Can SGLT2 Inhibitors Offer Options for Type 1 Treatment?

Better insulin formulations and glucose monitors have significantly improved the control of type 1 diabetes (T1D). Large studies in various countries have found that average glycated hemoglobin (A1C) levels have fallen by more than half a percentage point since the 1990s,^1,2 and that the disease shortens lifespan far less than it once did.³ Recent trials, moreover, have shown that sophisticated software can control the disease even better, at least in the short term, by continuously monitoring glucose levels using data to control the timing and precise amount of insulin treatment.⁴

Yet most patients with T1D still have elevated levels of A1C, and even those who do manage to keep their levels in the optimal range, below 7%, have significantly higher mortality rates than similar patients who don’t have T1D.⁵ Researchers, therefore, are looking for new tools to manage the disease, and many are looking hardest at medications developed to treat type 2 diabetes (T2D).

A class of drugs called sodium-glucose co-transporter 2 (SGLT2) inhibitors has attracted particular interest. Indeed, all 3 such drugs that are FDA-approved to treat T2D—dapagliflozin (Farxiga), canagliflozin (Invokana) and empagliflozin (Jardiance)—are under investigation for use in patients with T1D. This interest stems not only from the ability of SGLT2 inhibitors to reduce A1C levels, but also from their docu tions in blood sugar levels.

Early phase trials indicate that SGLT2 inhibitors perform both these functions in patients with T1D, but there is little evidence, to date, that such effects improve long-term outcomes. Obesity has not been common in the T1D population for long,⁶ so there is no proof that obese patients fare worse in the long run than thinner patients. As for the benefits of glycemic stability, patients have long reported that dramatic changes in blood sugar make them feel lousy, but the first decent evidence to date comes from a 2015 paper that found dramatic cardiovascular benefits in SGLT2 inhibitor users.

Alas, that study only looked at patients with T2D.

“Right now, the support for using SGLT2 inhibitors in T1D patients is weak. The trials that have been published, so far, demonstrate short-term safety and show us that these medications affect various biomarkers in ways that could produce long-term health benefits. The phase 3 trials are just getting under way, though, so we won’t have anything resembling long-term data on large numbers of patients for some time yet. As is true for all regulatory studies, the ‘longterm’ trial duration is 6 to 12 months using weight and A1C as end points, as opposed to actual microvascular or macrovascular outcomes,” said Irl B. Hirsch, MD, professor of medicine at the University of Washington.

“All that noted, I’m optimistic about the potential impact of SGLT2 inhibitors in T1D treatment, as are other researchers. The dangers of obesity have been so well established in virtually every population, that it’s hard to believe obese type 1 patients (now a common phenotype) would not benefit from treatment that kept them 10 pounds lighter than they’d otherwise be for decades on end. It’s also getting harder to believe that the abnormal rise and fall of blood sugar in type 1 patients, even those patients with low A1C levels, plays no part in their complications. Although to date we don’t have definitive data on the glucose variability hypothesis, it’s logical to think that SGLT2 inhibitors will help, which is why it’s important to have trials and also why it’s important to have randomized double-blinded trials that don’t let such preconceptions obscure the truth.”

There is, of course, significant evidence that moderate weight loss considerably improves outcomes among obese people in all populations, but the most concrete and compelling reason for optimism about the use of SGLT2 inhibitors in patients with T1D may come from an article that was published just this September in the New England Journal of Medicine.⁷

Some 7020 patients with previous cardiovascular disease were randomized among empagliflozin 10 mg, empagliflozin 25 mg, and placebo and then followed for a mean period of 3.1 years, while investigators tallied deaths from cardiovascular causes, nonfatal myocardial infarctions, and nonfatal strokes. At least 1 such event occurred in 490 (10.5%) of 4687 patients in the pooled empagliflozin group, and in 282 (12.1%) of the 2333 patients in the placebo group. Analysis of the relative hazard ratio (HR) of empagliflozin users to placebo users found an effect that just barely reached significance (HR, 0.86; 95% CI, 0.74-0.99; P = .04 for superiority). Indeed, there were no significant differences between the rates of myocardial infarction or stroke. Further analysis, however, found that empagliflozin use was significantly associated with a lower risk of death from cardiovascular causes (3.7% vs 5.9%; relative risk reduction [RR], 38%), hospitalization for heart failure (2.7% vs 4.1%; relative RR, 35%), and death from any cause (5.7% vs 8.3%; relative RR, 32%).

The investigators specifically noted that such results cannot be assumed in other T2D populations with differing characteristics (let alone T1D patients, who were not mentioned at all). They also noted that the trial was designed to find effects rather than explain their causes.

“The mechanisms behind the observed benefits are speculative,” the authors of the paper wrote. “We infer that the mechanisms behind the cardiovascular benefits of empagliflozin are multidimensional and possibly involve changes in arterial stiffness, cardiac function, and cardiac oxygen demand (in the absence of sympathetic-nerve activation), as well as cardiorenal effects, reduction in albuminuria, reduction in uric acid, and established effects on hyperglycemia, weight, visceral adiposity, and blood pressure.”

