SGLT2i: Good T2D Treatment in Older Adults, Safe for Kidneys

The latest study findings on the safety and efficacy of the SGLT-2i, ertugliflozin, offer strong assurance for use in managing diabetes in individuals at 65 years plus, and in others, without concerns for adverse effects on renal function.

with Richard Pratley, MD, and Juan Pablo Frias, MD

Prescribing a sodium-glucose cotransporter 2 inhibitor (SGLT2i) to patients with type 2 diabetes (T2D) appears likely to reduce the risk of cardiovascular events and overall mortality as well as forestall renal failure in those with established disease,1 according to data from a recent review of the literature.

Adults aged 65 years and older with diabetes require treatment for heart and kidney problems.Add ertugliflozin to the drugs that work just as well in managing diabetes complications in older adults as in younger patients. Photo: fatcamera@istock

Assessing Further Benefits of SGLT-2i Therapy in Type 2 Diabetes

The mechanism for the efficacy of SGLT-2i arises from the inhibition of SGLT-2 proteins originating in the renal tubules, allowing for the reabsorption of glucose back into circulation. This process, in turn, promotes glucose excretion into the urine. Adding a reduction in kidney impairment to the existing clinical data points to the SGLT-2 inhibitors as well-rounded glucose lowering agents: reducing hemoglobin A1c (HbA1c) levels, supporting weight loss and reducing blood pressure.1,2

 A further advantage has been confirmed—a low risk of hypoglycemia has been identified as a postive outcome of treatment with this class of drugs. There are four SGLT-2i currently on the market in the United States, including ertugliflozin (Steglatro), canagliflozin (Invokana), empagliflozin (Jardiance), and dapagliflozin (Farziga), with some notable differences to inform your treatment planning.2

Patients with severe kidney dysfunction or who are on dialysis, for example, are warned not to take ertuflilozin, which also induces dehydration and vaginal yeast infections, as well as, balanitis and balanoposthitis as possible side effects.2

Now, two poster presentations evaluating pooled analyses of the SGLT-2i, ertugliflozin (Steglatro), were presented at the European Association for the Study of Diabetes meeting in Barcelona, Spain. The aim of these analyses was to both shore up and expand on existing research to more closely assess the efficacy of ertugliflozin in the older population and the renal effects of those with diabetes.3,4

One analysis compared the use of ertugliflozin in those under and over age 65 year who were on the medication as compared to those not taking an SGLT-2i;3 the other study evaluated for any renal effects.4 In both cases, the findings overall were good, researchers said.

Sodium-Glucose Cotransporter 2 Inhibitors Effective Across Ages

"The bottom line is, this class of medications, and specifically ertugliflozin, can be used safety in the older patient population with comparable efficacy with that which we see in a younger patient population," says Richard Pratley, MD, a coauthor of the analyses of ertulgliflovin in the elderly. He is medical director of the Adventist Health Diabetes Institute and diabetes program lead of their Translational Research Institute for Metabolism and Diabetes in Orlando, Florida.

''There are always concerns about safety in older patients," Dr. Pratley told EndocrineWeb, ''but this data was quite reassuring that the older patients did just fine."

While he was not involved directly in the analysis of the data on renal function, he acknowledged being familiar with that research and so offered some insights: "Renal function is preserved when compared to people not on the drug" is the key finding from this inquiry, he said. “That is important because a decline in kidney function is a common occurrence in people with diabetes and [the SGLT-2i, ertugliflozin] seems to slow that process down.”

Examining Treatment Response to Ertugliflozin in Patients Beyond Age 64

The objectives of the study of ertugliflozin in older patients with type 2 diabetes was to assess the efficacy of this pharmacotherapy in those 65 years and over. The researchers evaluated data from seven randomized, double-blinded phase 3 trials, including one study of patients who had moderate renal impairment, comprising the ''broad pool." A subset of three placebo-controlled studies made up the ''placebo pool."

