Barriers to Obtaining GLP-1 Receptor Agonists and SGLT2 Inhibitors in a Free Clinic Population With Type 2 Diabetes and Cardiovascular Disease

Type 2 diabetes (T2D) affects over 37 million people in the United States, 11.3% of the population, and is a significant risk factor for cardiovascular disease (CVD) and other complications including chronic kidney disease.^1,2  In 2008, due to cardiovascular safety concerns of some previous diabetes medications for T2D, the U.S. Food and Drug Administration mandated that pharmaceutical companies conduct cardiovascular outcome trials (CVOTs) to assess the safety of all new medications for the treatment of diabetes.³  Beginning in 2015, several large CVOTs studying T2D were published demonstrating a reduction in major cardiovascular events and/or cardiovascular mortality with glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), independent of hemoglobin A1c. ^4–7  In 2018, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes revised their glycemic management recommendations advising that, in addition to metformin and lifestyle therapy recommendations, people with established atherosclerotic cardiovascular disease (ASCVD) should receive a GLP-1 RA or a SGLT2i.^8,9  In 2019, the ADA Standards of Medical Care were further modified to advise that a GLP-1 RA or SGLT2i should be started in people with T2D who have established ASCVD or chronic kidney disease (CKD).¹⁰  In response to additional CVOTs demonstrating beneficial cardiovascular effects with these agents, the ADA Standards of Medical Care further recommended adding a GLP-1 RA or SGLT2i in a patient with T2D at high risk for ASCVD in their 2020 guidelines.¹¹ 

The student-run free clinics (SRFC) affiliated with a local university provides free medical care and medications to homeless and underserved communities in San Diego County.¹²  Services are provided in an interprofessional setting by students of pharmacy, medicine, dentistry, holistic medicine and social work. Students are overseen by licensed clinicians and providers, including pharmacists and physicians. A large proportion of SRFC patients have T2D and other comorbidities, such as cardiovascular disease and may benefit from the addition of a GLP-1 RA and/or SGLT2i for cardiovascular protection. However, the SRFC have limited access to these agents due to their high cost. SRFC has a limited generic medication formulary that is supplemented by manufacturer sample products, when available. A student pharmacist team also assists eligible patients to enroll in manufacturer-sponsored patient assistance programs (PAP) and handles procurement of PAP medications when approved. However, it is currently unclear what proportion of SRFC patients with T2D and established ASCVD or those who are at high risk for ASCVD receive a GLP-1 RA and/or SGLT2i.

This study aimed to determine the proportion of patients with T2D and established ASCVD, or at high risk for ASCVD, who received a GLP-1 RA and/or a SGLT2i at the SRFC over a one-year time period. Additionally, the study aimed to determine potential barriers to GLP-1 RA and/or SGLT2i medication access for this population.

This study was a retrospective cohort study. All subjects with T2D seen at the SRFC between April 2019 and April 2020 were evaluated using an electronic medical record (EMR) system and manual data collection, when necessary.

The following baseline data were collected from subjects’ EMR: documented medical history of established ASCVD (defined as coronary heart disease, peripheral artery disease, cerebrovascular disease, angina or myocardial infarction).¹³  For subjects with T2D and no established ASCVD, a 10-year ASCVD risk score was calculated via the ASCVD Risk Estimator Plus calculator.¹⁴  Factors that were used to calculate this risk score were subject age, sex, race, blood pressure, total cholesterol, LDL-cholesterol, HDL-cholesterol, history of diabetes, smoking status, whether the subject is on hypertension treatment, receiving a statin and receiving aspirin therapy.¹⁴  Additional data collected included use of an SGLT2i and/or GLP-1 RA, average A1c between April 2019 and April 2020 and factors that may be contraindications or precautions to initiating an SGLT2i and/or GLP-1 RA, including medication allergies, adverse effects or intolerances, dehydration, CKD, low blood pressure, previous history of pancreatitis or ketoacidosis and a history or family history of thyroid cancer. Lastly, PAP applications or receipt of medication samples were collected to identify sources of medication access.

Per the ASCVD Risk Estimator Plus calculator, the 10-year risk for ASCVD was categorized as: low-risk (< 5%), borderline risk (5% to < 7.5%), intermediate risk (7.5% to < 20%) or high risk (≥ 20%).¹⁴  EMR and PAP records were assessed for all T2D subjects to identify established ASCVD or a 10-year ASCVD risk score of at least 20%.¹⁴  Study exclusion criteria included subjects for whom a 10-year ASCVD risk score was unable to be calculated (i.e., missing laboratory data, younger than 35 years or older than 79 years) and subjects with prediabetes, Type 1 diabetes, minors (< 18 years old) and pregnant women.

Data were evaluated using descriptive statistics from Microsoft Excel. Study subjects were divided into three groups for analysis: established ASCVD, ASCVD risk score ≥ 20% (high risk) and ASCVD risk score < 20% (low to intermediate risk).¹³  This study was approved by the university’s Human Research Protections Program.

From April 2019 to April 2020, 235 subjects with T2D were seen at the SRFC. A total of 115 subjects met study inclusion criteria (Table 1). Of these, 58 (50.4%) had established ASCVD, while 4 subjects (3.5%) had a 10-year ASCVD risk score ≥ 20%. Nine subjects (15.8%) with established ASCVD received a GLP-1 RA and/or SGLT2i, while no subjects with an ASCVD risk score ≥ 20% received either of these medications. Of the 53 subjects with an ASCVD risk score < 20%, 3 received a GLP-1 RA and/or an SGLT2i.

