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.

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.

 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 (

) 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.

 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.

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.

 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.

 These recent results might not be unexpected, since SGLT-2 inhibitors were shown to have a diuretic effect in a 2010 study.

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 (

). 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.

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

Sorting Out the Differences in the Market

. 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.

 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).

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.

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

	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

	 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]. 

	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]. 

	6. Cefalu WT. Paradoxical insights into whole body metabolic adaptations following SGLT2 inhibition [published online January 27, 2014]. 

	7. Niazi AK, Niazi, SH. A novel strategy for the treatment of diabetes mellitus: sodium glucose co-transport inhibitors. 

	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,

	9. Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ, List JF. Urinary tract infections in patients with diabetes treated with dapagliflozin. 

	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. 

	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. 

	 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

	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.

Articles

Evidence-Based Diabetes Management

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

Managed care faced an interesting dilemma in 2012 when the American Diabetes Association (ADA) released new guidelines for the treatment of type 2 diabetes mellitus (T2DM).

 The new guidelines replaced the previous iteration that was algorithmic in its recommendations of drug therapy with one that was more individualized to the patient. While diabetes is not a one-size-fits-all disease, the new guidelines did not recommend a preferred second- or third-line medication. Many diabetic medications are still branded and associated with a relatively high cost compared with older generic medications. Furthermore, newer medications continue to come to market in these newer categories, such as DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors. Despite comparative glycated hemoglobin (A1C)-lowering data, these medications have little clinical differentiation in terms of outcomes and safety. This should allow health plans to streamline their approach in managing drugs that treat diabetes.

Managed care continues to evaluate efficacy, safety, and cost as part of any drug review process. However, with little clinical differentiation, this approach allows organizations to focus on cost differences and comparative cost efficacy. It is also important to take rebates into consideration in these discussions for net cost comparisons. For example, in a medication class where there are 4 medications with the same mechanism of action and no clinical differentiation, a managed care organization can leverage rebates and market share to provide an overall cost savings to the health plan or employer group. It is not realistic that a payer should need to cover all the medications in this class. This is particularly important in the treatment of T2DM when there are more than 10 classes of medications available for the treatment of the disease. Therefore, approaches that a plan can apply include:

• Comparative effectiveness research (CER):

 As defined by the Federal Coordinating Council for CER, this is the conduct and synthesis of systematic research comparing different interventions and strategies to prevent, diagnose, treat, and monitor health conditions. The purpose of this research is to inform patients, providers, and decision makers, responding to their expressed needs, about which interventions are most cost-effective for which patients under specific circumstances.

 This requires multiple data sources. Managed care is in the unique position of having data from clinical trials, administrative claims, laboratory draws, and access to all of the healthcare stakeholders involved in the delivery of care.

 These allow flexibility in driving prescribing to preferred agents while still allowing appropriate clinical choice.

The old model of traditional disease management has proved largely ineffective. Approaches like mailing letters and newsletters or utilizing automated voice messaging to remind patients to take medication, etc, do not have significant influence upon behavioral change. New approaches are needed that empower patients to become active participants in their healthcare.

 The goal of a generic utilization improvement program is to conduct direct member outreach to curb inappropriate and wasteful spending among patients who are utilizing high-cost branded medications that have generic alternatives within their specific therapeutic class. By targeting nonadherent patients among this group, managed care organizations have an opportunity to improve quality outcome measures by positively impacting individuals who struggle to achieve their therapy goals due to an unknown understanding that equally effective lowercost choices are readily available.

At VRx, after an evidence-based CER approach to pharmacy and therapeutics, and after applying a closed formulary benefit, a novel and innovative approach to collaborating with patients and providers has been incorporated— Veridicus Care Management (VCM).

VCM provides integrated care management using a team comprising clinical pharmacists, nurse case managers, and mental health specialists. Our VCM program utilizes population management tools and predictive modeling to identify high-risk populations based on various clinical triggers. These services are offered to provide quality improvement solutions to pharmacy benefit managers (PBMs), health plans, and employer groups. One of the clinical tracks focuses on patients with “gaps in care,” such as diabetic patients who haven’t had an A1C drawn, lack an office visit, are missing key medications (ie, ACE-I/ARB and statin therapy). These targeted “gaps in care” are defined based on the National Council of Quality Assurance Healthcare Effectiveness Data and Information Set measures that promote improved quality in the delivery of care.

The VCM team identified a diabetic patient who was flagged as having “gaps in care,” who lacked treatment with an ACE-I/ARB and was noncompliant with his diabetic medications. The clinical pharmacist contacted the patient to address these issues and to provide comprehensive education regarding the patient’s specific expectations and goals of therapy. Upon further discussion, it was determined that the patient was noncompliant with his DPP-4 inhibitor due to the significantly high cost burden. Additionally, the patient also reported taking metformin 500 mg daily without any prior dose titration. The most recent A1C was 8.7% and the patient’s primary care provider had discussed initiating a new therapy with an SGLT2 inhibitor. The clinical pharmacist discussed the possibility of titrating the metformin to 2000 mg per day in divided doses, and replacing the DPP-4 inhibitor with generic pioglitazone. The case was then presented in the weekly VCM Clinical Coordination meeting, where additional insight was provided by the nurse case managers. The patient was then contacted by a nurse, who provided further diet and exercise education to supplement the recommended changes in medication therapy. All information related to the case was communicated to the patient’s primary care provider.

