What Is the Place of New SGLT-2 Inhibitors in Therapy and on the Formulary?

Diabetes mellitus continues to be an area of robust research and development for pharmaceutical manufacturers. An estimated 26 million Americans have the disease, and an estimated 79 million US adults have prediabetes, putting direct medical costs at $116 billion.¹

Investment ranges from the development of new therapies to control the disease, to innovations toward the so-called “artificial pancreas” for type 1 patients (T1DM), to work on preventing type 2 diabetes mellitus (T2DM) with therapies to combat obesity.

Until there is a decline in the number of patients with T2DM, both payers and the medical community will witness the introduction of a new category of agents for these patients every few years. Each new mechanism of action must then be proven in the crucible of clinical practice and in formulary decision making.

In the last cycle, the incretin mimetics, which include the dipeptidyl peptidase 4 (DPP-4s) and the glucagon-like peptide-1 (GLP-1s) were introduced and incorporated into practice and onto drug formularies. First came the GLP-1s with injectables like exanatide, and then came the DPP-4s with oral tablets like sitigliptin. The GLP-1s are thought to offer slightly better glycemic control than the DPP-4s, but some diabetics do not prefer the injectable form.

The incretin mimetics overall are considered an incremental advance over the thiazolidinediones or TZDs. Although not associated with cardiovascular events, unlike rosiglitazone, glycemic control with the incretin mimetics is less efficient.

It has been a story of evolution, with health plans and insurers watching carefully for signs of superiority or at least filling an unmet need in T2DM.

A New Mechanism of Action, A New Wave of Products

The current cycle of new agents has introduced the sodium-glucose linked transporter-2 (SGLT-2) inhibitors, which work by blocking glucose reabsorption in the kidney. The first entrant, dapaglifozin by AstraZeneca and Bristol-Myers Squibb, suffered a setback in January 2012 when the US Food and Drug Administration (FDA) expressed concerns over higher incidences of breast/bladder cancer, genital/urinary tract infection, and hepatotoxicity associated with the product compared with placebo.

Janssen Therapeutics was poised to take advantage of the delay. Its new drug application (NDA) for canagliflozin was sent to the FDA in June 2012, and it was approved in March 2013 under the brand name Invokana. Dapagliflozin was approved in January 2014, while the FDA issued a complete response letter for empagliflozin on March 5, 2014. The FDA requires that certain deficiencies in the Boehringer plant (where the product will be manufactured) be addressed prior to product approval.² Astellas’ ipragliflozin filed for approval in Japan in April 2013, but it is not clear when a US filing will occur.

Insulin dependence

The major advantage that SGLT-2 inhibitors offer is a new insulin-independent mechanism of action (Figure 1) in T2DM patients who are overweight or obese. The degree of glycemic lowering seems similar to that for other oral antidiabetic drugs (OADs), with average reductions in patients’ glycated hemoglobin (A1C) levels of around 0.9 percentage points.³ SGLT-2 inhibitors are indicated for use as addon therapy with metformin. They also could be an option for patients with impaired glucose intolerance or prediabetes. Clinical trials with canagliflozin also found an average weight loss of 3.5 kg after 12 weeks of treatment.³

However, results published in January 2014 added some complexity to the discussion around the mechanism of action and glycemic benefit. As noted above, SGLT-2 inhibitors increase the excretion of glucose through the urinary tract. However, studies involving dapagliflozin and empagliflozin were paradoxically found to generate a compensatory increase in the endogenous production of glucose and glucagon. The researchers reported that the greater production of glucose offset about half of the total glucose excreted in urine through SGLT-2 inhibition.^4,5 At some point in the future, it could mean that combining SGLT-2 inhibitor treatment with a drug that inhibits glucagon production (eg, GLP-1s or DPP-4s) could produce substantially greater reductions in plasma glucose levels.⁶ These recent results might not be unexpected, since SGLT-2 inhibitors were shown to have a diuretic effect in a 2010 study.⁷

