Targeting Postprandial Glucose as it Relates to A1C and Cardiovascular Disease

The future of measuring and controlling postprandial glucose using TIR (Time in Range). 

This article includes excerpts from our Q&A with Dan Pollom, MD, Senior Medical Advisor, Eli Lilly, and Company, about Lilly’s new rapid-acting insulin Lyumjev and how it increases TIR (Time in Range) and lowers A1C. To read the full interview, click here.  

Blood glucose readings, A1c levels, fasting blood glucose, and postprandial glucose (PPG) all have one similarity factor: to control and manage glycemic control in both type 1 and type 2 diabetes.  These measurements are key monitoring parameters that medical providers assess for each patient.  A1c levels have now been linked to the postprandial glucose levels as they correlate to the risk of cardiovascular disease.  In a recent study on the importance of postprandial glucose related to A1c and cardiovascular disease, the authors sought to describe PPG’s significance for the overall A1C levels.  This study provided results from multiple studies showing the cardiovascular benefit of PPG reduction and how different therapeutic agents can manage PPG in individuals with type 2 diabetes.    

In an online interview, Q&A with Dan Pollom, MD, Senior Medical Advisor, Eli Lilly, and Company, the question was asked:  Why is postprandial glucose a risk factor for cardiovascular disease? What are the benefits of postprandial glucose as it relates to A1C and cardiovascular disease? Dr. Pollom responded, “People with diabetes are at a greater risk for cardiovascular disease, and postprandial glucose (PPG) is an important metric in diabetes management and contributor to A1C levels.  While A1C reflects average blood glucose over two to three months, it only reflects one part of the larger picture in helping people with diabetes manage their condition and does not capture blood glucose highs and lows on a day-to-day basis.  For those who are not achieving their target A1C despite reaching their target pre-meal glucose levels, measuring and treating PPG may help.”  

The importance of PPG has received little attention, according to the authors of this review.  It is crucial to maintain long-term glycemic control.  Many studies have reported that PPG is an independent risk factor of cardiovascular (CV) mortality.  In a prospective study, the patients were not diagnosed with diabetes, had no fasting hyperglycemia, and received oral glucose tolerance testing.  This study demonstrated that women had a significantly increased risk of fatal CVD and heart disease than other patients without diabetes. In an evaluation conducted by Monnier and Colette, they reported PPG’s relative contribution was 70% in patients with A1C <7.3%, reducing to 30% in patients with A1C >10.2%.  A recent meta-analysis study of 14 studies with type 1 and type 2 diabetes participants significantly correlated with PPG and A1C compared to FPG and A1C.  The study showed a decrease in PPG equal to a more significant A1C reduction than fasting plasma glucose (FPG) reductions.    

The Honolulu Heart Program envaulted a group of Japanese American men showing an increased risk of coronary heart disease in patients with abnormal oral glucose tolerance results. The results reported from the Baltimore Longitudinal Study of Aging report a higher 2-hour PPG level related to CVD’s increased risk, CVD mortality, and all-cause mortality.  A 14-year follow-up study of type 2 diabetes patients found the study power for CV events and all-cause mortality.  Other studies reported provided support that PPG levels are definitely associated with CVD.  

The next question to ask ourselves is how we provide our patients with meaningful ways to manage and control their PPG to combat CVD risk. The authors stated, “postprandial self-monitoring of blood glucose (pp-SMBG) has shown to be associated with improvements in glycemic, lipids, and weight, as well as exercise and dietary habits in subjects who have already reached their A1C goals.” Continuous glucose monitoring (CGM), as stated by diabetes organizations, is an avenue that is acceptable for diabetes management.  The FDA has approved the Dexcom G6 used for SMBG to modify therapy in diabetes.  This system does not require a fingerstick for calibration and is user friendly.    

Reducing PPG is essential for patients when it comes to glycemic control.  The first line of therapy is lifestyle modifications, which includes physical activity and maintaining a healthy diet. Pharmacological treatments continue to be prescribed, as many patients struggle with lifestyle modifications.  As these therapies mainly focus on FPG, studies show the need for controlling PPG as it is an essential factor in A1C.  Studies reported that GLP-1 receptor agonists and basal insulin are exceptional options to manage both PPG and FPG.  In 2016, the FDA approved the use of iGlar-Lixi (lixisenatide) and insulin degludec and liraglutide (iDegLira) for the management of PPG and FPG.  A clinical trial study’s results found that once a day injection of these drugs provided a more significant A1C reduction than basal insulin or a GLP-1 receptor agonist alone.  They also found that weight gain, hypoglycemia, and gastrointestinal adverse effects were all reduced.    

The FDA recently approved Lyumjev, on June 15, 2020, to manage PPG levels.  Lyumiev is a formulation of insulin lispro; reports show a superior reduction in blood glucose spikes. In the Q&A, we asked: What are the significant benefits of using Lyumjev and Dexcom G6 CGM? What have you seen in the studies using Lyumjev and Dexcom CGM has been the average A1C?  Dr. Pollom stated, “In the absence of a clinical trial, we can’t speculate on the exact A1C reductions people with diabetes may see from taking Lyumjev and using the Dexcom G6 CGM.  We are confident in the value of assessing glucose levels and time in range in real-time with Dexcom CGMs.  Doing so can help HCPs better support people living with diabetes who struggle to manage their PPG levels and benefit from a treatment like Lyumjev.  PPG is often overlooked as a significant contributor to A1C, and our partnership with Dexcom aims to elevate PPG monitoring as an important component of treatment management.” 