Upon follow-up with the clinical pharmacist, the patient reported successfully switching to a pioglitazone/metformin combination product with proper titration to 2000 mg per day. The clinical pharmacist assessed compliance and tolerability of the new medication regimen. At a 3-month follow-up, the patient demonstrated a 1.5% reduction in his A1C (to 7.2%).

New approaches are needed in the current healthcare environment, and more specifically, in the treatment of diabetes. Old methods of patient-outreach are largely ineffective. Models should include CER, closed formulary benefit design, and improved coordination of care. Integrated care management improves on the old model of disease management by involving all stakeholders in the treatment of diabetes. By using an integrated model, these stakeholders become empowered to collectively take responsibility for all clinical and financial outcomes. Healthcare is slowly shifting to an outcomes- oriented, collaborative team-based approach to patient management. An integrated care management model is a natural fit for managed care organizations to participate in the future of healthcare, which will consist of Patient-Centered Medical Homes and Accountable Care Organizations. 

 Jeffrey D. Dunn, PharmD, MBA, is senior vice president of VRx Pharmacy Services.

Alexander Bitting, PharmD, is clinical pharmacy manager, Medicare Part D programs at VRx Pharmacy Services.

Alan D. Pannier, PharmD, MBA, is a managed care resident at VRx Pharmacy Services.

	1. American Diabetes Association. Standards of medical care in diabetes — 2012. 

	2. Health Services Research Information Central. Comparative Effective Research (CER). US National Library of Medicine, National Institutes of Health. http://www.nlm.nih.gov/hsrinfo/cer.html. Updated July 28, 2010. Accessed February 7, 2014.

For information contact Jeffrey D. Dunn, VRx Services, 19 E. 200 S., Floor 10, Salt Lake City, UT 84111. 

Evidence-Based Diabetes Protocol Development: Approaches and a Case Study

Robert Kritzler, MD, wears 2 hats: He has been a practicing physician for more than 30 years; with a specialty in pediatric endocrinology, he has seen the rise of obesity and diabetes and its effects on the healthcare system. Today, as a leader in a health plan associated with a major academic institution, he is also part of the national conversation on how to control rising costs, as more patients gain access to the system under the Affordable Care Act.

Have you observed progress in the community’s efforts to address diabetes mellitus in children as a public health problem?

 There has been some progress, but we need to break the progress down into type 1 and type 2 diabetes mellitus. Pediatric endocrinologists see more type 1 disease, and I think there’s been a lot of progress in terms of technology. As a clinician, many more of my young patients are using insulin pumps than in the past. Some of my patients are now using continuous glucose sensors (for continuous glucose monitoring, or CGM). As a managed care medical director, I can say that we’re seeing many more requests for insulin pumps and CGM monitors. That technology is changing how we treat the patient with type 1 disease. Alone, it is, however, not the whole answer. Our bigger concern right now is how we treat the many new young patients with type 2 diabetes, caused by the current epidemic of obesity in the community. We’ve seen a huge rise in the incidence of type 2 diabetes, particularly among teenagers. The obesity epidemic is throughout the United States, but it is hitting harder in the South, and Maryland’s numbers are rising. To an extent, community efforts have resulted in some progress, if not awareness. Clearly, First Lady Michelle Obama’s Let’s Move program has helped to address physical fitness and obesity, as have several other community-based programs. Overall, we’re still moving in the wrong direction with respect to type 2 diabetes.

What is the missing element from these efforts? Is it a matter of coordination? Is it a real motivation and commitment to participate in these efforts?

 You hit the nail on the head. For type 2 diabetes, tied to the obesity epidemic, there have been fits and starts—not one concerted effort. The effort needs to work down to things like school lunches, convenience foods, and fast foods, and work at the main reasons our population as a whole is gaining weight.

It’s seen by folks in the field, but not by the general public, as a public health emergency. I question whether all medical professionals consider it the public health emergency that it really is.

 It’s hard to say. The data are already there. We see today the increased incidence of type 2 diabetes in teenagers and young adults. The data on the long-term costs of diabetes to the system are also there. Beyond that my crystal ball is as cloudy as everyone else’s.

	From my perspective as a managed care medical executive, we’re trying to conquer the cost of medical care by weeding out unnecessary high-tech imaging and focusing on how much we pay for each individual service, but we don’t pay enough attention to the major public health problem that’s right in front of us.

You had mentioned the increased use of pumps and sensor devices for type 1 diabetes. What’s your view on our progress toward the artificial pancreas?

 It’s interesting that you asked me that, because not a day goes by when I’m not asked by one of my patients whether the artificial pancreas is right around the corner. To some extent, the answer is no, although patients and their families desperately want this solution. Today, we have smart pumps that are hooked up to sensors. It even looks achievable with today’s computer technology.

