Ask the
Experts
Akankasha Goyal, MD
 
SGLT2 Inhibitors in the Treatment of Type 2 Diabetes
 
Akankasha Goyal, MD

Hospital and Institutional Affiliations

Instructor of Medicine, NYU Langone Health

Practice Niche

Endocrinology


Question 1. How do you approach risk-benefit discussions regarding sodium-glucose cotransporter2 (SGLT2) inhibitor use in patients who have type 2 diabetes?


Answer
When we start a patient on any antihyperglycemic medication, we need to be careful about a couple of things. The first is to make sure the medication doesn't cause any weight gain, because these patients are trying to lose weight and they are trying to maintain their lost weight. In addition, we want to be confident that the medication does not cause hypoglycemia because that can have far-reaching consequences. It increases your appetite and food cravings, causing weight gain; it can cause dizziness and lightheadedness, and can lead to accidents because of that; it can cause arrhythmias and cardiovascular events; it can cause coma and death; and it can result in hospitalization, which adds to financial, economic, and personal morbidities.

The SGLT2 class of inhibitors are novel. They inhibit the sodium-glucose cotransporter in the proximal tubules of the kidney, which causes loss of glucose in the urine. They therefore help in decreasing blood glucose. They also help with weight loss because patients are losing calories through the urine. SGLT2 inhibitors help decrease systolic blood pressure because patients are losing fluid and that has a positive effect on the vasculature and stiffness of the arteries. SGLT2 inhibitors do not cause hypoglycemia.

SGLT2 inhibitors have been shown to complement the action of other antidiabetic medications without interfering with them, having interactions with them, or causing more side effects. They have been shown to reduce albumin excretion in the urine (albuminuria), and they have long-term renal benefits, which we will talk about later. They have also been shown to improve cardiovascular mortality, cardiovascular morbidity, and all-cause mortality. These are the benefits, which far outweigh the risks.

However, as with any medication, risks exist. Because SGLT2 inhibitors cause so much fluid loss in terms of increased urination, they can also cause symptomatic hypotension because of decreased intravascular volume. We tell our patients to assess their volume status and keep hydrated while on this medication because they will be urinating a lot. SGLT2 inhibitors can also cause acute kidney injury because of the intravascular volume contraction, so we keep an eye on kidney function in these patients, and if the glomerular filtration rate [GFR] is less than 45, we try to avoid it. It can develop into urosepsis because there is glucose in the urine, so there is a greater risk for urinary tract infection and pyelonephritis, especially in patients who have a history of urinary tract infections.

Genital mycotic infections can occur in patients known to have a history of these infections. SGLT2 inhibitors can also cause a slight increase in low-density lipoprotein cholesterol levels, but these patients should also be taking a statin as they are already at high risk for heart disease. In addition, canagliflozin has been shown to be associated with a slight increase in lower extremity amputations, especially toe and metatarsal amputation. There have been minimal above-ankle amputations, although that is currently being studied further.


Question 2. What SGLT2-inhibitor treatment initiation strategies have you employed in the past, particularly with regard to titrating baseline diabetes medication?


Answer
One of the first-line medications for diabetes is metformin. Our aim is to increase the dosage of metformin to the maximum that is tolerated by the patient. If a patient is at the maximum dose of metformin, then we would add an SGLT2 inhibitor. If the patient cannot tolerate the maximum dose of metformin, we can still add the SGLT2 inhibitor, but we start with a low dose of the medication. The 3 medications approved in this class include canagliflozin, dapagliflozin, and empagliflozin. All of these come in 2 doses: a low dose and a high dose. We start with the lower dose and we expect fingerstick glucose values to improve within a week to 2 weeks. If the patient's levels have not reached hemoglobin A1c goals or glucose goals, then we can up-titrate the medication to the high dose within 3 months. There has been a very small, modest benefit in glucose control between the low dose and the high dose. Therefore, often patients will come in on the low dose because the benefit with the higher dose may not be profound.

