James R. Gavin, Mark W. Stolar, Jeffrey S. Freeman, Craig W. Spellman. Improving Outcomes in Patients With Type 2 Diabetes Mellitus: Practical Solutions for Clinical Challenges. J Am Osteopath Assoc 2010;110(5_suppl_6):S2–S14. doi: .
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The incidence and prevalence of type 2 diabetes mellitus (T2DM) in the United States continue to rise, and the disease has become an enormous health concern. While effective glycemic management reduces the risk of diabetes-related complications in patients with T2DM, many patients are unable to reduce their glucose levels to target goals. The authors review key elements in the management of T2DM with an emphasis on achieving and maintaining glycemic control. Strategies are offered to provide practical solutions to the challenges faced by healthcare providers and patients with T2DM. The importance of implementing evidence-based practice guidelines while empowering patients to participate in self-management of their disease is highlighted.
Legacy Effect in Metabolic Memory
Dr Stolar: The newer concept of legacy effect in metabolic memory—and even cellular mechanisms for metabolic memory—suggests that in early diabetes, glycemic control is important.
Dr Gavin: The point of the legacy effect is to see what happens when patients with diabetes are treated as they should be, with an emphasis on diabetes as a chronic disease...you institute therapy and you do the best you can to maintain the treatment goal for as long as you can. The data suggest, when adjusted for any confounding variables, that instituting early glycemic control makes the difference.
Interpreting Cardiovascular Trials
Dr Spellman: The reanalysis of ACCORD really gives a better message...most likely it was not hypoglycemia [that caused the excess mortality]...the patients who started with higher HbA1c levels had greater mortality rates...both the intensive and conventional groups had hypoglycemia. In terms of safety, trying to establish the HbA1c goal carefully, slowly, and judiciously would be appropriate.
Dr Stolar: The data will ultimately show that the majority of the mortality was in nonresponders [personal communications with David Kendall]. The patients in the intensive management [group], who had the highest HbA1c levels and were not responding, and therefore were not accruing significant hypoglycemia, had the highest mortality. That makes sense because the most insulin-resistant patients are likely to have more cardiovascular events overall.
Dr Gavin: ADOPT, ACCORD, ADVANCE, PROactive—all of these were trials involving patients with established disease. But they were specifically designed, in some instances, to test the effect of an agent on improving glycemic control and to see whether or not it modified outcomes.
Key Elements in Diabetes Management: Glycemia, Blood Pressure, Lipids
Dr. Spellman: The concept of diabetes requires three things...if you haven't addressed sugars, blood pressure, and lipids, you haven't done your job.
Dr. Stolar: The reason that we say cholesterol lowering is beneficial is because we target an LDL [low-density lipoprotein cholesterol] of 70 mg/dL, which is physiologic in humans. We have lowered our blood pressure goals to 120/80 mm Hg as aggressive management, because it's physiologic. An HbA1c of 6.5% is not physiologic glycemia for humans...it's clinically acceptable on an outcome basis. So in order to truly compare the impact of cholesterol lowering, blood pressure lowering, and glycemic control as valid interventions, you would have to compare an HbA1c of 5.0%. That would be impossible and unnecessary to achieve clinically, but by accepting non-physiologic glycemia in our risk management, we diminish the overall importance of glycemic control.
Monitoring Glycemic Control
Dr Gavin: HbA1c is a gold standard right now...even more powerful than the self-monitored glucose. HbA1c is the only number that is associated with outcomes.
Dr Freeman: Diabetes control is a trilogy...fasting plasma glucose, postprandial glucose, and HbA1c.
Dr Gavin: You've got three legs on a stool—if you fix the fasting glucose and the HbA1c is still bad, you have one more leg of the stool to explore...that's when you look at postprandial glucose levels.
Self-Monitoring of Blood Glucose
Dr Freeman: By empowering patients to check the results of their fingersticks, it actually engages them in therapy...it involves them in what they're doing and what their targets are.
Dr Gavin: Self-monitored glucose is the snapshot, but the HbA1c is the movie.
Role of Incretin-Based Therapies
Dr Stolar: Incretin-based therapies should be used earlier. If their job really is improving β-cell function and slowing β-cell loss, they have to be used earlier. You can't salvage what's not there.
Dr Gavin: The data indicate that incretins might have some real surprises with respect to the pleiotropic nonglycemic effects...like cardiovascular protection.
Dr Spellman: DPP-4 inhibitors are the 21st century sulfonylureas without the side effects of hypoglycemia.
Concerns About Weight Management
Dr Stolar: Many people are worried about weight gain.
Dr Freeman: It's weight loss that's the driver and patients need to have realistic expectations of weight loss.