	What people don’t fully understand is that glucose regulation involves more than just injecting insulin. We have known for a very long time that glucose regulation involves many hormones beyond insulin. A true artificial pancreas would have to regulate, to some extent, many of those hormones. It’s a more complicated construct than people think. Trials are under way, mostly in Europe, testing multi-channel pumps.

	Today’s smart insulin pumps connected with continuous glucose monitoring is a way station towards a more functional artificial pancreas. We’re making progress, but a true artificial pancreas, enabling something approaching more rational glucose control, is further away. I believe this will occur before we see everyday islet cell transplants or that sort of thing. That’s looking into my own crystal ball.

And a true synthetic pancreas, constructed through some type of regenerative tissue engineering? How far away are we, realistically, from that?

 We’re a long way from this. Some pretty good research is ongoing, but we’re not anywhere near clinical utility.

Johns Hopkins is a major research institution. How involved is Hopkins in researching these types of new technologies?

 Researchers from Johns Hopkins University and the University of Maryland are partners in the JHU-UMD Diabetes Research Center. It is headed by Dr Fredric Wondisford, an adult endocrinologist and metabolism physician. The Center is involved in a tremendous number of studies, probably way more than I know.

Let me ask you to put on your managed care hat. I’d like to talk about young patients with type 2 diabetes or prediabetes and how they transition from adolescents to teens and young adults.

Coordination is a challenge, not specifically for Hopkins, but in general. Patients with type 1 diabetes primarily receive their care through endocrinologists. Patients with type 2 disease receive their care through a combination of primary care doctors— pediatricians, family physicians, and adult internal medicine&mdash;and endocrinology consulting. Coordination can be a real issue. And at some point, teenagers have to transition from a pediatric care system to an adult care system. That’s an issue, even for those with type 1 diabetes, and it’s something the medical community doesn’t do as well as we should.

	As with any other hand-off in health care you’re handing off between one provider to another or in some cases between one group of providers, primary care, endocrinologists, to a different group of providers. We all have different styles and different approaches. As a clinician, I tend to continue to see my patients with type 1 diabetes through their college years. These patients are undergoing life transitions at the same time. At some point, we have to transition these patients from pediatric to adult care. As with any other transition in medical care, it can be a challenge.

It really has very little to do with the medical care system itself. Part of the real challenge is the transition from being an adolescent to being an adult. They’re undergoing numerous life transitions themselves, including from having a parent overseeing their care (particularly in type 1 disease), to having to oversee it themselves. They go to college, out into the workforce, and they move out of the parent’s home. Suddenly they’re adults, or at least the world calls them adults, and they have to take on more responsibility and accountability. For many of us in pediatric endocrinology, one of the things we try to do, particularly with our type 1 patients, is to be sure the transition to self-care begins well before the transition between pediatric medicine and adult medicine. I have many 11-, 12-, and 13-year olds who pretty much know how to run their own pumps and how to reprogram and how to change their basal levels, without a lot of input from their parents. But I also have 16-year-olds who can’t. That becomes a problem. With young type 2 patients, our first interventions are generally exercise and promotion of weight loss before we start medication therapy, and that’s also a question of taking adult responsibility for themselves.

 I can imagine this would be extremely challenging for a patient with type 1 disease who goes off to college. They’re exposed to an entirely new environment, new stresses, the same risks that face other teenagers, including excessive drinking, and different eating habits and eating options…

 Yes, everybody talks about the “freshmen 15”—new freshmen who gain 15 pounds on dormitory food. This is a bigger problem if you’re already overweight and have prediabetes or diabetes: the freshman 15 can easily be the “freshmen 30.”

Can you do any special preparation, other than reinforcement and education, to prepare these kids for major life change?

 It is one of the challenges. That’s why care for type 1 and type 2 diabetes is such a team effort. By team, I mean the physician, advanced practice nurse or other physician extender, clinical diabetes educator, nutrition educator, social worker, and psychologist.

	By the time the patient is transitioned to an adult-care provider, we assume that he or she has already moved through these various changes. That’s why I believe the pediatric care system, which is more family oriented, probably does a bit of a better job in facilitating those transitions.

In terms of treating younger patients with type 2 diabetes, you mentioned that it is not usually an endocrinologist but family physicians. They don’t seem to be as comfortable treating these patients as children as they are as adults. Why does that seem to be the case?

 Overall, I find that very few primary care physicians are comfortable treating type 1 diabetes, whether they’re pediatricians or family physicians or internists. So those patients are left to the endocrinologist. As for type 2 diabetes, there are just too many people with type 2 disease for the number of specialists available. So our primary care colleagues have to treat them.

	Family physicians need to have a much wider span of knowledge to treat so many disorders appropriately and in so many age groups. I know some family physicians who are very good with kids and teenagers, and I know some who certainly don’t like to treat younger kids and are uncomfortable with teenagers. Then consider the specialty of adolescent medicine, in which youre primary training could be in any one of the pediatrics, family medicine, or internal medicine. This has become a larger subspecialty over the years, for the exact reason that adolescents are not children or adults. They are an entity unto themselves.

