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Considerations for Diabetes Management

Evaluating Different Pathways to Achieve Target A1c Levels

Dr. Robert Henry discusses the current issues and challenges in achieving glycemic control and what healthcare providers may want to consider for their next move in T2DM patients who are uncontrolled on OADs.

Title: Evaluating Different Pathways to Achieve Target A1c Levels

As healthcare providers who treat patients with diabetes, it is important for us to acknowledge that despite the increased availability of resources, education, and treatments, about half of the patients with diabetes are not at their individualized target hemoglobin A1c level.

Hello, I am Dr. Robert Henry from the University of California in San Diego in La Jolla.

Today, I am going to discuss the current issues and challenges in achieving glycemic control, which we, as healthcare providers, may want to consider when we think about our next move for patients with type 2 diabetes who are uncontrolled on oral antidiabetics and ready for injectable therapy.

The management of diabetes remains a challenge for many patients and their healthcare providers. The 2014 National Diabetes Statistics Report found that in the United States, 29.1 million people, or 9.3% of the population, have diabetes, and of those, 21 million people are actually diagnosed with diabetes.

And, according to the most recent National Health and Nutrition Examination Survey data, of the 21 million Americans diagnosed with diabetes, 47.8%, or approximately 10 million people, are not reaching the American Diabetes Association's HbA1c target of less than 7%.

Now, I’d like to take a look at some data from Ali and colleagues. They tracked the progress of achieving the goal of an A1c less than 7%, from 1999 to 2010 in the United States, using the records of 3,355 patients who received the diagnosis of diabetes from a healthcare provider.

From 1999 to 2002, 44.3% of patients had an A1c of less than 7%, while 55.7% did not achieve that goal.

Moving on, from 2003 to 2006 we see that 56.8% of patients had an A1c of less than 7%, whereas 43.2% did not. Then, from 2007 to 2010, 52.2% of patients had an HbA1c of less than 7%, while 47.8% did not.

I’d also like to point out that since 2000, 29 treatments for diabetes have become available. And from 1999 to 2010, 7.9% more patients reached an HbA1c of 7%.

As the data show, we are making some progress, but we still have a ways to go.

Lastly, I think it is important to note the percentage of patients with A1c of 8% or above in each National Health and Nutrition Examination Survey cohort. In 1999 to 2002, it was 32.6%; in 2003 to 2006, it was 22%; and in 2007 to 2010, it was 20.9%. Again, the numbers are improving, but there is still much work to be done.

Negative consequences can occur early when patients have elevated glucose levels. By the time of diagnosis, patients with type 2 diabetes may have already experienced years of negative consequences related to hyperglycemia.

Here, we see data from the United Kingdom Prospective Diabetes Study that imply that over approximately 10 years prior to diagnosis, a loss of about 50% of β-cell function occurs.

And, patients with the most severely impaired glucose tolerance at the time of diagnosis had already lost 80% to 85% of their β-cell function.

Additionally, a separate study of patients with retinopathy indicated that before being diagnosed with type 2 diabetes, patients may be exposed to the damaging effects of elevated plasma glucose for at least 4 to 6 years.

However, we also know that early and intensive intervention following diagnosis improves current and future outcomes. Holman and colleagues studied outcomes of patients 10 years after the UKPDS. In this slide, we see the study design and limitations.

Holman and colleagues found a sustained legacy effect of an intensive glucose-control strategy that appears to be longer than previously reported and indicates that intensive glucose control starting at the time of diagnosis is associated with a significantly decreased risk of myocardial infarction and death from any cause. This is in addition to the well-established reduction in the risk of microvascular disease.

These findings strengthen the rationale for attaining optimal glycemic control as early as possible in patients with diabetes.

Even though we are all aware of the risk reductions associated with attaining optimal glycemic control early on in diabetes, changes in treatment for our patients do not always occur as quickly as recommended.

The stepwise approach recommended by the American Diabetes Association includes counseling patients on lifestyle modifications as well as diet and exercise, as a foundation for type 2 diabetes mellitus management. It also directs physicians to evaluate A1c approximately every 3 months in patients not reaching their glycemic target, followed by the titration of the dose of current therapy or the addition of another treatment.

I’d like to point out that according to the guidelines of the American Association of Clinical Endocrinologists, most patients require combinations of medications, which may include combinations of oral therapies and combinations of injectable therapies.