The figures from the trial were immediately hailed as “a landmark result,” by Steven E. Nissen, MD, the chairman of cardiovascular medicine at the Cleveland Clinic, and the architect of the trial design that’s currently used to test the cardiovascular impact of all new medications for diabetes. Better still, officials from Johnson & Johnson announced that they expect similar cardiovascular trial results from their drug canagliflozin, and all other drugs in the class.⁸

The question, of course, is whether SGLT2 inhibitors will produce similar effects in T1D patients or even any subgroup of T1D patients. While a large and lengthy trial could answer that question with any degree of certainty, results from trials published so far suggest that SGLT2 inhibitors have similar basic effects in patients with both T1D and T2D.

A phase 2a trial of dapagliflozin,⁹ for example, randomly assigned 70 adults with T1D to 2 weeks of placebo or 1 of 4 doses of the once-daily pill: 1 mg, 2.5 mg, 5 mg, or 10 mg. At the end of the study period, investigators noted that pharmacokinetic parameters were similar to those observed in patients with T2D. Glucosuria rose 88 grams per day (95% CI, 55 to 121 g/d) with dapagliflozin 10 mg, and fell by 21.5 grams per day (95% CI, −53.9 to 11.0 g/d) with placebo.

A week into the trial period, users of dapagliflozin 10 mg saw the following changes: 24-hour average blood glucose, −2.29 mmol/L (95% CI, −3.71 to −0.87); mean amplitude of glycemic excursions, −3.77 mmol/L (95% CI, −6.09 to −1.45); mean change in total daily insulin use, −16.2% (95% CI, −29.4% to −0.5%). Placebo users, on the other hand, saw smaller changes: 24-hour blood glucose, −1.13 mmol/L (95% CI, −3.63 to 1.37); mean amplitude of glycemic excursions, −0.45 mmol/L (95% CI, −4.98 to 4.08); mean change in daily insulin use, 1.7% (95% CI, −22.8% to 33.9%), respectively. These differences did not reach the level of significance, as measured by the 95% confidence intervals, but, as the investigators noted, they were about what you would see in T2D patients after the same period of time.

There were no signs of weight loss or blood pressure reduction among either dapagliflozin or placebo users during the 2-week trial, but patients from both groups (unlike their counterparts in almost any T2D trial) began the trial with healthy blood pressure measurements and body mass indexes. As for adverse events, there were no significant differences in hypoglycemia among the various groups, nor were there incidents of the adverse events that are most associated with the use of SGLT2 inhibitors: infections of the urinary tract and genitals. Such infections are probably unavoidable in the long run because all the medications in the class reduce A1C levels by reducing the amount of glucose that enters the blood via SGLT2 in the proximal renal tubules. This, in turn, increases the amount of glucose excreted via urine as well as the total amount of urine that users excrete. SGLT2 inhibitors thus have a diuretic effect and leave some patients prone to infection. (They also increase the frequency with which patients must urinate, so they should be taken in the morning rather than before bed.)¹⁰

Indeed, investigators did find an elevated risk of infection when they conducted a phase 2 study that randomized 300 patients among 18 weeks of canagliflozin 100 mg, canagliflozin 300 mg, or placebo.¹¹ They also saw the weight loss and A1C reductions that SGLT2 inhibitors produce in T2D patients. Mean weight changes were -4.2 kg (-5.1% of baseline weight) for canagliflozin 300mg users, -2.6 kg (-3.1%) for canagliflozin 100mg users, and +0.2 kg (+0.3%) for placebo users. Mean change in A1C levels was -0.24 percentage points among canagliflozin 300mg users, -0.27 percentage points among canagliflozin 100mg users, and +0.01 percentage points among placebo users. The percentage of users who achieved both end points of the trial—an A1C reduction of at least 0.4 percentage points and no weight gain—was 41.4 in the canagliflozin 300mg groups, 36.9 in the canagliflozin 100mg group, and 14.5 in the placebo group. Nevertheless, canagliflozin use was not associated with any increase in hypoglycemia.

Results have been similar in trials of empagliflozin.^12,13 A third trial, moreover, measured the ability of empagliflozin to affect arterial stiffness and heart rate variability (HRV) in patients with T1D and found positive effects.¹⁴ Investigators measured HRV and circulating adrenergic mediators during clamped euglycemia (blood glucose 4 to 6 mmol/L), and hyperglycemia (blood glucose 9 to 11 mmol/L) in 40 normotensive T1D patients. They then treated the patients with 8 weeks of empagliflozin and took the measurements again.

The euglycemia measurements showed declines in systolic blood pressure (111 ± 9 to 109 ± 9 mm Hg, P = .02) and augmentation indices at the radial (−52% ± 16 to −57% ± 17, P = .0001), carotid (+1.3 ± 17.0% to −5.7 ± 17.0%, P < .0001) and aortic positions (+0.1 ± 13.4% to −6.2 ± 14.3%, P < 0.0001). The hyperglycemia measurements showed no changes in blood pressure but similar effects on arterial stiffness.