In this broad pool of participants—3,605 patients under age 65 years and 1,354 individuals over 64 years—each individual were given either ertugliflozin (5 mg or 15 mg) plus sitagliptin or non-ertugliflozin (ie, placebo, glimepiride, or sitagliptin) in addition to background therapy for up to 104 weeks.1

The patients in the placebo cohort—which included 1,189 individuals under 65 years and 355 individuals age 65 years and older—were randomized to receive either a dose of ertugliflozin (either 5 or 15 mg) or placebo for a minimum of 26 weeks but were permitted to extend their trial.1

Among the highlighted findings, the authors reported:

At week 26, the participants receiving ertugliflozin achieved a meaningful reduction in HbA1c and fasting blood glucose from baseline values compared with those receiving the placebo—in both age groups. In assessing for change in HbA1c, for instance, patients in the 15 mg group showed a decline of 11.4 mmol among those under 65 group and a reduction of 8.7 mmol in the cohort of 65 year olds and up. The change in HbA1c in the placebo group was -9.4 and -6.6, for those under age 65, and 65 years and above, respectively.1

In addition to improving glycemic control, ertugliflozin demonstrated improvements in body weight and systolic blood pressure.

The incidence of adverse events (AEs) and serious AES were higher in the older patients; however, there was no notable difference when comparing those receiving the SGLT-2i medication against placebo in either age group. The number of deaths (8 in the younger cohort; 13 among those 65 years plus) were too few to draw conclusions,1 the researchers said.

Those 65 years or older experienced a higher incidence of volume depletion when treated with the drug. However, Dr. Pratley said, these numbers were very small, too. There were 21 patients in the older cohort compared to four people in the untreated group of participants age 65 years or above.

Pooled Analyses—A Closer Look at Renal Effects of SGLT-2i in Diabetes

In another presentation,2 this team of researchers reviewed two randomized clinical trials assessing ertugliflozin versus non-ertugliflozin for its effect on kidney function. The treated group included 652 patients while there were 644 randomized to the placebo group, all of whom had type 2 diabetes.

They looked at changes in estimated glomerular filtration rate (eGFR) and assessed for albuminuria. Over 104 weeks, eGFR values were higher with the ertugliflozin cohort than in the control group. The researchers concluded that this is suggestive of renal function preservation.4

Treating for Multiple Comorbidies: Applications in Clinical Practice

For endocrinologists, the research findings are more confirmatory than offering any new clinical data, said Juan Pablo Frias, MD, medical director and principal investigator of the National Research Institute in Los Angeles, California; he is also assistant clinical professor of medicine at the University of California in San Diego.

Among the key findings, Dr. Frias told EndocrineWeb, are the lower HbA1c, which he considered robust. The amount of weight loss and change in blood pressure were also noteworthy, he said. "From an efficacy standpoint, the patients over 65 years did just as well as those under," which is very good news.

Although there was a small tendency toward more adverse effects relative to volume depletion and renal events, those occurrences are typical of that seen in older patients as compared with younger individuals for most medications, he said. In addition, acute kidney injury was not reported in any patients not receiving ertugliflozin and those taking 5 milligrams of the SGLT2i, but two patients on the higher dose SGLT2i (15 mg) did experience this adverse effect.

"The conclusions in the abstract [on older patents] are correct," Dr. Frias said. Again, "the efficacy was very good" and safety is not deemed of any concern. “And the analysis on renal function was also confirmatory of previous research.”

Other SGLT2 Inhibitors Offer Renoprotective Effects Too

To evaluate the efficacy of the SGLT2i class of drugs with regard to chroinc kidney disease, Neuen et al conducted a review of the literature to provide a clearer clincal understanding of their role in people with type 2 diabetes. Four randomized trials that targeted cardioavscular disease or kidney dysfunction met the inclusion criteria were selected for analysis and reflected data from three SGLT2i: empagliflozin, canagliflozin. and depagliflozin.6-8

Among patients who were taking one of the prescribed SGTL2 inhibitors, significant reduction in the risks of dialysis, mortality associated with kidney failure, and acute renal disease were found, according to the authors. There was also a decrease in end stage renal disease.5

While the authors reports some evidence for a relative effect of SGLT2 inhibitors on declining kidney function (Ptrend = 0.073), the findings of benefit were more clear and pronounced across all eGFR subgroups, including patients who presented with a eGFR of 30–45 mL/min per 1.73 m² (P = 0·0080) at baseline. Patterns of renoprotection were also found between all four studies regardless of baseline albuminuria (Ptrend = 0.66) and use of RAS blockade (Pheterogeneity = 0.31).5

The researchers concluded that for patients with type 2 diabetes, the use of these SGLT2 inhibitors would provide improved outcomes with regard to prevent progression of kidney disease outcomes.5-9

Dr. Pratley reports no financial conflicts of interest regarding this research while Dr. Frias serves on the Merck speaker's bureau and has studied ertugliflozin as an investigator. Financial disclosures for the other poster authors can be found on meeting abstract page.

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