Liraglutide and Robust A1C Reductions Among People With Type 2 Diabetes Requiring Appetite Control: A Review of Two Cases Free

A 63-year-old Black man with a medical history significant for type 2 diabetes, HIV, ASCVD (two coronary stents and a myocardial infarction), CKD, hypertension, and heart failure with reduced ejection fraction was referred to an outpatient clinic’s in-house pharmacist-run diabetes education and management service with an A1C of 12.8%, weight of 116.6 kg (257 lb), and BMI of 34.86 kg/m². He had not tolerated metformin in the past and was currently taking sitagliptin 100 mg daily, insulin glargine U-100 50 units once daily, and insulin aspart 15 units before meals, and his premeal self-monitored blood glucose values ranged from 230 to 410 mg/dL. He reported adherence with all medications and that his HIV had been well controlled for several years.

When the patient was diagnosed with HIV, he had learned about HIV wasting syndrome, involving unintentional weight loss from both fat and muscle. Fearing this outcome, he exercised daily for at least 1 hour, including both aerobic and resistance training, and he appeared to be quite muscular. He also felt a compulsion to overeat at meals to avoid HIV wasting and felt that he could not stop himself from eating such large quantities. He skipped lunch to avoid at least one meal of overeating. His breakfast consisted of four eggs, four sausages, four pieces of toast, a large bowl of cereal, a banana, and a small cinnamon roll. A typical dinner was fish sticks, mashed potatoes, a salad, nuts, a cinnamon roll, and popcorn. He ate large portions but did not snack throughout the day. Despite having received counseling about portion control and carbohydrate counting on many occasions, he showed little A1C improvement.

During the first 8 months in the pharmacist diabetes service, his insulin was titrated to very large doses of insulin glargine U-100 80 units twice daily and insulin aspart 50 units with meals. These dose increases resulted in a greatly improved A1C of 8.8%, but weight gain to 133.4 kg (294 lb) and a BMI of 39.87 kg/m².

The patient’s sitagliptin was then switched to liraglutide, titrated to 1.8 mg daily. All other medications remained unchanged. Over the next 8 months on liraglutide, the patient’s A1C improved gradually to 7.9%, then 7.7%, and ultimately 5.8%. During these months, he reported having less of an appetite, which allowed him to greatly reduce his portion sizes at meals and overcome his compulsion to overeat. His weight gradually improved to 118.4 kg (261 lb) and a BMI of 35.4 kg/m².

Because of subsequent hypoglycemia, his insulin was greatly reduced; insulin aspart was completely stopped, and insulin glargine U-100 was reduced to 30 units once daily. Previously, it was thought that his large insulin doses were needed because of severe insulin resistance; however, they had actually been needed because of extreme carbohydrate intake secondary to his overeating. Liraglutide allowed him to overcome the compulsion to overeat, and he was able to maintain glycemic control. After initiating liraglutide, his A1C dropped 3%, which is three times the expected A1C reduction for liraglutide. However, after accounting for the reduction of insulin doses as a result of liraglutide use and the maintenance of a controlled A1C level, an argument could be made that liraglutide, as a replacement for insulin, accounted for an astounding 7% reduction in A1C (Figure 1).

A 63-year-old White man with a medical history of type 2 diabetes, HIV, hypertension, and neuropathy was referred to the same clinical pharmacy service with a 2-month-old A1C of 13.2%, weight of 122.5 kg (270 lb), and BMI of 34.67 kg/m²; 1 month later, his A1C was 13.6%. With regard to his diabetes treatment, he had not tolerated metformin in the past and was currently taking linagliptin 5 mg daily and insulin degludec U-100 40 units once daily, and his self-monitored fasting blood glucose levels ranged from 230 to 350 mg/dL. He reported adherence with all medications and that his HIV had been well controlled for several years.

He reported eating only one meal daily, such as a frozen dinner, hamburger stew, spaghetti and meatballs, or enchiladas. However, he frequently snacked on sweets throughout the day and drank juice. He said he “overdoes it every time” he eats and felt this was his main problem that he could not control. He did not exercise because of pain and dependence on a walker for mobility. Despite having received nutrition education on many occasions, his A1C did not improve.

The patient’s linagliptin was switched to liraglutide, titrated to 1.8 mg daily. In 7 months, his A1C dropped from 13.6 to 7.1%—a 6.5% reduction (Figure 1). He reported noticeable improvements in portion control and eating habits and now feeling more control over how much food he consumed. However, he did not lose any weight and in fact gained weight, to 124 kg (273 lb) and a BMI of 35.1 kg/m². No other adjustments were made to any other medications and no other factors were found to contribute to his improvement in glycemic control.

Liraglutide is a GLP-1 receptor agonist that mimics the actions of the natural incretin GLP-1 to increase glucose-dependent insulin secretion, decrease glucagon secretion, increase β-cell growth/replication, delay gastric emptying, and increase satiety, thereby decreasing food intake (18). Liraglutide is generally recommended as a second-line agent for patients with type 2 diabetes (19,20) and may curb appetite, resulting in weight loss. Guidelines favor the use of a GLP-1 receptor agonist over basal insulin in patients with elevated A1C (19) and those with or at high risk for ASCVD. The American Diabetes Association’s (ADA’s) guidelines for the treatment of diabetes also recommend GLP-1 receptor agonist therapy for patients with type 2 diabetes and an eating disorder (19).