Early Signs of Canagliflozin Utilization

The real question remains: Does the category fill an unmet need? Or do currently available OADs provide sufficient options, and what of the next cycle of diabetes medications due to go off patent? The still unknown answer to the following questions may help define the Medivalue and place of these new agents in the marketplace: Will SGLT-2s be found to preserve beta-cell function? On a related note, will SGLT-2s be found to delay progression to the need for insulin? The question of coverage is complicated by an issue that has dogged managed care executives in the recent past: Will payers take into account the fact that a medication produces a secondary, positive benefit of weight loss?

Early returns show some promise for coverage and utilization of canagliflozin. After its launch in early 2013, its uptake by endocrinologists and primary care physicians gave Janssen hope that it would catch on quickly in the provider community. According to data from IMS Health, a healthcare technology and information company, canagliflozin generated $90,864,000 in sales through November 2013, on the strength of 306,000 dispensed scripts (unpublished data, IMS Health, 2014).

In parallel, it has gained some early important formulary coverage wins, both in the commercial market and in Medicare (Table 1). A Janssen representative stated that “Invokana is available at a tier 2 or preferred status for over 105 million lives (48% of commercially insured lives and 11% of Medivalue care Part D lives), and more than 80% of commercially insured patients can get Invokana without a prior authorization.”

As the first SGLT-2 to market, this is not surprising; however, it could have implications for new market entrants. Following the fallout over rosiglitazone, the FDA now requires post marketing studies of canagliflozin to assess its cardiovascular risk. And now that BMS and AstraZeneca’s dapagliflozin has been approved by the FDA, manufacturers will find out quickly what the managed care market will require in terms of clinical results, contracting offers, and pricing for subsequent formulary acceptance.

Table 2 illustrates the current status of the SGLT-2 market (both newly ap proved and under clinical investigation).

Sorting Out the Differences in the Market

Dapagliflozin. In a long-term extension of a phase III placebo-controlled trial of dapagliflozin as add-on therapy to metformin, dapagliflozin 10 mg was found to sustain an average 0.78-point reduction in A1C levels from a mean baseline of 8.06% after 102 weeks.8 This compared with a 0.02 percentage point increase in A1C in the group receiving metformin plus placebo (P <.0001). Body weight decreases averaged 1.10 to 1.74 kg after 102 weeks. The risk of hypoglycemia on epimedication was low. The key side effect of mycotic genital infection, which is thought to be related to the flushing of excess glucose through the kidney and bladder, was up to 14.6% in patients receiving dapagliflozin, compared with 5.1% in those receiving placebo.

Other researchers revealed that in a study of 12 randomized controlled trials, the incidence of diagnosed infections associated with dapagliflozin was lower than anticipated, even though urinary glucose levels were found to be relatively high.⁹ They found that the frequency of urinary infections did not increase with drug dose: 2.5 mg (3.6%), 5 mg (5.7%), and 10 mg (4.3%), versus placebo (3.7%).

A meta-analysis confirmed that dapagliflozin was associated with significantly greater weight loss than DPP-4 inhibitors (mean, —2.74 kg) and sulfonylureas (mean, –4.67 kg).³

In a phase III placebo-controlled study of dapagliflozin 5 mg or 10 mg as monotherapy in an Asian population not receiving previous diabetes treat ment, investigators found a 1.04-point reduction in A1C level for the 5-mg dose and a 1.11-point reduction for the 10-mg dose.¹⁰ The incidence of genital or urinary tract infection was low (<5.5%) though higher than placebo. The risk of hypoglycemia (<1% for both dos ages) was deemed small in this 24-week study.

Empagliflozin. Empagliflozin has been tested in a number of settings, including in combination with basal insulin.

References

1. Diabetes Facts. National Diabetes Education Program. National Institutes of Health 2013. (http://ndep.nih.gov/diabetes-facts/). Accessed January 14, 2014.

