Kidney Week 2014 conference attendees had come to learn about “SGLT2 Inhibition: From Basic to Clinical,” but as befits a nephrology meeting, they first had to learn about kidney's role in glucose production.
“It's both taking up glucose as an energy source and it's producing it,” said Ralph A. DeFronzo, MD, FACP, a professor of medicine and division chief of diabetes at the University of Texas Health Science Center in San Antonio.
The kidney also filters and reabsorbs glucose, Dr. DeFronzo told attendees at the conference, held in Philadelphia in November 2014. “The kidney filters about 180 grams of glucose per day, and all of this glucose is reabsorbed. Some 90% is reabsorbed by the SGLT2 transporter, the other 10% by the SGLT1 transporter, and the net result is that no glucose appears in the urine,” he said.
SGLT2 inhibitors, a new class of diabetes drugs, change that dynamic. Canagliflozin (Invokana) was approved by the FDA in March 2013, followed by dapagliflozin (Farxiga) in January 2014 and empagliflozin (Jardiance) in August.
Dr. DeFronzo and other experts talked about the mechanisms, benefits and risks, and remaining uncertainties of these new drugs, which lower blood glucose through their effects on the kidney, during the conference session, which was sponsored by an independent educational grant from AbbVie.
How it works
The effectiveness of the SGLT2 inhibitors relies on the fact that although the kidney usually reabsorbs all the glucose it filters, at a certain blood glucose level, it will start excreting sugar in urine. In nondiabetic patients, that cutoff is usually around 180 mg/dL, but it is higher in diabetics, even those who have well-controlled disease.
“With an A1c of just 6.5[%], the threshold is 206 [mg/dL],” said Dr. DeFronzo. “It's very paradoxical. The higher your A1c, the more the signal goes to the kidney to take back glucose.”
An SGLT2 inhibitor lowers that threshold in anyone who takes it by preventing the SGLT2 transporter from reabsorbing glucose. “You start spilling at a glucose of 40 [mg/dL]. That's why everybody, diabetic and nondiabetic, as long as you have reasonable renal function, is going to respond to this drug,” said Dr. DeFronzo.
The result is that a patient on a drug in this class will excrete between 70 and 100 g of glucose in his urine during a day. That glycemic lowering effect can be intensified by combining the SGLT2 inhibitor with other antidiabetic medication. “You can put it with any other drug, because the mechanism of action to lower glucose is different. You'll always get the complete additive effect,” said Dr. DeFronzo.
Although they cause glucose excretion in everyone, the drugs do have differing effects in individual patients, noted Ele Ferrannini, MD, PhD, a professor of medicine at the University of Pisa in Italy and an adjunct clinical professor of medicine at the University of Texas Health Science Center.
“There is a direct association between glycosuria, induced pharmacologically, and the eGFR [estimated glomerular filtration rate] and the fasting glucose level. The clinical implication could be that you ... predict in the individual patient the amount of glycosuria that this patient is likely to have in response to this treatment,” said Dr. Ferrannini.
Patients with higher eGFR, based on creatinine measurement, and higher fasting glucose levels are likely to have greater response to the drug. “You may have someone with an eGFR of 50 [mL/min/1.73 m2] but a high plasma glucose concentration, or somebody with an eGFR of 120 [mL/min/1.73 m2] but with a low plasma glucose concentration presenting with the same amount of glycosuria,” he said.
Another unusual attribute of the drug class is its speed of onset. “Glycosuria was induced within minutes [in studies]. It's a fast-on effect,” said Dr. Ferrannini. “It continues for 24 hours, perhaps a bit longer. Then, when you stop treatment, glycosuria disappears, so this is a fast-off kind of effect.”
In addition to reducing blood glucose, trials of the drug class have shown a number of other effects. “Weight decreases by about 2 to 3 kilograms, and we also see that blood pressure declines by about 4 to 6 mm Hg systolic,” said David Cherney, MD, PhD, an assistant professor of nephrology at the University of Toronto in Canada.
Weight loss from the drug makes sense, given that patients are effectively urinating sugar, but the observed effects are a little mysterious, according to Dr. Ferrannini. “The expectation of at least simple-minded people like me is that you are leaking something like 200 to 300 calories per day into the urine [and that would correspond to] body weight you should be losing when you are chronically on this drug,” he said.