Well, if you have primarily family physicians treating these children with type 2 diabetes, at what point do you feel it’s appropriate that they should be referred to specialists? What becomes the tipping point?

For type 2 diabetes in children, most family physicians and pediatricians are comfortable when they’re just dealing with diet and exercise, and the glycemic levels are not widely abnormal. At that point, some are comfortable starting—certainly adult primary care physicians are&mdash;the first couple of oral antidiabetic drug steps for their patients. Pediatricians and family physicians may be less so in those younger than 18, because the higher incidence of type 2 diabetes in these patients is a pretty new phenomenon.

	Many of the pediatricians are not trained in medical school in the use of these oral antidiabetes drugs. I was trained as a general pediatrician, and I was never trained in the use of oral antidiabetic medications. This has changed recently, because of the necessity of it.

	I believe it can be helpful to refer to a specialist for one or two consultations, as glycemic levels demand, when beginning medications. Personally, I see a number of young patients with type 2 diabetes in order to start their medication therapy, because the general pediatrician or family practitioner is not as comfortable doing that. But they’re comfortable enough managing the patient once the medication regimen is started and glucose levels are controlled. This may be different in an integrated system, where general pediatricians may be more comfortable dealing with diabetes, even type 1 to some extent. They usually have specialists more available for phone and E-consults.

Is this supported through your regular diabetes disease management programs?

 At JHHC, we don’t do disease management much anymore; instead, we focus on embedded, nonspecific case management. As a health plan, we’re most interested in chronic disease.

If you could change one diabetes-related Health Effectiveness Data and Information Set (HEDIS) measure, what would it be and how would you change it? (HEDIS consists of 75 measures of healthcare quality and service.)

I think that most of the HEDIS measures on diabetes are directionally correct. I think one of the things that people forget about HEDIS measures are that they are population health measures, not individual patient measures.

	Consider that there still is no consensus among the professional societies as to whether the goal A1C measure should be 7.0% or 6.5% (guidelines of the American Diabetes Association and the American Association of Clinical Endocrinologists, respectively). And diabetes blood pressure targets have just been changed, which would affect a large number of patients. The HEDIS measures are really just averages for what the population-wide target should be. Health care professionals can get caught up thinking, “I have patient Sally Smith in front of me, and she needs to meet all of these measures and all of these targets.” That’s not the intent of HEDIS.

	I don’t really have any beefs with any of the HEDIS diabetes measures as long as people remember the context in which they’re meant to be used. For example, an elderly patient with type 2 diabetes who has had previous hypoglycemia should not have a target A1C of below 8.0%. An average A1C level of 7.5% among 5000 patients is very reasonable. I don’t think there’s a right answer.

On that same note, would you like to add a HEDIS measure for the future, one that might be helpful as an additional guide?

 Keeping in mind that it’s a population-wide measure, I think the existing HEDIS measures on diabetes are about right. I don’t think there’s much we need to add. Some people talk about measuring long-term outcomes in type 2 diabetes, such as amputations, renal failure, those types of things. But I wouldn’t add anything right now to HEDIS with regard to diabetes care.

 Let me ask you a question about current therapies. A new class of therapies has just been introduced—the SGLT-2 inhibitors for type 2 diabetes. As a medical director, you’ve probably been involved in some coverage decision making on these agents and the previous categories of drugs. What’s your overall opinion not necessarily of just the SGLT-2 inhibitors but of the recent new oral diabetes therapies that have come along in the last 5 years?

 It’s an exciting area. For type 2 diabetes, exercise and weight loss are still the mainstays of treatment. Metformin is still the first medication choice, but there has been so much exciting research and many new medication choices, whether you’re talking about the DPP-4s, GLP-1s, or the newest classes. And I’m sure that a year from now, we’ll see yet another class.

	From a managed care point of view, you’re absolutely right. We look at a cost benefit in terms of where we’ll place it on our formularies, what agents may have to be stepped through in order to cover the drug, and what we’ll ask the patients to pay for them, assuming they are more expensive than the last class of treatments introduced. As each new class comes along or within a class, a medication may be introduced in a once-weekly injection instead of a oncedaily injection, which can lead to better adherence. Each time something new comes out, we have to evaluate the gain versus the cost—the value.

	The number of new options has resulted in the professional societies loosening their relatively rigid guidelines, recognizing what we in managed care are also recognizing, that one size doesn’t fit every patient. There are a number of possible permutations and combinations, and we on the managed care side try to make those available within reason to our patients and to our clinicians.

	That being said, I believe that insulin is not utilized as much as possible in patients with type 2 diabetes. Insulin’s not new or sexy, but there are new formulations, there are new delivery systems, and there are pumps. Very few patients with type 2 disease are using insulin pumps, although we’re starting to see an occasional request for them. Insulin is still an important therapy for type 2 diabetes, and it is underutilized.