Yet, years of delay in treatment intensification can occur at multiple stages of a patient’s journey. This was demonstrated in a study by Khunti and colleagues that examined a total of 80,000 patients with type 2 diabetes and A1c of approximately 7% through a retrospective database cohort analysis.

The study found that patients who were not reaching A1c targets with 1 oral antidiabetic drug, or OAD, did not receive another OAD for 1.6 to 2.9 years, in contrast to the 3 months recommended by the guidelines.

In the same study, it was found that insulin was introduced, on average, 6 to 7 years after patients with type 2 diabetes first missed A1c targets on regimens including 3 OADs…

…again, this is despite the fact ADA guidelines recommend intensification approximately every 3 months in patients not reaching their glycemic target.

Here are additional elements of the study design and limitations.

So, we have seen the effect of early glycemic control, but that the actual time to intensification of diabetic treatment regimens, on average, lags well behind what the guidelines recommend, resulting in patients spending more time being uncontrolled.

And this brings us to another important concept…

…the complexity of type 2 diabetes mellitus may not be easily addressed by a single approach.

As a reminder, under normal conditions, the body manages glucose levels throughout the day. In this conceptual profile of physiologic insulin secretion, we can see that the body releases a basal supply of insulin, and the body also secretes incretins such as glucose inhibitory peptide and glucagon-like peptide-1, or GLP-1, which stimulates the release of additional insulin to manage increased blood sugar levels after a meal.

Research has shown that GLP-1 is released from intestinal cells in response to meals and has glucose-dependent insulinotropic action.

Endogenous GLP-1 is synthesized and released from the neuroendocrine intestinal L-cells in response to nutrient ingestion; is rapidly degraded in the circulation by the enzyme dipeptidyl peptidase-4; has glucose-dependent insulinotropic action; has glucose-dependent glucagon-suppressing action; and delays gastric emptying.

With all this information in mind, one approach to managing elevated glucose could be to attempt to mimic the body’s physiologic response.

Looking at data, such as these demonstrating the relative contributions of fasting hyperglycemia and postprandial hyperglycemia to A1c levels, it is apparent that A1c levels are influenced by both FPG and PPG levels.

Woerle and colleagues studied the impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes. They looked at a group of patients who were not at goal, and who subsequently underwent treatment intensification via lifestyle intervention changes, including diet and exercise. Patients took 7-point diurnal blood glucose measurements, including FPG and PPG every day over the 3 months of intensified treatment. After 3 months of therapy, they compared the FPG and PPG levels of patients achieving HbA1c less than or equal to 7% as compared to those with HbA1c greater than 7%. We see that despite differences in HbA1c, FPG concentrations were virtually identical; 117 versus 119 mg/dL with a non-significant P value equal to 0.63. However, those who achieved an HbA1c of less than or equal to 7.0% had significantly lower PPG levels, 153 versus 180 mg/dL with a P value equal to 0.001. These findings highlight the importance of controlling postprandial glycemia to achieve target HbA1c levels.

A more physiological approach to managing fasting and postprandial hyperglycemia in patients falling short of their A1c targets may include combining oral or injectable therapies.

An approach that addresses both physiological responses may help patients reach A1c targets. Both the ADA and the AACE guidelines recommend the use of combinations of oral therapies and combinations of injectable therapies that address different pathways.

To address the complexity of type 2 diabetes, consider an approach that targets different physiological abnormalities.

We know that type 2 diabetes is a complex metabolic disorder involving multiple physiologic abnormalities as depicted in this diagram.

Insulin is the key hormone responsible for stimulating liver, muscle, and fat to remove glucose from the blood.

Combining therapies—whether combining orals, which we do quite frequently—or combining injectable therapies, can address some physiological abnormalities linked to type 2 diabetes.

In summary, due to the complexity of type 2 diabetes, consider early and intensive use of oral drugs and injectable drugs in combination.

Clinical rationale for using multiple therapies in combination may include targeting different physiological changes that contribute to hyperglycemia; tailoring treatment to better meet individual patient needs; and managing HbA1c elevation by addressing fasting hyperglycemia, postprandial hyperglycemia, or both.

As we wrap up today’s program, those of us who treat type 2 diabetes would be well-served to ask ourselves the following question: “If the patient uncontrolled on OADs needs injectable therapy, will your next move do enough?”

That concludes today’s program. Thank you for your time and attention.