2. U.S. Food and Drug Administration Issues Complete Response Letter for Empagliflozin. Eli Lilly website. https://investor.lilly.com/ releasedetail.cfm?ReleaseID=830463. Accessed March 5, 2014.

3. Goring S, Hawkins N, Wygant G, et al. Dapagliflozin compared with other oral anti-diabetes treatments when added to metformin monotherapy: a systematic review and network metaanalysis

[published online November 14, 2013]. Diabetes Obes Metab. doi: 0.1111/dom.12239.

4. Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production [published online January 27, 2014]. J Clin Invest.

doi:10.1172/JCI70704.

5. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients [published online January 27, 2014]. J Clin Invest.

doi:10.1172/JCI72227.

6. Cefalu WT. Paradoxical insights into whole body metabolic adaptations following SGLT2 inhibition [published online January 27, 2014]. J Clin Invest. doi:10.1172/JCI74297.

7. Niazi AK, Niazi, SH. A novel strategy for the treatment of diabetes mellitus: sodium glucose co-transport inhibitors. N Am J Med Sci. 2010(12):556-560.

8. Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind,

placebo-controlled 102-week trial. BMC Med. 2013;11:43.

9. Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ, List JF. Urinary tract infections in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013;27(5):473-478.

10. Ji L, Ma J, Li H, Mansfield TA, et al. Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study. Clin Ther. 2014;36(1):84-100.e9.

11. Hach T, Gerich J, Salsali A, et al. Empagliflozin improves glycaemic parameters and cardiovascular risk factors in patients with type 2 diabetes: pooled data from four pivotal phase

III trials. Presented at the 2013 meeting of the European Association for the Study of Diabetes; September 23—27, 2013; Barcelona, Spain. Presentation 943.

12. Häring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo controlled trial. Diabetes Care. 2013;36:3396-3404.

13. Woerle HJ, Kadowaki T, Haneda M, et al. Safety and efficacy of empagliflozin monotherapy in a 52-week study in Japanese patients with type 2 diabetes mellitus. Presented at the 2013 meeting of the European Association for the Study of Diabetes; September 23—27, 2013; Barcelona, Spain. Presentation 930.

14. Rosenstock J, Jelaska A, Wang F, Kim G, Broedl UC, Woerle HJ. Empagliflozin as add-on to basal insulin for 78 weeks improves glycaemic control with weight loss in insulin-treated type 2

diabetes mellitus. Presented at the 2013 meeting of the European Association for the Study of Diabetes; September 23—27, 2013; Barcelona, Spain. Presentation 931.

15. Nucci G, Amin NB, Wang X, Lee DS, Rusnak JM. The sodium glucose co-transporter-2 (SGLT2) inhibitor, PF04971729, provides multi-faceted improvements in diabetic patients inadequately

controlled on metformin (abstract). Diabetologia 2011;54:S347.

16. Business Wire. Research and Markets: Astellas Pharma’s (SGLT-2 inhibitor) Ipragliflozin - Type 2 Diabetes- Forecast and Market Analysis to 2022. (http://www.businesswire.com/news/

home/20131213005339/en/Research-Markets-Astellas-Pharmas-SGLT-2-inhibitor-Ipragliflozin#.Ut_xsZ4o5Mw). Published December 13, 2013. Accessed January 18, 2014.

17. Chugai Pharmaceutical: License Agreement of SGLT2 Inhibitor “CSG452” in Japan [press release]. First Word Pharma; October 26, 2012. http://www.firstwordpharma.com/node/1028

158?tsid=17#axzz2r9dMVCi8. Accessed January 21, 2014.

18. Ikeda S, Takano Y, Cynshi O, et al. A novel and selective SGLT2 inhibitor, tofogliflozin improves glycaemic control and lowers body weight in patients with type 2 diabetes mellitus. Presented at the 2013 meeting of the European Association for the Study of Diabetes; September 23—27, 2013; Barcelona, Spain. Presentation 768.