But patients who have taken the drug haven't progressively lost weight with continued use. Instead, they lose a few kilos and then plateau at their new weight.
“There can only be one explanation, and that is that intake, particularly carbohydrates, but caloric intake increased after the initial 10 to 12 weeks to make up for the calorie loss,” Dr. Ferrannini said. He noted that patients with lower body mass index and higher GFR were most likely to lose less weight than expected.
That finding led Rajiv Agarwal, MD, professor of medicine at Indiana University in Indianapolis, to offer an alternative explanation for the weight loss. “Caloric loss can lead to body weight changes and change in lean body mass, but another important consideration is change in volume,” he said. “If these drugs are truly also wasting sodium in the urine, which they do, then it's possible that some of the weight loss that you see with these drugs may be related to sodium loss.”
Volume depletion is one of the potential side effects of SGLT2 inhibitors. Factors that increase that risk include a low-sodium diet, a baseline low blood pressure, and concomitant use of loop diuretics. “Elderly people are more susceptible,” added Dr. Agarwal.
Canagliflozin specifically has also been associated with hyperkalemia. “How do these drugs cause hyperkalemia? It turns out concomitant K-sparing diuretic use or blockers of the renin-angiotensin-aldosterone system. These are the same drugs that are typically associated with hyperkalemia,” Dr. Agarwal said.
There are also the adverse effects that one would expect from urinating glucose: genital mycotic infections and urinary tract infections, polyuria, and hypoglycemia. In addition, SGLT2 inhibitors interact with certain drugs. Patients on rifampin, phenobarbital, phenytoin, or ritonavir will require a higher dose of SGLT2 inhibitors to be effective, while patients taking digoxin will have higher levels of that drug if they are also taking an SGLT2 inhibitor.
The drugs also change cholesterol levels, definitely increasing HDL cholesterol levels but also possibly increasing LDL cholesterol, with the overall cardiovascular effects still uncertain, the experts said.
“Finally [there's] a concern about bladder cancer with dapagliflozin only—a handful of cases. We are not sure at all whether there's a cause and effect relationship there, but it's in the package insert,” said Dr. Agarwal.
Experts are also unsure about SGLT2 inhibitors' long-term impact on the kidney. “Do these drugs cause renal protection like ACE [angiotensin-converting enzyme] inhibitors do or renal harm? We don't know,” said Dr. Agarwal.
On the harm side, data show that patients have an increase in serum creatinine on the drugs. “The eGFR falls by at least 10% to 15%,” said Dr. Agarwal. The increase in creatinine could possibly lead to acute kidney injury (AKI). If a patient develops AKI, “you have to keep in mind could it be these drugs, the SGLT2 inhibitors, producing AKI, and you might have to back off [them],” he said.
On the other hand, the decrease in GFR was a helpful effect of the drugs in trials of patients with type 1 diabetes and hyperfiltration. “In response to empagliflozin, GFR decreased by 33 [mL/min/1.73 m2] or a 20% reduction. In contrast, there was no significant effect on GFR in the normal filtration group,” said Dr. Cherney. “The magnitude of the effect is probably similar to what we usually use in renal protective therapies.”
Also on the plus side, patients on SGLT2 inhibitors have also shown improvement in albuminuria. “Truly, the safety of these drugs will be much more complete when we do this large randomized trial with long-term follow-up,” said Dr. Agarwal. He noted that the CREDENCE trial is currently assessing the impact of canagliflozin on renal and cardiovascular outcomes in patients with diabetic nephropathy, specifically albuminuria and an eGFR between 30 and 90 mL/min/1.73 m2.
Dr. Cherney is also continuing to study the effect of SGLT2 inhibitors on the kidney, particularly when combined with a renin-angiotensin-aldosterone system blocker. “Our next series of experiments will hopefully be to look at adding these two agents together to hopefully safely normalize hyperfiltration without excessively reducing intraglomerular pressure and increasing risk for acute kidney injury,” he said.
Farther in the future, Dr. DeFronzo hopes to see even more innovative drug combinations, because he's not yet satisfied with the quantity of glucose removed by the SGLT2 inhibitors. “I've always said you should block SGLT1 along with SGLT2,” he said. “If you put an SGLT1 inhibitor together with an SGLT2 inhibitor, you should be able to double or even more the efficacy of the drug. Drug development really should be thinking [about this].”