The Expanding Role of New Medications in the Treatment of Type 2 Diabetes Mellitus

We examined the prevalence of use and cost impact of DPP-4 inhibitors and GLP-1 receptor agonists in people with diabetes.
Published Online: August 21, 2013
Kristen Harrison, MPH; Frederick Brown, PharmD; Brandeis Seymore, RPh; Anthony Palmieri, PharmD, MBA; Olga S. Matlin, PhD; and Steven M. Kymes, PhD
It is estimated that 26 million people in the United States have diabetes mellitus.1 Diabetes mellitus describes a number of metabolic conditions, but the most common forms are type 1 diabetes mellitus, a condition in which the body destroys insulin cells, requiring the person to receive insulin injections to properly control their blood glucose levels; and type 2 diabetes mellitus (T2DM), whereby the body is unable to either produce or respond to insulin in a manner sufficient to maintain normal blood glucose levels. Our analysis will focus on T2DM, which accounts for 90% to 95% of all cases of diabetes in the United States.1

Over 1.4 million new cases of diabetes are diagnosed each year among people over the age of 40 years—virtually all are T2DM. Risk factors for T2DM include older age, obesity, and inactivity.1 As the prevalence of these risk factors will increase with the aging of the baby boomer generation, the prevalence of T2DM is expected to increase dramatically as well. T2DM places a tremendous burden on the US healthcare system. People with T2DM have twice the mortality risk of people of similar age without T2DM. The Centers for Disease Control and Prevention reports that diabetes (types 1 and 2 combined) places a burden of over $174 billion annually on the US economy ($116 billion in direct medical costs and $58 billion from disability and productivity loss).1

The goal of treatment for a diabetic patient is to maintain blood glucose levels at normal or near-normal levels. This is essential in the prevention of diabetic complications, as increased blood glucose levels are associated with loss of vision (retinopathy), kidney failure, and cardiovascular disease.2 The recommendations for medical management of diabetes have evolved with the introduction of new treatment options, particularly incretin-based therapies—dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists.

The incretin response, or activity, is reduced in adults with T2DM, resulting in excess blood glucose. DPP-4 is an enzyme that breaks down incretins and, by inhibiting DPP-4 production, incretin levels in the blood increase, resulting in the reduction of excess blood glucose.3 GLP-1 receptor agonists increase the levels of cyclic AMP inside cells by binding to GLP-1 receptors found in the pancreas which, when blood glucose concentrations are elevated, results in insulin secretion. As blood glucose concentrations decrease and approach normal levels, insulin secretion decreases.4

We will examine how utilization and prescribing patterns have evolved for patients with existing diabetes and those newly diagnosed, paying particular attention to the role of GLP-1 receptor agonists and DPP-4 inhibitors in members who were historically treated with biguanides and/or sulfonylureas.


We conducted 3 related analyses using deidentified CVS Caremark pharmacy benefit claims from the funded commercial population from 2008 to 2012. For all analyses, members were required to be at least 40 years old and members with prescription fills for insulin were excluded to eliminate people with type 1 diabetes mellitus from our sample. Our first analysis was a description of members with prevalent diabetes between 2008 and 2012. The cohort used for this analysis consisted of all members who had at least 1 prescription fill for a diabetes medication between 2008 and 2012 (we refer to this as the Prevalence Cohort).