19. Lapuerta P, Neutel P, Zambrowicz B. LX4211, a dual inhibitor of sodium glucose transporters SGLT1 and SGLT2, reduces blood pressure in patients with type 2 diabetes. Presented at the

2013 meeting of the European Association for the Study of Diabetes; September 23—27, 2013; Barcelona, Spain. Presentation 948.

20. Ye G-L, Ogbaa I, Lapuerta P, et al. Favourable gastrointestinal and genitourinary safety profile of LX4211 added-on to metformin in a Phase 2b study. Presented at the 2013 meeting of the

European Association for the Study of Diabetes; September 23—27, 2013; Barcelona, Spain. Presentation 186.

Boehringer Ingelheim researchers collated the results of empagliflozin’s phase III trials on nearly 2500 patients, employing either 10-mg or 25-mg daily dose given for 24 weeks as monotherapy, added to metformin therapy, combined with metformin and sulfonylurea, or added to pioglitazone plus metformin treatment.¹¹ They found that empagliflozin reduced A1C levels by 0.70 percentage points (10 mg) and 0.77 points (25 mg) compared with 0.08 points for placebo (P < .001). This was accompanied by a significant drop in fasting plasma glucose levels (as much as 23.2 mg/dL), greater than 2 kg reduction in body weight, and small but significant reductions in systolic and diastolic blood pressure, across all of these phase III trials. In their study of whether empagliflozin would improve glycemic control in patients who were inadequately controlled with a combination of metformin and sulfonylureas,¹² once-daily empagliflozin 10 mg or 25 mg was added to combination treatment of 225 and 216 patients, respectively, and the results were compared at 24 weeks against combination therapy plus placebo. Empagliflozin 10 mg lowered A1C by 0.82 percentage points and empagliflozin 25 mg reduced glycated hemoglobin levels by 0.77 points, compared with placebo (—0.17 points, P <.001). Urinary tract infections occurred in up to 10.3% of patients taking empagliflozin compared with 8.0% in the placebo group, but the incidence was higher in women (18.0% in the 10-mg group). Genital infections in those taking empagliflozin were not as common, but still slightly higher than placebo rates (2.7% for empagliflozin 10 mg and 2.3% for 25 mg, 0.9% for those receiving placebo). A Japanese phase II dose-extension study of empagliflozin monotherapy revealed patients’ A1C levels decreased by a mean 0.86 percentage points with the 25-mg dose, and this was accompanied by an average 31.2 mg/dL decline in fasting plasma glucose level.¹³ Body weight declined by more than 3 kg after 52 weeks of treatment. Hypoglycemia occurred in only 1 patient in each study group, and in none of these epimedication sodes did the patient require additional health care measures. The incidence of urinary tract infections and genital tract infections was low (no more than 2.6% and 3.0%, respectively, in each dosage group). Interestingly, Rosenstock and colleagues¹⁴ evaluated empagliflozin over 78 weeks in patients whose T2DM was inadequately controlled with basal insulin alone (baseline A1C, 8.2%). Patients were randomized to receive empagliflozin 10 mg (169 patients), 25 mg (155 patients), or placebo (170 patients) in addition to a constant dose of basal insulin for 18 weeks, after which insulin dose adjustments were made as needed. Significant reductions were observed in A1C levels at 18 weeks (0.57 points, 10-mg dose; 0.71 points, 25-mg dose; P <.001) and at 78 weeks (0.48 points, 10 mg-dose; 0.64 points, 25-mg dose; P <.001). Insulin doses were reduced (e.g., —1.21 IU/day for empagliflozin 10 mg, P <.01) at week 78 compared with baseline for both active treatment groups. Patients receiving empagliflozin lost approximately 2 kg of body weight at 78 weeks. The researchers again noted an increased incidence of urinary tract (15%) and genital infections (8%). Ertugliflozin. Merck and Pfizer are copromoting another investigational SGLT-2 inhibitor, ertugliflozin. Four phase III studies of ertugliflozin are currently recruiting patients, according