Limitations of Algorithms
Dr Gavin: The default runs the risk of being too simplistic. Algorithms are basically decision trees—they have been designed to be somewhat reductionist in nature. Algorithms fundamentally focus on what and rarely focus on how...The AACE road map, however noble its intent, had some pitfalls. It was just too much. It was like drinking from an algorithmic water hose.
Newer Algorithms: How They Differ
Dr Gavin: The new AACE Guidelines attempt to help the clinician make the best decision for patients. The goals included simplification and ease of communication to providers...to use a method of stratification of patient risk that incorporates a measure that is available to everybody—the HbA1c—not duration of disease, not symptoms or lack of symptoms, but the entry level HbA1c that represents the entry level of risk factors. The algorithm provides a pathway for making a treatment decision based on whether patients are candidates for monotherapy or dual therapy, what combinations would be appropriate, and what generally makes sense for patients who meet certain criteria.
Dr Freeman: One thing is that the new AACE guidelines are encompassing, and that's favorable because drugs are presented within the scope of where they can be used by clinicians treating diabetes. The previous ADA/EASD [European Association for the Study of Diabetes] algorithm was somewhat exclusionary of various drugs for a variety of reasons.
Dr Gavin: One of the other differences between this algorithm and the ADA/EASD is the degree to which the DPP-4 inhibitors and the GLP-1 agonists really figure a lot more prominently.
The Challenges of Lifestyle Modification
Dr Gavin: Some patients will be more successful in terms of what they do and what they accomplish with lifestyle modifications. Some people really believe in it, and they're zealots about it. Some patients become frustrated if they don't achieve adequate results from attempts at lifestyle modifications, so we move more quickly in adding pharmacotherapies in those cases. Every drug that has ever been approved for the treatment of T2DM is predicated on being an adjunct to lifestyle modifications.
Newer Algorithms: Role of Incretin-Based Therapies
Dr Stolar: Incretin deficiency is a major physiologic defect. It is a clearly documented deficiency that seems to be present in virtually all patients with T2DM, although the reason for this remains unclear. There is a valid evidence base that the incretin defect can be addressed in virtually all patients with T2DM, with varying degrees of clinical success.
Dr. Stolar: The AACE algorithm does a much better job than the ADA guideline in both achieving and maintaining glycemic control—the ADA algorithm puts agents with documented durability and preservation of β-cell function either below the “recommended” dotted line or not on it at all. Incretin-based therapies remain very valuable in their impact on β-cell function.
Dr Freeman: The expectation of trust is a critical component of the physician-patient relationship. The patient should not fear telling the truth...if they are taking a three times daily medication once a day, or not at all, they should not be reluctant to tell the doctor that they are not taking it three times a day.
Dr Freeman: A key concept is to progress therapy carefully because there are toxicity issues and drug interactions. Some patients have aversions to needles, and the challenge for those individuals is to show them the injection process and how easy it is. Once they have self-injected, it is usually not a problem, and the barrier is overcome.
Dr Spellman: It is important to keep in mind that the patient is the one with the disease, and he or she should assume responsibility for participating in the management of the disease. The clinician's job is to make recommendations and show the patient what is available.
Dr Gavin: Clinicians should try to help patients understand why the medicine is helping; that insight will drive patients' change in behavior. This takes time because clinicians have to teach and demonstrate.
Dr Stolar: Clinicians spend too much time focusing on the numbers and not enough time on helping the patient understand what is going on with their disease at each visit. If the HbA1c comes down, the patient should understand why he or she was successful. Conversely, if the patient is doing poorly, he or she should understand how the clinician can address the failures.
Dr Spellman: The physician's job is to outline a course of action. It is the patient's job to implement and the provider's job to guide them. Be aggressive early on and always emphasize the cornerstones of management—sugars, blood pressure, and lipids.
Dr Freeman: Be sensitive to the patient's needs. Be flexible. Be aggressive in achieving glycemic control, but be very cautious and careful. Consider whether a medication regimen fits the needs of the patient. Try to give incentives for the patient in some way, at least to inspire them to be part of the team in terms of taking care of diabetes in a very holistic manner.
Dr Gavin: We actually have better tools emerging than we have had before. We are seeing a transition in terms of the tools that are available to manage diabetes. Our challenge is going to be to make sure that, at all times, we balance efficacy, safety, and cost in ways in which we can leverage these tools to the best benefit of patients.
Dr. Stolar: The problem is that we have been doing reactive “bottom-up” management rather than treating top-down. Rather than being aggressive early in the disease, with combination therapies to normalize blood sugars and then backing off, as we do for other disease states, we do reactive management as treatment fails. Becoming aggressive only when the disease has progressed cannot work in this disease model as β-cell loss continues its inevitable progression. Earlier treatment is far more durable as you have modified the disease by addressing β-cell function earlier. It is a difficult disease to treat when forced to play catch-up, which epitomizes “bottom-up” management.
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