For many years, needle phobia has been cited as a principal reason why the transition to insulin has been so difficult. Do you think there are certain things that are just so difficult to overcome; cultural, social, in terms of the insulin use that we’re never really going to get that number where it needs to be in terms of equalization?

 I’ve been practicing 30 years, give or take, and during that time, the insulin needles have become progressively smaller, to the point now that it’s not the kind of needle phobia that existed when my grandmother took insulin in 1955. It’s a little bit overrated as a barrier. You could point out that the many GLP-1s are given by injection, not as frequently administered as basal insulin, but you’re still giving them with a needle.

	There are clearly people who can’t adjust to using needles, particularly some of the elderly. However, every one of my patients with type 1 diabetes use needles because they really have no choice—they’re either on multiple injections a day or they’re on a pump, which involves a needle. Everybody adjusts to a needle if they need to.

We alluded to the shortage of endocrinologists earlier. Do you see any action in payment reform that might someday attract more doctors to the endocrinology field?

 Endocrinology in general is like most of the cognitive specialties; it is on the lower end of the pay scale. Of my medical school class in 1977, two-thirds went into primary care. Of last year’s graduates, maybe 8% or 10% went into primary care. As a cognitive specialty, endocrinologists don’t do many procedures other than thyroid biopsies. People just aren’t attracted to it as a profession, because it carries pay that is relatively low. To the degree that we value endocrinologists, we’ll see more people go into the specialty.

	Let me make a related comment: There’s a very nice set of programs out of the University of Connecticut where the provider is taking risk for diabetes care, especially type 1. The provider accepts global payments for care and then has to sort it out within their own system, taking some risk for performance. That sort of payment reform is very exciting to me, in terms of any chronic disease.

Is that program based on the patient-centered medical home concept?

 I don’t think they call it a patient-centered medical home, but rather a diabetes home. A patient-centered medical home for kids with type 1 diabetes pretty much describes the model. This and other similar experiments around the country will do little to attract more people to endocrinology, but what it will do is support the team care concept. On a fee-for-service basis, some of the non-physician team members don’t always get reimbursed very well. If you think primary care physicians and endocrinologists are not reimbursed well, diabetic nurse educators and nutritionists are paid far less. A diabetic medical home allows caring for more patients with a multidisciplinary team, which I think in some ways may be as important as some of the technological advances, at least in the short run for type 1 diabetes care, anyway. 

What might it take to raise that level of alarm?

Managing the Transition to Adulthood With Type 1 Diabetes Mellitus; An Interview With Robert Kritzler, MD, Pediatric Endocrinologist, and Deputy Chief Medical Officer, Johns Hopkins Health Care LLC

In early January, the US Food and Drug Administration (FDA) granted an orphan drug status to the immunotherapy drug DV-0100, manufactured by the technology company DiaVacs.

 This cell-based therapy to treat type 1 diabetes mellitus (T1DM), also known as juvenile diabetes, is the company’s first product, based on a proprietary platform technology. The technology, according to the company website, is based on retraining a patient’s dendritic cells (DCs) to prevent a T-cell stimulation-based autoimmune reaction.

Orphan drug status is granted by the FDA for drugs treating rare diseases (<200,000 patients) and conditions for which adequate treatment options have not been developed. The sole purpose of this class of drugs is to incentivize research in an otherwise unprofitable field for drug developers. A number of large pharmaceutical companies (AbbVie, Bayer, Bristol-Myers Squibb, GlaxoSmithKline) have been investing in this field by focusing on biologics (like immunotherapy drugs), which make up 60% of the orphan drug market.

 Other T1DM drugs granted orphan drug status include teplizumab (MGA031) in 2006, developed by Macrogenics and Eli Lilly and Company, which completed phase 3 trials in 2013, and TOL101 (Tolera Therapeutics Inc), which was granted the status in 2010 and recently concluded a phase 2 trial.

 According to the Orphan Drug Act of 1983, the manufacturer of an orphan drug receives the following benefits to hasten the process of getting the drug to market:

  • Tax credits for research expenses • An annual grant to defray the costs of qualified clinical testing • Assistance in clinical research study design • Seven years of exclusive marketing post approval • Waiver of Prescription Drug User Fee Act filing fees ($1 million per application for 2008).

These benefits amount to significant cost savings to the manufacturing company, but the savings are not necessarily reflected in drug pricing. Although DV-0100 is in very early stages to predict efficacy in long-term clinical trials or to estimate its cost, 5 of the most recently approved orphan drugs, for various indications, were estimated at $150,000 per patient per year, and 3 of them were estimated to cost $300,000 or more annually. With the increasing number of orphan drugs being approved by the FDA (13 of the 39 drugs approved in 2012 were orphan drugs, >350 approved since 1983) that cover a wide spectrum of disease conditions such as AIDS, melanoma, ovarian and pancreatic cancer, and cystic fibrosis, payers are being more cautious.