according to ClinicalTrials.gov. They cover monotherapy, a combination of metformin and glimipiride, metformin and sitigliptin, and in patients with chronic kidney disease. Little information has been published regarding phase II trial results for ertugliflozin. One presentation at the 2011 European Association for Study of Diabetes reported on a phase II trial of 328 patients with T2DM placebo, ertugliflozin (1 mg, 5 mg, 10 mg, or 25 mg), or sitigliptin 100 mg for 12 weeks.15 From a baseline A1C level of 8.1%, patients receiving ertugliflozin experienced up to 0.83-point reductions (dose dependent) compared with a 0.87-point reduction for those taking sitigliptin and a 0.11-point reduction in the placebo group. Fasting plasma glucose levels dropped by up to 31.5 mg/dL, compared with a 17.3 mg/dL reduction for sitigliptin and a 2.7 mg/dL increase in the placebo group. Body weight reduction approached 3 kg in the ertugliflozin group, although the placebo group also registered a mean loss of 0.75 kg. The incidence of genital fungal infections in the ertugliflozin groups was roughly twice that for the placebo groups, although both were relatively low (3.6% vs. 1.8%, respectively). Ipragliflozin. In the third quarter of 2013, Astellas Pharma Inc and Merck announced that they would copromote Astellas’ SGLT-2 inhibitor, ipragliflozin. Although Astellas has filed for product approval in Japan based on the strength of phase III trials in that country, it has been reported that Astellas is not intending to proceed with US trials and or an NDA, owing to increased competition in the area. The phase II studies conducted to date indicate similar (or slightly less) effect on A1C levels, with a comparable safety profile to the other SGLT-2 inhibitors. Tofogliflozin. This SGLT-2 inhibitor was originally developed by Chugai Pharmaceutical of Japan, who had entered into a development and marketing agreement with its majority stakeholder, Roche. In 2012, Roche returned the development and marketing rights back to Chugai, before the start of phase III trials. A new co-development partnership was formed, which included Sanofi- Aventis. Information on its phase II trial program is also limited, but in a 12- week placebo-controlled dose-finding study, 398 patients were randomized to receive tofogliflozin 2.5 to 40 mg daily or placebo, with or without metformin.18 Glycated hemoglobin reductions ranged up to 0.87 points for the highest dose of tofogliflozin compared with 0.27 points for placebo. Placebo-adjusted body weight loss was approximately 2 kg in the tofogliflozin group, and an increase in genitourinary infections were noted with the active drug. LX4211. Phase II trials are underway for LX4211, a dual inhibitor of SGLT-1 and SGLT-2. Whereas SGLT-2 affects sodium excretion in the kidney, SGLT-1 mediates sodium absorption in the gut. A study of 299 patients demonstrated that LX4211 was associated with a significant, dose-dependent decrease in glycated hemoglobin levels, as well as small decreases in systolic blood pressure after 12 weeks of treatment.19 However, in those with baseline systolic blood pressure of at least 130 mm Hg, placebo-adjusted reductions in those taking LX4211 400 mg were 14 mm Hg (P = .002). In comparison, only a 1 mm Hg decrease was seen in patients whose baseline systolic pressure was below 130 mm Hg. Another phase II study showed that LX4211 was also associated with some mild genitourinary infections, none of which caused study discontinuation. Consistent Effects It seems that the SGLT-2 inhibitors exert consistent plasma blood glucose and HbA1c effects in patients with T2DM, and the incidence of body weight reduction and adverse effects is characteristic across the drug class. This may make it more difficult for a new SGLT-2 inhibitor to differentiate itself from those already approved, and may spur considerable contracting/pricing competition among the products, as canagliflozin faces new market entrants.

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