Reuter’s announced in January that diabetes deaths in the United States continue to surge well above pre-pandemic levels with over 100,000 Americans dying from diabetes in 2021. Given COVID-19’s relationship to diabetes, we may see this trend continue. Increasing deaths from diabetes is a clear call to action for new solutions. Historically, diabetes has been treated as a chronic disease, managed with a lifetime of medications. However, a new line of thinking about diabetes remission permeates the literature. Two new pathways have been proposed in the literature: high-intensity therapy or lifestyle change. Such a change in diabetes management will impact all healthcare stakeholders, including physicians, payers, and manufacturers. However, the benefit of these interventions to patients depends on the feasibility of implementation.
Diabetes Care released a consensus report in August of 2021 to define remission in diabetes.
Physicians view diabetes as a continuum, not a simple present/not present. In addition, people with a history of hyperglycemia can have complications; therefore, the expert panel determined that remission was the appropriate term (vs cure or reversal). Moreover, one must cease all glucose-lowering medications before a diagnosis of remission can be made. Physicians must monitor patients for diabetes relapse and microvascular and macrovascular effects resulting from hyperglycemia. Of course, the duration of remission and the long-term effects still need to be defined. Despite the uncertainty, experts developed this report to clarify appropriate intensive medication therapy or lifestyle change outcomes as studies around diabetes remission increased.
Intensive medication therapy
Diabetes treatment options have expanded over the last 20 years, starting with the first GLP-1 in 2005, DPP-4s in 2006, and SGLT-2s in 2013. Despite these innovations, patients with diabetes often have poor outcomes. Researchers are looking at alternative ways to use treatment options. A recent study by McInnes and coauthors titled “Remission of Type 2 Diabetes Following a Short-term Intensive Intervention with Insulin Glargine, Sitagliptin, and Metformin: Results of an Open-label Randomized Parallel-Design Trial” just missed statistical significance of the primary endpoint: diabetes remission at 24 weeks. Other studies have also looked at intensive therapy using an insulin-based regimen. In 2020, researchers looked at the combination of insulin glargine, metformin, and dapagliflozin to induce short-term remission. Again, more patients in the intervention group achieved remission, but the study did not reach statistical significance. Studies aimed at lifestyle change have had similar difficulties.
Lifestyle change
The Diabetes Prevention Program taught us early that lifestyle changes can lead to sustained prevention of diabetes. In the 2012 Look AHEAD trial, 1.3% had a 1-year complete remission in the lifestyle change program, but 10% of patients had a 2-year sustained partial remission, while 1.3% had a 1-year complete remission. Investigators halted the trial early because it did not meet its primary endpoint: cardiovascular events. However, a more recent study, the DiRECT trial, was designed to look at sustained remission. One-third of patients had diabetes remission for 2 years using a primary care-led weight management program. This study did reach statistical significance, albeit in a small population. Over time, we should expect studies around lifestyle change and intensive therapy to continue, given vendors like Virta and branded medications. Still, these interventions will be complex because of their effects on physicians, payers, manufacturers, and, most importantly, patients.
The physician’s workflow
The pandemic exacerbated the physician shortage issue because of physician deaths and burnout. Unfortunately, this has worsened patients’ already poor access to physicians. New strategies to induce diabetes remission may require that physicians see patients more frequently, increasing demand on schedules. In addition, intensive medication therapy will be a paradigm shift, as diabetes has always been a disease of chronic management. Physicians may be wary of potential side effects and costs. The McInnes trial intervention group had 3 times more hypoglycemic events than the control group. Strict management and rapid lowering of glucose can induce retinopathy. In addition, coverage by insurance companies may be difficult.
Impact on payers
Payers manage a limited set of resources to maximize the health costs and outcomes of a population. Undoubtedly, lifestyle interventions ordered by the primary care physician will be less expensive than intensive medication therapy. At the same time, coverage for additional resources like health coaching may change the dynamic. Intensive medication therapy presents more challenges for the payer. First, there must be sufficient evidence that the intervention induces remission without additional side effects like hypoglycemia that may raise medical costs with ER visits and hospitalizations. Second, often there must be guideline support to drive change. Third, payers must understand the population most suited for this intensive medication regimen. Finally, there must be an accounting of cost. For example, does early intensive therapy lead to a remission that reduces pharmacy and medical expenses over the next 1-2 years? Payers may require further research into efficacy and cost-effectiveness before coverage.
How will manufacturers respond?
Manufacturers will respond based on profitability and market share. Lifestyle change programs do not benefit this stakeholder. Intensive medication therapy may lead to greater use of branded medications versus generics like metformin. However, successful patients will terminate therapy once in remission, using fewer medications and affecting profitability. Then again, if this treatment regimen only applies to a limited population, it may not be a measurable change. The question is: how many patients would benefit?
Who is the right patient?
Often payers and manufacturers look at safety and efficacy. Evaluating access and feasibility may not be a priority, even though many patients will not be able to institute lifestyle changes or intensive pharmacologic therapy. Importantly, we don’t know if either of these approaches to diabetes remission will benefit patients in the long term. Even if studies show long-term benefits, patient access will likely be variable, leading to disparities. Choosing the right patient involves considering patient activation, insurance coverage, copay amounts, and lifestyle. Both intensive medication therapy and lifestyle change require a high degree of commitment and health literacy on the part of the patient. Receiving an initial diagnosis of diabetes can be overwhelming and lead to diabetes distress, which can impair a patient’s ability to self-manage. For intensive medication therapy, regimens include branded drugs from either the GLP-1 or SGLT-2 classes and insulin. Copays may accompany these medications, leading to financial toxicity for the patient. In addition, continuous glucose monitoring may be an added component that requires training, insurance coverage, and copays. Complications like hypoglycemia or retinopathy need to be discussed, mitigated, and ultimately may affect patient adherence. Similarly, a lifestyle change that includes dietary and physical activity modification may be unattainable for patients facing multiple social determinants of health like food deserts and unsafe exercise spaces. Cultural norms may also impact a patient’s ability to make food and physical activity choices commensurate with a successful outcome. As a result, patients who face more negative social determinants of health in terms of nutrition, income, employment, and housing may not benefit from approaches to induce diabetes remission.
We must consider feasibility
Society has the pharmacologic tools and scientific knowledge to manage diabetes successfully. It has not invested resources to make these tools and knowledge work for most patients. Black, Asian, and female patients have limited access to newer diabetes therapies, highlighting treatment inequities and engendering poor management. When we think about the feasibility of a trial, we ask, “Can it be done?” But once the intervention is on the market, will the treatment be impossible for patients to implement, or will the intervention contribute to widening health inequities? If the answer is yes, we will need to consider feasibility studies for these complex interventions and co-launch strategies for implementation; otherwise, we risk widening health inequities.