 The front-end cost of immunotherapy is expensive enough that at least 1 national payer said it’s not a foregone conclusion that this treatment would be covered. Ed Pezalla, national medical director for pharmaceutical policy at Aetna, stated in an interview conducted last year that even with orphan drug expenditures increasing 20 to 25% (of healthcare spending per year) compared with 15% for other medications, managed care companies are not always allowed to drastically increase premiums. Pezalla added that the increase in orphan drug cost is much higher than increases in premiums, which would ultimately raise issues for patients to qualify for coverage.

 A study published late last year evaluated the acceptance of cost-effectiveness analysis (CEA) by payers for orphan disease coverage.

 The study included 7 health insurance companies, estimated to cover 75% of the US private insurance market and approximately 157 million individuals. Based on interviews and a survey, the study concluded that despite being concerned about the cost of orphan drugs, insurance companies have not directed efforts toward generating appropriate cost-assessment tools to regulate orphan drug cost. CEA is not considered useful due to a dearth of medicines for appropriate comparisons. Further, the Affordable Care Act (ACA) clarifies 2 points about orphan drug coverage:

  • Medicare does not have any special coverage rules for orphan drugs; drugs are covered irrespective of whether they are reasonable and necessary • Medicare and Medicaid cannot make coverage decisions for any drug solely based on its cost-effectiveness.

 released by the Centers for Disease Control and Prevention (CDC), of the 25.8 million (8.3%) Americans who were estimated to have diabetes in 2010, only 18.8 million were diagnosed. Further, 215,000 (0.26%) of this diagnosed population was younger than 20 years, 15,600 of whom were newly diagnosed with T1DM between 2002 and 2005. Based on the statistics provided by JDRF (formerly the Juvenile Diabetes Research Foundation), the estimated total cost (direct and indirect such as loss of productivity and absenteeism) of diabetes in 2012 was $245 billion, with T1DM estimated at $14.9 billion; the average expenditure incurred by a diabetic patient was $11,700 per year in 2009.

 A study published in early 2010 estimated that elimination of the disease by therapeutic intervention (the aim of the current immunotherapy approaches) in the current cohort of T1DM patients could yield projected savings of about $422.9 billion (lifetime cost, which includes disease maintenance with insulin, constant monitoring, and loss of productivity).

 The study estimated the average annual medical expenditure of T1DM patients at about $10,000, compared with $3500 estimated for matched controls. A majority of T1DM patients fall in the 10-to-19-years age group, and they are expected to generate costs (medical and indirect) of about $10 billion.

Considering these high costs of disease treatment (

), therapies that can help control or reduce the loss of beta cells could lead to significant cost savings. “We are an early-stage company, and the therapy is still in the early development stage. We have not yet discussed pricing with the payers,” replied Hara Hartounian, PhD, CEO, of DiaVacs, in an e-mail.

T1DM, an autoimmune disease that may be regulated by family history, genetic and environmental factors, or viral infections, is associated with a varying preclinical period that results in autoimmune destruction of the insulin-secreting beta cells of the pancreatic islets and a subsequent upsurge in blood glucose levels. The disease remains preclinical until greater than 80% of the beta cell mass is destroyed, before clinical manifestation.

 Typical disease symptoms include extreme fatigue, frequent urination, continued thirst, and severe hunger pangs. Pharmacologic immunosuppression for T1DM using agents such as cyclosporin A, although successful, is associated with unacceptable adverse events (AEs), while administration of insulin is associated with complications that can lead to morbidity and mortality.

According to JDRF, none of the current therapies can prevent or cure T1DM. Insulin treatment is mandatory for these patients, and the lack of glucose homeostasis could lead to devastating conditions, including heart disease and kidney failure.

 The preclinical period associated with T1DM could present a therapeutic window in which to slow down or inhibit the loss of pancreatic beta cells by targeting the immune system, which can result in an increase in cell mass.

Several clinical trials have explored immune cells as therapeutic targets or modified tools to treat T1DM patients.

 A collaborative phase 2 trial completed in 2008 by the University of Texas Health Science Center and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) evaluated the efficacy of oral interferon-alpha in slowing the immune attack on the islet cells of T1DM patients.

 The trial reported that patients receiving 5000 units of human recombinant interferon alpha (hrIFN-α) maintained more beta-cell function at 1 year after enrollment compared with the placebo.

Antigen-based immunotherapy was another approach that was evaluated in both children and adults in a trial that was completed in 2011. Glutamic acid decarboxylase (GAD), a major target of the T1DM autoimmune response, was administered subcutaneously over 4 to 12 weeks, and the loss of insulin secretion was monitored over 1 year. However, the encouraging results obtained in animal models did not translate to humans: the loss of insulin production between the controls and the GAD-injected subjects was not different.

An ongoing phase I safety trial sponsored by the University of California, San Francisco, is investigating whether regulatory T cells (Tregs) can stabilize the beta cells from further destruction in T1DM.4 The study, initiated in 2010, is estimated to be completed by 2016. 