Potential barriers or reasons for not receiving an SGLT2i or GLP-1 RA were identified for 35 subjects (66%) with established ASCVD or ASCVD risk score ≥ 20% (Table 2). The most common barrier included delays with PAP application and procurement of medications. The most common reasons included history of CKD, dehydration and/or low blood pressure.

Despite recommendations from diabetes management guidelines for the use of an SGLT2i or GLP-1 RA in people with T2D with ASCVD,^8–11  our study found that only 15.8% of subjects at the SRFC with T2D and established ASCVD received a GLP-1RA and/or SGLT2i during the one-year study period. Further, no subjects with a high ASCVD risk score received a GLP-1 RA and/or SGLT2i. These results appear consistent with similar studies in different populations.¹⁵  In a veteran population across multiple Veteran Affairs facilities in 2020, only 11.2% of patients with T2D and ASCVD had received an SGLT2i, while 8% received a GLP-1 RA.¹⁵ 

The most common barrier or reason identified for not receiving these agents in our study was a history of CKD. Although the ADA guidance during our study period advised that patients with an estimated glomerular filtration rate (eGFR) of ≥ 30 mL/min can be safely initiated on these medication classes,⁹  regular monitoring and follow-up visits are often more difficult for patients of a free clinic population since they lack insurance coverage, ready access to medical clinics and their housing may be transitory. A free medical clinic in southeastern U.S. reported that less than 50% of their patients schedule a follow-up appointment, and of those follow-up appointments, only 75% show up.¹⁶  Concerns for loss to follow-up or declining renal function may have factored into reasons these medications were not initiated during the study period. Other potential reasons included history of dehydration and low blood pressure. SGLT2i agents require that patients maintain adequate hydration, due to the risk of euglycemic DKA.^17,18  In addition, SGLT2i agents can modestly lower systolic blood pressure by 3.7–5.4 mmHg, so patients with low blood pressure may be at risk for further blood pressure lowering. ^17,18  In contrast, GLP-1 RA may be safely administered in T2D patients with moderate to severe renal impairment and do not lower blood pressure.^19,20  GLP-1 RA could be used in many situations when an SGLT2i is contraindicated.

Although the exact barriers for underuse of both GLP-1 RA and SGLT2i remains unclear, there has been growing attention on the role that clinical inertia may play.²¹  In a recent article, Schernthaler et al. cited clinical inertia for low GLP-1 RA and SGLT2i prescribing for cardiorenal protection in high risk T2D patients and urged clinicians to address barriers to prescribing these agents to reduce death and hospitalizations in this population.²¹  Given that the SRFC relies largely upon volunteer efforts from students and providers, with many volunteers attending the SRFC infrequently or inconsistently, clinical inertia may be a barrier. In addition, since these agents are relatively newer classes of medications, particularly SGLT2i, unfamiliarity with their use may be another contributing factor to low rates of use in our study. This may be an opportunity for pharmacists and student pharmacists to educate other providers on the benefits of these agents and proactively identify high risk patients with T2D that could benefit from initiating of one of these agents.

The SRFC also has limited financial resources. Medication classes that are frequently prescribed for T2D, such as biguanides, sulfonylureas, NPH and regular insulins, are less expensive than GLP-1 RA and SGLT2i, and thereby, more readily available. The SRFC uses sample brand medications, when available, but consistent supplies are not guaranteed. While GLP-1 RA and SGLT2i may be available through PAP programs, not all patients qualify. Additionally, there may be delays in obtaining the medications due to incomplete paperwork, shipping delays and changes in manufacturer application rules. With these challenges in mind, providers may elect to initiate patients on diabetes medications that are readily and consistently available without these barriers. Furthermore, since the SRFC is in the border community of San Diego, many people who seek care at the SRFC are undocumented immigrants. PAP application requirements for GLP-1 RA and SGLT2i available during the study period required an applicant to be a permanent, legal resident of the United States, Puerto Rico or U.S. Virgin Islands and/or include their social security number on the application.^22–26 

This is a significant barrier for patients who are undocumented immigrants in the U.S. and likely contributes to a lack of overall PAP applications for these medications. On May 1, 2022, the state of California expanded Medicaid coverage (Medi-Cal) to all adults 50 years or older, regardless of immigration status.²⁷  While Medi-Cal eligibility rules and income limits still apply, this expansion may significantly improve accessibility of GLP-1 RA and SGLT2i to T2D patients within vulnerable populations, including many older, undocumented immigrants seen at the SRFC.²⁷ 

There were significant limitations to our study. Our sample size of 115 subjects was small. It was also a retrospective design and data collection relied on accuracy and completeness of EMR data. Subjects who had visits with outside providers or obtained diagnostic or laboratory tests performed outside of the SRFC may not have had their results entered into the EMR. Missing or incomplete lab values factored into the exclusion of subjects from this study, as this data was needed to calculate a 10-year ASCVD risk score. In addition, subject charts were manually reviewed to assess for potential barriers to medication access, based on a predetermined list created by the authors (Table 2). This included factors such as PAP delays or product discontinuations as well as contraindications and/or precautions based on the approved prescribing information. Other potential barriers may exist that were not listed and therefore not identified by the authors. Some PAP records may have been incomplete, resulting in missing data.

Many subjects with T2D and established ASCVD or who are at high risk for ASCVD did not receive GLP-1 RA and/or SGLT2i medications at a university-affiliated SRFC over a 12-month period, despite strong evidence for cardiovascular benefits with these agents. Barriers or reasons for lack of initiation of these medication classes in this population should be identified and addressed to ensure that patients with T2D and ASCVD or at high risk for ASCVD, are able to obtain these beneficial agents.