“At the very least, the results we’ve seen so far indicate that SGLT2 inhibitors may prove to be another tool for doing the same sorts of things to reduce blood glucose that insulin does, but in a completely unique manner. And that alone would be a valuable addition because we need more tools in this fight against diabetes. Most people with type 1 diabetes do not have the condition under good control,” said Robert Henry, MD, the lead author of both the canagliflozin and dapagliflozin studies and the head of both the Center for Metabolic Research and the Section of Endocrinology, Metabolism & Diabetes at the Veterans Affairs Healthcare System of San Diego.

“If all goes well in clinical trials, SGLT2 inhibitors may prove to add considerable advantages to the management of type I diabetes—and not only for the growing number of type 1 patients who suffer from obesity and high blood pressure. Even patients who consistently keep their A1C levels below 7% may show greater glycemic variability throughout the day than people who don’t have diabetes. SGLT2 inhibitors smooth out similar highs and lows in type 2 patients. They make mountains into hills and valleys into ditches and they seem to do much the same thing in type 1 patients. They also bring many other biomarkers and metabolic measurements that are unaffected by insulin closer to normal, and there is real hope their mechanism of action will benefit patients significantly more than you’d expect solely from their effect on A1C.”

Companies that develop SGLT2 inhibitors certainly seem to have real hope of receiving approval for the treatment of T1D patients. Bristol-Myers Squibb and AstraZeneca are currently recruiting for a phase 3 study of dapagliflozin in T1D patients.¹⁵ Lilly and Boehringer, meanwhile, are recruiting for a similar study of empagliflozin.¹⁶ (The database at ClinicalTrials.gov did not show any comparable study for canagliflozin.)

None of the companies involved would provide researchers to comment on the phase 3 trials or their expectations for SGLT2 inhibitors in T1D patients. The lead academic investigators also declined comment. References

1. Gerstl EM, Rabl W, Rosenbauer J, et al. Metabolic control as reflected in HbA1C in children, adolescents and young adults with type 1 diabetes mellitus: combined longitudinal analysis including 27,035 patients from 207 centers in Germany and Austria during the last decade. Eur J Pediatr. 2008;167(4):447-453.

2. Rosenbauer J, Dost A, Karges B, et al. Improved metabolic control in children and adolescents with type 1 diabetes. Diabetes Care. 2012;35(1):80-86.

3. Miller RG, Secrest AM, Sharma RK, Songer TJ, Orchard TJ. Improvements in life expectancy of type 1 diabetes: the Pittsburgh epidemiology of diabetes complications study cohort. Diabetes. 2012;61(11):2987-2992.

4. Russell SJ, El-Khatib FH, Sinha M, et al. Outpatient glycemia control with a bionic pancreas in type 1 diabetes. N Engl J Med. 2014;371(4):313-325.

5. Lind M, Svensson AM, Kosiborod M, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med. 2014;371(21):1972-1982.

6. Wood K. Young people with diabetes increasingly likely to be obese; experts urge dietary changes. DiabetesCommunity.com http://www.diabetescommunity.com/news/2015/07/young-people-with-type-1-increasingly-likely-to-be-obese-experts-urge-dietary-changes.html. Published July 9, 2015. Accessed November 5, 2015.

7. Zinman B, Wanner C, Lachin JM, et al.EMPA-REG OUTCOME Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes [published online September 17, 2015]. N Engl J Med. doi:10.1056/NEJMoa1504720.

8. Pierson R. Update 1:J&J says its diabetes drugs should have the same survival edge as Lilly’s. Reuters website. http://www.reuters.com/article/2015/10/13/johnsonjohnson-invokana-idUSL1N12D10720151013#xZtbuXqkBs4fdJYs.97. Published October 13, 2015. Accessed November 5, 2015.

9. Henry RR, Rosenstock J, Edelman S, et al. Exploring the potential of the SGLT2 inhibitor Dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study. Diabetes Care. 2015;38(3):412-419.

10. Smith A. Studies show SGLT2s also help control hypertension, eliminate some side effects. Am J Manag Care. 2015;21(SP5):SP154-SP155.

11. Henry RR, Thakkar P, Tong C, Polidori D, Alba M. Efficacy and safety of canagliflozin, a sodium glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 2 diabetes [published online October 20, 2015]. Diabetes Care. doi:10.2337/dc15-1730.

12. Pieber TR, Famulla S, Eilbracht J, et al. Empgliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1). Diab Obes Metab. 2015;17(10):928-935.

13. Perkins BA, Cherny DZ, Partridge H, et al. Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: results of an 8-week open-label proof-of-concept trial. Diabetes Care. 2014;37(5):1480-1483.

14. Cherney DZ, Perkins BA, Soleymanlou N, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. CardiovasEc Diabetol. 2014;13:28.

15. DEPICT2. Dapagliflozin Evaluation in Patients With Inadequately Controlled Type 1 Diabetes. Clinical Trials website. https://clinicaltrials.gov/ct2/show/NCT02460978. Accessed November 5, 2015.

16. EASE-2. Empagliflozin as Adjunctive to insulin therapy in Type 1 Diabetes Over 52 Weeks. Clinical Trials website.https://clinicaltrials.gov/ct2/show/NCT02414958?term=empagliflozin&rank=25. Accessed November 5, 2015.

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