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Exploring Glycemic Challenges With Experts in T2DM

Reevaluating the Current Approach to Type 2 Diabetes Management

Dr. John Anderson gives an overview of the current state of type 2 diabetes management, including its prevalence, A1C levels, physiologic approaches, hyperglycemia, and more. Find out how to help your patients achieve their glycemic targets.

Title: Reevaluating the Current Approach to Type 2 Diabetes Management

As most of you know, the number of Americans with diabetes is increasing, as a 2013 analysis of data from the National Health and Nutrition Examination Survey, or NHANES, reveals.

Spanning the years from 2007 to 2010, 47.8% of Americans with diabetes—or about 10 million people—had an A1C of 7.0% or greater, which is above the general goal set by the ADA for non-pregnant adult patients. Please note, the ADA recommends that each patient's target be individualized based on their specific needs and disease factors.

That said, there has been some progress in helping patients achieve glycemic targets. From 1999 through 2010 the trend in the NHANES data indicates that more patients are reaching the general A1C goal of below 7.0%.

The modest improvement is surprising when considering it has occurred during a time when the number of treatment options have increased considerably. In fact, since 2000, the FDA has approved 29 treatments for diabetes.

Let’s explore why it’s so important to get more patients to their A1C goal. One reason is that negative consequences can happen early, when patients experience elevated glucose before symptoms develop and type 2 diabetes is diagnosed.

An example can be seen here. In the decade it typically takes a patient to be diagnosed, he or she will have lost about 50% of β-cell function. And those with the most severely impaired glucose tolerance may have already lost 80 to 85% of β-cell function.

Considering this early hyperglycemic damage, should we be doing more to help patients meet their glycemic targets? As you can see in this set of charts…

…the answer may be yes in some patients. In this study, newly diagnosed patients were initially randomized to either a pharmacologic treatment or dietary restriction. Most patients were treated with sulfonylurea or an insulin-based approach, while overweight patients took metformin. Significant improvements were observed for any-cause mortality, and other diabetes-related outcomes in those patients who were randomized to intensive therapy using pharmacologic interventions.

These results were observed many years later—a legacy effect of intensive intervention. These data imply that early and intensive intervention following a diagnosis may improve current and future outcomes.

The importance of frequent monitoring of patient A1C, and then taking action to reduce elevated A1C, is emphasized by the ADA and AACE treatment guidelines, which recommend follow‐up 3 months after any treatment change.

Every patient’s therapy is individualized according to his or her specific needs, but begins with lifestyle modifications—healthier eating, weight control, increased physical activity, and diabetes education to help patients throughout therapy.

When patients are meeting their glycemic targets they typically remain on that therapy, as long as they tolerate it. For those not achieving their A1C target, guidelines prompt further action. As the disease progresses, many patients may need intensified therapy, often leading to use of combinations of oral and combinations of injectable therapies.

Considering the 3-month evaluation and intensification recommendations, it may surprise you to see how long delays to treatment intensification can actually be in clinical practice. To illustrate, let’s take a look at the results of a large retrospective cohort study.

This study looked at the length of time it took for patients on their first oral antidiabetic to receive a second oral antidiabetic. For those patients with an A1C of 7.0% or more, it was 2.9 years, while it was 1.6 years at the higher A1C threshold of 8.0%. Longer delays to treatment intensification were seen among patients taking 3 oral antidiabetics: 7.1 years in patients with an A1C of 7.0% or above, and 6 years in patients with an A1C of 8.0% or above, before they received insulin.

These results indicate that, in spite of the guidelines that recommend frequent reassessment of treatment, patients may often spend prolonged periods of time with A1C levels that exceed their targets.

The complexity of type 2 diabetes itself also contributes to the management challenge. In short, type 2 diabetes may not be easily addressed by any single approach.

Let’s quickly review how the body manages blood glucose.

As we know, under normal conditions, the body manages blood glucose levels throughout the day by secreting insulin.

Additional insulin is also secreted in response to meals, which helps to manage spikes in postprandial glucose. Insulin, therefore, plays an important role in managing both FPG and PPG levels.

Hormones classified as incretins also contribute to the management of blood glucose levels. Such hormones, gastric inhibitory polypeptide, or GIP, and glucagon-like-peptide-1, or GLP-1, are important in managing PPG levels.

When food is ingested, intestinal L-cells synthesize GLP-1.

This chart illustrates how GLP-1 secretion shifts the balance between insulin and glucagon. It exerts both glucose-dependent insulinotropic action and glucagon-suppressing action. These normal responses help to limit spikes in PPG levels.

So what have researchers learned about the relative contributions of elevated FPG and elevated PPG to total hyperglycemia?

The contribution of fasting hyperglycemia to A1C levels is greater in patients whose A1C values are uncontrolled at or above 8.5%. Postprandial hyperglycemia is a greater contributor among those patients with A1C levels closer to goal, with an A1C less than 7.3%.

The effect of therapy on the relative contributions of fasting and postprandial hyperglycemia to A1C has also been evaluated.

In this study, patients with type 2 diabetes and A1C levels above 7.5% were treated using individualized titration regimens. The goals of treatment, using a varied array of therapies, included reducing FPG to 100 mg/dL or less, and reducing 90-minute postprandial glucose to 140 mg/dL or less. After 3 months, mean A1C level declined from 8.7% to 6.5%. The patients were grouped according to whether they achieved an A1C of 7.0% or below, or remained above 7.0% after 3 months. FPG values declined with treatment in both of these groups, and were not significantly different. On the other hand, PPG levels were significantly lower among the patients who reached an A1C of 7.0% or below, after 3 months of therapy.

These results indicate that reducing FPG is necessary but may not be sufficient for meeting treatment goals in some patients if PPG levels are not controlled. Therefore, when A1C remains above target despite controlled FPG, the cause may be elevation in PPG.

To address the complexities and challenges associated with type 2 diabetes, we may consider an approach that includes combinations of oral therapies and combinations of injectable therapies to manage FPG as well as PPG excursions.

However, while the complexity of type 2 diabetes includes relative contributions of fasting and postprandial hyperglycemia, it also includes multiple physiologic abnormalities, as this diagram will demonstrate.

As we’ve already discussed, insulin is a key hormone in glucose balance as it induces liver, muscle, and fat cells to remove glucose from the blood. But increased glucose reabsorption by the kidneys, decreased intestinal secretion of incretins, and neurotransmitter dysfunction can also contribute to hyperglycemia. This collection of dysfunctions is sometimes referred to as the “Ominous Octet.”

Several drug classes can be used to address multiple physiological abnormalities, including both oral and injectable therapies. With that in mind, both the ADA and AACE guidelines recommend combinations of oral therapies as well as combinations of injectable therapies that address different pathways.

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