With the use of CGMs, we see a new measurement emerge that can impact A1C and Quality of Life issues, called Time in Range (TIR). We asked: What is TIR, and how does using Lyumjev and CGM benefit TIR, and what benefits have we seen in any of the studies looking at TIR?  Dr. Pollom responded, “Time in range is an indicator of glycemic control, as it measures the percentage of time a person spends with their blood glucose levels in a specific target range.  Maintaining blood glucose levels in the target range is a daily balancing act for people living with diabetes.  In PRONTO-T1D, a clinical study evaluating Lyumjev in adults with type 1 diabetes, continuous glucose monitoring was performed in a subset of participants.  At 26 weeks, Lyumjev provided significantly more time in range during the day (+44 minutes, 4% increase) and a similar time in range during the night than Humalog (insulin lispro). That’s one reason why we believe Lyumjev is an important treatment option to help adults with diabetes manage their blood glucose.  With the ability to assess glucose levels and time in range in real-time with Dexcom G6 or Dexcom G6 Pro, either in a blinded or unblinded mode, HCPs can quickly identify their adult patients with type 1 and type 2 diabetes who struggle to manage their PPG levels and who may benefit from a treatment like Lyumjev.  Overall, this data can be used to help inform diabetes management.”   

As we know, there are many side effects and adverse events that come with taking therapies like Lyumjev. “Adverse reactions observed with Lyumjev include hypoglycemia, injection site reactions, allergic reactions, lipodystrophy, and weight gain.  In clinical studies, Lyumjev and Humalog had similar safety and tolerability profiles,” stated Dr. Pollom. Hypoglycemia is the most common adverse reaction associated with insulins, including Lyumjev.  Lyumjev is contraindicated during hypoglycemia episodes and in patients with hypersensitivity to insulin lispro or one of the excipients in Lyumjev.  Hypoglycemia, which can be severe and life-threatening, is the most common adverse reaction associated with insulins, including Lyumjev,” said Dr. Pollom.  

PPG is a vital contributor to A1C and a very significant risk factor for CVD, as seen in many studies presented.  Patients reporting an A1C ≥ 10.2% showed a PPG up to 30% of 24-hour A1C; while in patients much closer to goal A1C ≤ 7.3%, PPG was ~70% of 24-hour A1C.  This alone proves that PPG targeting therapies are essential for controlling and managing glycemic control in diabetes patients.  We asked, what percentage of reduction in PPG do you foresee when using Lyumjev? “In the Phase 3 trials PRONTO-T1D and PRONTO-2TD, Lyumjev demonstrated a superior reduction in blood glucose spikes at both one hour and two hours after a test meal compared to Humalog,” stated Dr. Pollum. What percentage of reduction seen in A1C using Lyumjev? Dr. Pollum said, “In the PRONTO clinical trial program, Lyumjev met the primary endpoint of non-inferior A1C reductions compared to Humalog in people with type 1 and type 2 diabetes, respectively.  Lyumjev demonstrated a – 0.12 percent change from baseline (7.3 percent mean A1C) and a -0.36 percent change from baseline (7.3 percent mean A1C) at 26 weeks in the PRONTO-T1D and PRONTO-T2D trials respectively.”   

Reports show many therapeutic options to target PPG, which includes AGIs, amylin analogs, glinides, dopamine agonists, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and rapid-acting insulins.  We asked What makes Lyumjev superior over other antihyperglycemic medications? Dr. Pollom stated, “The only head-to-head trial for Lyumjev is versus Humalog.  In the Phase 3 trials PRONTO-T1D and PRONTO-T2D, Lyumjev provided non-inferior A1C reductions compared to Humalog in people with type 1 and type 2 diabetes, respectively.  Lyumjev demonstrated a superior reduction in blood glucose spikes at both one hour and two hours after a test meal than Humalog.” 

Many HCPs are enduring the many changes seen with the pandemic.  To ensure we continue to provide meaningful information, we must come to terms with the epidemic and reach above it to get information.  With the current pandemic, how are you getting information out to healthcare providers? “Together, Lilly and Dexcom will enhance U.S. HCP education through a variety of channels to help them use data to inform diabetes management. This includes digital and virtual channels, among others,” said Dr. Pollum.    

Future studies are emerging for PPG as it relates to A1C.  What future technology and medicines do you see that will enhance controlling diabetes? “At Lilly, we believe there is a need to look at treatment outcome measures more holistically – including managing blood glucose levels at mealtime – and develop treatment options to support improved outcomes.  We developed Lyumjev to provide an important new option for people managing their diabetes. This new, rapid-acting formulation of insulin lispro represents a meaningful development for people with diabetes who want their insulin to help manage their A1C and reduce those post-meal spikes.  As part of our commitment to addressing unmet needs, we currently have ongoing Phase 3 trials to assess the use of Lyumjev in pediatric patients, and we plan to conduct additional clinical studies of Lyumjev in insulin pumps.  We also anticipate that Lyumjev will be an important component of our connected diabetes solutions, which are currently under development,”  stated Dr. Pollum.    

Practice Pearls:  

• Postprandial glucose targets are among the many measurements to manage and control glycemic levels.  
• It is imperative to provide patients with tools and therapies to achieve target PPG, as many patients can achieve FPG while still having high A1C.  
• Reductions in A1C provide positive outcomes for reducing the risk of cardiovascular disease.   

Kenneth S. Hershon, Barbara R. Hirsch, Ola Odugbesan.  Importance of Postprandial Glucose in Relation to A1C and Cardiovascular Disease. Clinical Diabetes Jul 2019, 37 (3) 250-259; DOI: 10.2337/cd18-0040 https://doi.org/10.2337/cd18-0040  

Interview, Dan Pollom, MD, Senior Medical Advisor, Eli Lilly, and Company 

Tarshay Boyd, PharmD. Candidate, LECOM School of Pharmacy