Eleven Things Every Clinician Should Know About the “Egregious Eleven”

A recent paper published in Diabetes Care proposes a new classification system for diabetes that challenges our existing paradigm and has significant implications for our treatment approach to diabetes.¹  Here are eleven key takeaway points that every practitioner should know about the proposed beta-cell centric classification schema:

Background:

1. Our current nomenclature no longer represents our current knowledge of diabetes.  The nomenclature we use to classify diabetes and its broad spectrum of sub-classifications are out-of-date.  While terms like “juvenile diabetes” and “adult onset diabetes” are long gone, “insulin-dependent” and “non-insulin dependent” have also fallen out of favor.  The terms “Type 1” and “Type 2” have helped to differentiate the two most common broad categories of diabetes, but these terms don’t address the finer points of the pathophysiology in an individual patient.  Furthermore, the current nomenclature has led to a dichotomous view of treatment.  For example, from the perspective of many third party payers and regulators, many agents are not “indicated” for people with Type 1 diabetes, despite the potential benefits.

2. The abnormal beta-cell is the primary defect in diabetes.  Regardless of the type of diabetes that a patient may have, an abnormal beta cell is at the core.  Avoiding the functional loss of beta cells should be a primary goal.

3. Approaches to treatment must be patient-specific.  Current insurance coverage generally require a patient “fail” a medication before other medications can be added, often following a strict linear algorithm.  However, clinical practice guidelines have taken a more patient-specific approach where the disease processes occurring in the specific patient (e.g. insulin resistance, insulin deficiency, overactive appetite) is treated, rather than treating everyone the same.^2,3  Clinicians should be recommending the least number of agents which target the greatest number of mediating pathways present in the specific patient case (while minimizing hypoglycemia and weight gain).

4. The ominous octet is still relevant!  Back in 2009, Ralph DeFronzo proposed a target-specific approach to directing treatment in patients with type 2 diabetes known as the “ominous octet.”⁴  The proposed targets for treatment included the beta cell, alpha cell, gastrointestinal tract, adipose tissue, muscle cells, liver, brain, and kidney.  The authors of the new paradigm (coined the “egregious eleven”) have emphasized that their work builds on the ominous octet, rather than replacing it.  Check out figure 3 to get a clearer picture about the egregious eleven and the treatment paradigm.

What This New Paradigm Adds:

5. New treatment target #1: systemic low-grade inflammation and immune dysregulation.  These two elements are observed in all subtypes of diabetes, yet have not been traditionally seen as pharmacologic targets.  The authors note that there is some preliminary evidence that incretin-based treatments may have anti-inflammatory effects.^5,6  Whether other pharmacologic agents (either currently on the market or new molecular entities) can prove beneficial in treating the low-grade inflammation and immune dysregulation observed in patients with diabetes is an important area for research.

6. New treatment target #2: changes in gut microbiota.  Changes in the gut microbiome have been associated with the development of diabetes and obesity, and potentially explains why only some overweight individuals develop diabetes while others do not.  Again, this is an emerging area of research which warrants further investigation.^7-10

7. New treatment target #3: decreased amylin production.  Pramlintide — an amylin analog —decreases gastric emptying and glucose absorption in the small intestine.^11-12  Unfortunately, its widespread use has been limited by the increased injection burden (must be used in conjunction with prandial insulin) and the additional cost.  However, identifying new ways to increase amylin production is an important target and deserves more research.

8. “Sulfonylureas and glinides should be ardently avoided.”  This is quite possibly the most passionate and direct statement in the entire manuscript. The authors conclude that the benefit of their low cost is outweighed by their risks, including hypoglycemia, weight gain, potential for beta cell exhaustion, increased risk of cardiovascular events, high rate of treatment failure, and the potential for increased mortality.

9. When insulin therapy is needed, consider it an add-on therapy rather than a substitution.  When patients start basal/bolus insulin therapy, many clinicians stop all oral agents —including metformin— due a perception that it is ineffective if the A1c has started to climb, despite the multiple benefits associated with metformin beyond glycemic control.¹³  The new paradigm includes a call to clinicians to consider continuing previous treatment when starting insulin therapy … and vice versa, adding agents to insulin … when appropriate (e.g. pharmacologic agents that have insulin sparing effects, decreased gluconeogenesis, delayed gastric emptying).

Future Implications:

10. Treating diabetes with greater precision.  Further study is needed to identify the clinical utility of existing tests (e.g. C-peptide, islet cell autoantibodies, markers of inflammation, measures of insulin resistance) and new biomarkers (e.g. improved assays for beta cell mass, markers of environmental damage, markers for various mediating pathways of hyperglycemia) to guide treatment decisions.

11. Policies regarding third party reimbursement for diabetes treatments.  Current treatment algorithms tend to promote a “first/second/third line” sequencing which (unfortunately) establishes competition between pharmacologic categories rather than acknowledging each category’s unique qualities and potential benefits.  Moreover, step therapy necessitates a trial and failure approach, even if the 4^th line therapy would be much better suited for the patient’s specific circumstances.  For example, a sulfonylurea may be the preferred pharmacologic category on a patient’s insurance plan, even when insulin resistance is the patient’s predominant problem, rather than a state of insulin insufficiency.  Updates to policies regarding third party reimbursement are necessary to align with current treatment approaches.

What are your thoughts regarding this new paradigm?  Do these assessments of the current landscape of diabetes treatment strategies align with your approach?