabetes therapy for patients with a risk for cardiovascular disease or patients who have a history of heart failure. There are discussions about using these medications as initial therapy or for primary prevention, but we’re not there yet.

Question

Canagliflozin treatment has demonstrated potential renal benefits in certain patients with type 2 diabetes, as shown by the lower incidence of albuminuria progression in the CANVAS trial. Can you review the role of medication as part of a renoprotective strategy in type 2 diabetes?

Answer

SGLT2 inhibitors have also been shown to have renoprotective effects. Both EMPA-REG and CANVAS demonstrated significant renal benefits in patients with type 2 diabetes taking SGLT2 inhibitors. Although the trials were not designed to specifically look at renal outcomes, SGLT2 inhibitors have been shown to prevent deterioration of the glomerular filtration rate and reduce the progression of albuminuria in patients with diabetes-associated kidney disease. This very exciting, as diabetic nephropathy is the most common cause of end-stage renal disease worldwide, and there are data showing the net renoprotective effect of these medications.

However, dedicated renal outcome trials are still needed. Therefore, at this time, I would not recommend that these medications be used for primary prevention. However, in the right setting, these are great options for add-on therapy for patients who need to achieve better glycemic control.

Question

How do you approach conversations with your patients regarding the risk for diabetic ketoacidosis when being treated with SGLT2 inhibitors?

Answer

Euglycemic, usually referring to glucose less than 250 mg/dL, diabetic ketoacidosis has been reported in patients taking SGLT2 inhibitors. The exact mechanism is unknown. However, the overall risk is low. This was found to occur primarily in patients with type 1 diabetes. However, there is also an increased risk for diabetic ketoacidosis in patients with type 2 diabetes who are insulinopenic (ie, not producing enough insulin) or patients with latent autoimmune diabetes in adults. The SGLT2 inhibitors can be very dehydrating, and it is possible that can lead to a situation predisposing a patient for diabetic ketoacidosis. So therefore, at Mount Sinai, when I have a discussion about starting these medications in patients, I tell them about the importance of staying well hydrated with water, and that if they were to develop symptoms of nausea, vomiting, and fatigue, to stop the medication and call the office.

There are probably other situations in which it would make sense to stop the medication, such as if a patient is not feeling well because they have developed food poisoning or gastroenteritis, which are examples of situations when patients may become dehydrated, and therefore stopping the medications might be prudent as well.