The technology currently being utilized by DiaVacs is a result of the pioneering work by Nick Giannoukakis, PhD, associate professor of pathology and immunology at the University of Pittsburgh School of Medicine. In an interview published late last year in the journal 

, Giannoukakis shared the story behind DV-0100. The extremely exciting findings with DC and T1DM by his research group were funded by venture capitalists, which led to the foundation of the biotechnology company DiaVacs. Giannoukakis, who actively serves on the Scientific Advisory Board of the company, believes that DC therapy can eventually help cure T1DM.

According to Hartounian, “The granting of this orphan drug designation represents a key milestone for the company. We are excited by the promise that DV-0100 showed in our phase 1 clinical trial and look forward to assessing its therapeutic potential in the ongoing phase 2 clinical trial for this indication.” The procedure involves acquiring DCs from the patient’s own blood, modifying them using small interfering oligonucleotides, and vaccinating the patient by intradermal injection of the modified cells13 (Figure 1). The most important hurdle that this technology has overcome is the generation of tolerogenic DCs, with a low T-cell stimulatory function in vitro, poor-allogenic T-cell proliferation in vitro, and the capacity to induce Foxp3+ Tregs in vitro, among others. To deal with concerns about DC maturation in vivo, resulting in a loss of tolerogenic properties and promotion of alloimmunity, maturation-resistant DCs have been generated

No safety issues were documented in the phase I trial, which was conducted in 10 generally healthy insulin-requiring T1DM patients between 18 and 60 years of age. The clinical trial results, published in the journal Diabetes Care, demonstrated no discernible AEs in any patient, except for a rise in B2 20+ CD11c— B-cell population.

If the promising results obtained in the animal model translate to the phase 2 trials initiated by DiaVacs, DV-0100 could revolutionize the treatment spectrum for T1DM patients.

According to Gordon C. Weir, MD, chairman, Diabetes Research and Foundation, Joslin Diabetes Center, DC cells are a promising treatment approach for T1DM, but he believes the therapy, although safe, is in too early a stage to predict efficacy.

Encouraging results were obtained from a trial conducted in early 2013, led by researchers at the Stanford University School of Medicine. The trial evaluated the efficacy of a 12-week regimen of an intramuscular DNA vaccine (plasmid- encoded proinsulin) in 80 adult T1DM patients.

Blood insulin levels were monitored using C-peptide as a surrogate marker. The study was conducted on the hypothesis that by shutting off only a subset of immune cells (in this case the CD8+T cells) instead of the entire immune spectrum, a muchcontrolled response could be achieved. This vaccine was designed to shut off an immune response, unlike conventional vaccines that turn on a specific immune response. The vaccine improved the C-peptide levels in the blood and specifically reduced proinsulin-reactive CD8+T cells, without any serious AEs. However, the effects started declining after administration of the vaccine was stopped at 12 weeks. Large-scale studies over a longer duration are definitely called for to further these results.

	1. Fiore K. EndoType: Orphan status for type 1 diabetes immunotherapy. http://www.medpagetoday.com/Endocrinology/Diabetes/43691. Published January 8, 2014. Accessed January 15, 2014.

	2. DiaVacs website. http://diavacs.us.com/technology/. Accessed January 14, 2014.

	3. Hyde R, Dobrovolny D. Orphan drug pricing and payer management in the United States: are we approaching the tipping point? 

. 2010;3(1):921-929. http://www.ahdbonline.com/issues/2010/january-february-2010-vol-3-no-1/97-feature-97. Accessed January 23, 2014.

	4. ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed January 23, 2014.

	5. Silverman E. Beware the increasing cost and number of orphan drugs. 

	6. Handfield R and Feldstein J. Insurance companies’ perspectives on the orphan drug pipeline. http://www.ahdbonline.com/issues/2013/november-december-2013-vol-6-no-9/1623-insurance-companies-perspectives-on-the-orphandrug-pipeline. 

	7. General diabetes facts. JDRF website. http://jdrf.org/about-jdrf/fact-sheets/general-diabetesfacts/. Accessed January 27, 2014.

	8. Tao B, Pietropaolo M, Atkinson M, Schatz D, Taylor D. Estimating the cost of type 1 diabetes in the US: a propensity score matching method. 

	9. Barcala Tabarrozzi AE, Castro CN, Dewey RA, Sogayar MC, Labriola L, Perone MJ. Cell-based in-terventions to halt autoimmunity in type 1 diabetes mellitus. 

	10. Brod S. Ingested type-I interferon—state of the art as treatment for autoimmunity part 2. 

	11. Wherrett DK, Bundy B, Becker DJ, et al. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial.

	12. Giannoukakis N. Immunoregulatory dendritic cells to treat autoimmunity are ready for the clinic: interview by Katie Lockwood. 

	13. DiaVacs’ immunotherapy product for treatment of type 1 diabetes receives orphan drug status desgination from the FDA [press release]. DiaVacs website. http://diavacs.us.com/wordpress/wp-content/uploads/2014/01/Orphan-Press-Release-v4.pdf. Published January 6, 2014. Accessed February 13, 2014.