In the second analysis we examined patterns of medication use among members who were new users of diabetic medication. This cohort consisted of members using a diabetic medication between 2008 and 2012 who did not have a prescription fill for that medication in the 6 months prior to their first prescription fill between 2008 and 2012. In order to establish treatment-naïve status, we required these members to be continuously eligible for benefi ts for 6 months prior to their first fill of diabeticmedication (we refer to this as the Naïve Cohort). In the third analysis, we described trends in the use of DPP-4 inhibitors and GLP-1 receptor agonists as an adjunct treatment to biguanides and sulfonylureas. For this, we identified a cohort of members who had at least 1 prescription fill for either a biguanide or a sulfonylurea in 2011 and no prescription fills for either a DPP-4 inhibitor or GLP-1 receptor agonist that year. We required these members to be continuously eligible from 2011 to 2012, over the age of 40 years in 2011, and have no prescription fills for a DPP-4 inhibitor and/or a GLP-1 receptor agonist 6 months prior to their fi rst biguanide/sulfonylurea fill in 2011. We identified members of the 2011 cohort using biguanides and sulfonylureas who added (or switched to) a DPP-4 inhibitor or GLP-1 receptor agonist in 2012. Switching away from a sulfonylurea to a GLP-1 receptor agonist and/or a DPP-4 inhibitor was defi ned as the last fill of sulfonylurea before the first fill of either a GLP-1 receptor agonist or a DPP-4 inhibitor, allowing for a 7-day overlap. We refer to this as the Uptake Cohort.

In these analyses, cost was defined as the total paid charges for the medication by combining the payer and member portions of the health plan’s allowable charges. Our statistical analyses were conducted using SAS 9.1 (SAS Institute, Cary, North Carolina).


Among plan members 40 years and older, we found that 9.6% used diabetes medications and on average, 1.2% started diabetes therapy each year during our 5-year observation period. Between 2008 and 2012, the prevalence of diabetic medication use increased by 1.4 percentage points, from 8.7% to 10.1% (Figure 1). There was little change in incidence of diabetic medication use between 2008 and 2012, as it fluctuated between 1.0% and 1.3%. The average age in our Prevalence Cohort was 62.2 years (standard deviation [SD]: 11.8 years), and 49.1% were male. Members of our Naïve Cohort were younger than those in the Prevalence Cohort, with an average age of 58.6 years (SD 11.1), and 52.3% were male.

In Table 1, we describe trends in medication use for the Prevalence Cohort. Between 2008 and 2012, utilization of biguanides as monotherapy or in combination increased by 5.3 percentage points, from 46.1% to 51.4%. During this same period, utilization of sulfonylurea as monotherapy or in combination declined by 3.9 percentage points, from 27.7% to 23.8%. Utilization of DPP-4 inhibitors as monotherapy or in combination increased from 8.3% in 2008 to 14.2% in 2012, and utilization of GLP-1 receptor agonists increased by 1.0 percentage point, from 3.5% in 2008 to 4.5% in 2012.

In Table 2, we detailed the observed trends in cost of pharmaceutical treatment for people with diabetes from 2008 to 2012. Between 2008 and 2012, the average annual cost of providing pharmaceutical care for a person with T2DM increased from $667 to $741 (11.1%). During this period, the cost of the those drugs most commonly prescribed for T2DM—biguanides, sulfonylureas, and their combination—declined by over 33%, driven by a generic dispensing rate in excess of 96% for these drug classes. Conversely, the observed increase in cost of care for people with T2DM was driven by the increased annual cost of medication in less commonly prescribed drug classes: the DPP-4 inhibitors, GLP-1 receptor agonists, amylin analogue, and meglitinide agents. Of these, only the DPP-4 inhibitors and GLP-1 receptor agonists had a utilization rate in excess of 2%, and the increase in cost between 2008 and 2012 for DPP-4 inhibitors was 44% and for GLP-1 receptor agonists was 75%.

Between 2008 and 2012, approximately 85% to 90% of people naïve to diabetic medications initiated treatment on monotherapy (Table 3). Most commonly, these people with diabetes were started on biguanide monotherapy(63.8% of utilizers during the study period). For biguanides, the utilization rate as monotherapy increased from 55.5% in 2008 to 67.0% in 2012. During the same period, utilization of sulfonylurea monotherapy decreased from 14.2% to 10.8%. Between 9.9% and 14.7% of people naïve to diabetes therapy were started on more than 1 medication over the study period, most commonly on a combination of sulfonylurea and biguanide, or a combination of sulfonylureas, biguanides, and at least 1 additional drug (Table 3).

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