Published Online: March 13, 2014
Stanton R. Mehr and Marj P. Zimmerman, BSPharm
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.
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.
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