	14. Giannoukakis N. Tolerogenic dendritic cells for type 1 diabetes. 

	15. Giannoukakis N, Phillips B, Finegold D, Harnaha J, Trucco M. Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. 

	16. Roep BO, Solvason N, Gottlieb PA, et al. Plasmid-encoded proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8+ T cells in type 1 diabetes. 

The out-of-the-box immune-modulation approaches initiated by researchers could spare the patients a lifetime of dealing with insulin injections, pumps, counting carbohydrates, and associated health effects of the disease. A critical question that the ongoing phase 2 trial can answer is whether DV-0100 could eradicate the immune disorder in T1DM patients. Success of the trial would nullify all arguments on treatment coverage for orphan drugs, at least in the T1DM domain. 

New Orphan Drug in the T1DM Realm: Another Immunotherapy Success Story?

 declared that cigarette smoking caused lung cancer in men and probably caused it in women, the news was alarming but easily understood. After all, the action of smoking involves inhaling. With each successive Surgeon General’s Report, evidence mounts about smoking’s insidious path of destruction through the human body, not just for smokers but for all around them: their families, their unborn children, and, depending on where they travel, the hospitality workers who serve them. Statistics show that most of these bystanders will never pick up a cigarette themselves.

Now, type 2 diabetes mellitus (T2DM) can be added to the roster of health ailments that, while not caused solely by cigarettes, can be caused by them. Diabetes is most certainly aggravated by smoking. A mountain of long-term evidence shows that smoking wreaks havoc with the body’s ability to maintain insulin levels, but it’s the research of the past decade that’s even more troubling: nicotine’s effects hit at the cellular level in the developing fetus, setting up the next generation to battle America’s fastest-growing epidemic.

For payers, especially state Medicaid officials, the implications of these findings are daunting, as the evidence escalates of interwoven relationships among cigarette smoking, diabetes, and poverty (

Diabetes was part of the evidence entered into history January 17, 2014, when Acting Surgeon General Rear Admiral Boris D. Lushniak, MD, MPH, Department of Human Services Secretary Kathleen Sebelius, and a host of others, including relatives of the pioneering Surgeon General Luther Terry, gathered to release 

The Health Consequences of Smoking: 50 Years of Progress

 While the 980-page report includes information on both T2DM and type 1 diabetes mellitus, most of discussion on the disease focuses on T2DM.

Two top officials with the Center for Disease Control and Prevention’s Office of Smoking and Health—Director Timothy McAfee, MD, and Associate Director for Science Terry F. Pechacek, PhD&mdash;discussed the findings and implications of the report with 

The report made 3 chief conclusions about diabetes and smoking: • The evidence is sufficient to infer that cigarette smoking is a cause of diabetes. • The risk of developing diabetes is 30-40% higher for active smokers than nonsmokers. • There is a positive dose-response relationship between the number of cigarettes smoked and the risk of developing diabetes.

Some of the findings in the report are not brand new, Pechacek explained, but the report consolidates and draws a greater level of attention to studies released over the past decade that show how smoking and nicotine affect a diabetic’s ability to control insulin levels, and how oxidative stress accelerates diabetes symptoms.

Pechacek cited smoking’s relationship to kidney damage, and to the studies referenced in the report over an extended period that show smoking’s association with known markers associated poor insulin control.

 He also mentioned studies that cite impairment of the body’s endothelial function.

 The report’s long-term evidence is important for payers, especially as the Medicaid rolls expand nationwide under the Affordable Care Act: treating a smoker with diabetes costs more than treating a nonsmoker, because of research that shows the smoker will require more insulin to maintain glycemic control.

More recent findings, the report says, “indicate that people with diabetes may be particularly susceptible to the detrimental effects of smoking on insulin resistance.” 

 “All these things are not really new,” Pechacek said. “We have not placed enough emphasis on the evidence that was already out there. We’re focusing more attention on the fact that smoking is one of the more dangerous aspects of the increasing diabetes incident prevalence.”

March 2014

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

Evidence-Based Diabetes Protocol Development: Approaches and a Case Study

Managing the Transition to Adulthood With Type 1 Diabetes Mellitus; An Interview With Robert Kritzler, MD, Pediatric Endocrinologist, and Deputy Chief Medical Officer, Johns Hopkins Health Care LLC

New Orphan Drug in the T1DM Realm: Another Immunotherapy Success Story?

OSH Officials Discuss How 50th Anniversary Report Highlights Link Between Smoking, Diabetes

The Continuing Evolution of Employer-Based Intervention in Diabetes Disease Management

Study on Protective Gene Mutations for T2DM Appears to Have Strong Implications for Drug Development

A Big Step Forward in Treating Chronic Diabetic Foot Ulcers

Diabetes Patients More Susceptible to Flu Complications

Dietary Patterns, and Effect on Population Health, Get Attention from Advisory Panel

New Studies Affirm Mediterranean Diet's Potential for Patient Self-Management, Prevention of T2DM

Evidence Shows Taking Part in School Nutrition Programs Helps Students Make Better Dietary Choices

The Link Between a Common Type of Bariatric Surgery and Increased Alcohol Use

My Initial Impressions of Medtronic's New Pump