An important consideration is that before initiating the medication, volume status has to be assessed for every patient. We have to ensure that they do not have hypotension or euvolemia. We tell them that they have to keep hydrated and have 6 to 8 glasses of water every day because the glucose will be depleted by urination, so they need to maintain intravascular volume.


Question 3. What are the long-term benefits of SGLT2- inhibitor treatment you discuss with your patients when considering SGLT2-inhibitor therapy?


Answer
As I mentioned, SGLT2 inhibitors are a novel class of medication with 2 far-reaching benefits: one is on the kidneys and the other is on the heart. As we know, most patients with diabetes either have heart disease, or heart disease will develop in the future. There are very few things we can do for patients with diabetes and advanced heart disease. SGLT2 inhibitors are medications that have been shown to decrease all-cause mortality. The hazard ratio is 0.8, so it has been very effective in reducing all-cause mortality. They have also been shown to decrease major adverse cardiac events, which is a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. They have also been shown to decrease hospitalization from heart failure, which has decreased by approximately 35% in trials done. The curves start separating as early as 2 weeks after starting the medication.

If you want to put this into perspective, you can say for every 1000 patients who are treated for 3 to 5 years, you will have a decrease in 23 to 25 major adverse cardiac events, there will be approximately 17 fewer patients with the renal composite end point, and there are 16 fewer patients being hospitalized for heart failure, which is profound.

In terms of the kidneys, SGLT2 inhibitors have been shown to decrease the progression of albuminuria. They have also been shown to have a profound benefit in the renal composite end point, and the hazard ratio for that is as high as 0.6, which translates to a 40% decrease in doubling of the serum creatinine, need for renal replacement therapy or being on dialysis, or renal death, which again is profound.


Question 4. 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
The most common cause of renal failure in the Western Hemisphere is diabetes. It has been shown that 30% of patients with diabetes will have some kind of renal disease, either early- or late-onset renal disease. This group of medications has been shown to decrease albuminuria significantly by approximately 27%. It has also been shown to be associated with a dramatic reduction in the renal composite end point, as I discussed earlier, which is a composite of a 40% reduction in eGFR, end-stage renal disease, or renal death. Therefore, we keep checking the serum creatinine in these patients, at least every 6 months. We also check with a spot albumin-to-creatinine ratio at least annually for these patients.

The mechanism of the renoprotective effects of these medications is not very clear, but there are a few possibilities. One is a reduction in the intraglomerular pressure, either caused by the atrial natriuretic peptide or the glomerulotubular feedback. The second is a modification in the tubular absorption of albumin. The third is a reduction in the GFR in these patients that can cause a decrease in filtration and thereby decrease albuminuria. It is unclear, but there is an ongoing trial — the CREDENCE trial with canagliflozin — and the end point is focused on the renal composite end point. Results of that study are expected in 2019 or 2020, and they should provide us with more information about why we have these benefits in the kidneys.


Question 5. How do you approach conversations with your patients regarding the risk for diabetic ketoacidosis when being treated with SGLT2 inhibitors?


Answer
Diabetic ketoacidosis is a serious, life-threatening complication that requires urgent hospitalization. We tell our patients if they have nausea, vomiting, abdominal pain, or any signs of metabolic acidosis, even if their blood glucose is 200 or 250, they must stop the medication, go to urgent care, and get their urine checked for ketones. Diabetic ketoacidosis can occur even at glucose levels of 200. People need to receive medication for the ketoacidosis and stop the [SGLT2 inhibitor] and then we can determine whether the patient needs the [SGLT2 inhibitor] again in the future.

To prevent ketoacidosis, I tell my patients — first and foremost — if you are undergoing any surgery, stop the [SGLT2 inhibitor] a few days ahead of time. If you have the flu, stop the [SGLT2 inhibitor] until you recover from the flu. If you have any kind of nausea or vomiting, a stomach bug, or any gastrointestinal disease, do not take your medication until you recover from the condition.

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