Although liraglutide has been shown to reduce A1C by ∼1%, in patients who overeat, the enhanced-satiety effect may lead to better portion control and A1C reductions greater than expected, as seen in the two cases described here (Figure 1). In case 1, liraglutide led to a clear 3% A1C reduction, but considering that liraglutide was able to replace so much of the patient’s insulin requirement, it accounted for a sustained 7% A1C reduction overall. In case 2, liraglutide resulted in an A1C reduction of 6.5%. In both cases, the patients reported reduced appetite and an improved ability to reduce their meal and snack portion sizes. Dramatic reductions in their daily carbohydrate intake made the A1C reductions possible. The following published cases support these findings.

A 2012 Japanese case reported by Senda et al. (21) involved a patient with Prader-Willi syndrome (PWS). PWS is a genetic disease characterized by a morbid obsession with food, reduced satiety, and earlier postprandial return of hunger that often results in the development of type 2 diabetes and severe morbid obesity related to hyperphagia. Having been diagnosed with PWS at the age of 10 years, the patient, at 25 years of age, developed type 2 diabetes from hyperphagia, with a BMI of 44.3 kg/m² and an A1C of 12.6%. Despite efforts to modify her diet and exercise, as well as taking sitagliptin, pioglitazone, and metformin, her outcomes did not improve. All medications were discontinued, and liraglutide 0.3 mg/day was initiated and increased weekly to the maintenance dose of 0.9 mg/day (the maximum dose in Japan) and maintained for 12 months. The patient's appetite was suppressed immediately and for the duration of treatment. She felt full more often and ate less, with fewer hunger events throughout the day. Her BMI decreased from 39.1 kg/m² at initiation of liraglutide to 35.9 kg/m², and her A1C dropped from 12.6 to 5.1% in the 12-month treatment period—a reduction of 6.5%.

In a 2015 report by Wiley et al. (22), a 27-year-old woman presented to a diabetes clinic with a history of type 2 diabetes, hypertension, and dyslipidemia and a weight of 120.2 kg (265 lb). After many struggles with adherence to medications and lifestyle interventions, she admitted that the stress of her disease caused her to overeat. Several insulin regimens, including NPH insulin, regular insulin, and a basal-bolus insulin regimen failed to improve her glucose control beyond a slight improvement in A1C from 11.1 to 10.8%, which occurred along with a weight gain to 134.7 kg (297 lb). To minimize her injections, she was switched to premixed insulin aspart protamine/aspart 70/30 45 units twice daily, and 1 month later, liraglutide was added and titrated to 1.8 mg daily. After 3 months on liraglutide, her A1C was down to 7.6%, and her insulin dose was decreased to 30 units twice daily because of hypoglycemia. After 6 months of liraglutide therapy, her A1C was 7.7%, she had lost 9 kg (20 lb), and her BMI had decreased by 3 kg/m². Ultimately, she experienced dramatic improvement in A1C, with a reduction of 3.2%, as a result of the GLP-1 receptor agonist being added to her diabetes treatment regimen without additions of other glucose-lowering medications or lifestyle counseling.

A 2020 retrospective multicenter observational study published by Berra et al. (23) and involving the use of a different GLP-1 receptor agonist implied that the large A1C reductions seen in these cases could be observed, in part, because of grossly elevated baseline A1C levels. This Italian real-world study measured A1C change in 626 patients with available A1C data at baseline and 6 and/or 12 months after taking dulaglutide at its previous maximum dose of 1.5 mg weekly. After 12 months, A1C decreased significantly more in patients with a higher baseline A1C, with those having a baseline A1C >9% dropping 2.3% and those with a baseline A1C of 8.1–9% dropping 1.2%. The study demonstrated that GLP-1 receptor agonist therapy can lead to a more robust drop in A1C in people with a higher baseline A1C, as was seen in the presented cases.

Some relevant studies have focused on the effects of GLP-1 receptor agonist therapy in patients with binge eating disorder or subclinical binge eating. In 2015, Robert et al. (24) reported on a randomized, prospective pilot study in which 44 patients with obesity and subclinical binge eating and without diabetes were randomized to lifestyle modification alone or lifestyle modification plus liraglutide 1.8 mg daily for 12 weeks to assess the impact on Binge Eating Scale (BES) scores, among other measures. The BES is a validated tool used to identify people who binge eat and to monitor treatment effectiveness. Scores <18 are categorized as non–binge eating. Patients using liraglutide had significant BES score reductions compared with the control group of 11 (interquartile range [IQR] 7–16) versus 20 (IQR 18–27) (P <0.001), and 81% of those in the liraglutide group improved from a binge eating to a non–binge eating category. A 2020 study by Da Porto et al. (25) evaluated the effects on BES scores of 60 patients with type 2 diabetes and binge eating disorder (average baseline BES 23.7) using dulaglutide 1.5 mg weekly versus gliclazide 60 mg/day. Patients had A1C levels of 7.5–9%, were already taking metformin, and were randomized to either group for 12 weeks. Patients using dulaglutide showed a significantly greater reduction in binge eating severity compared with the gliclazide group (change in BES score −12.07 vs. −0.47, P <0.0001). Participants in both studies also experienced significant weight loss and improved A1C. These findings are logical in that resolving overeating reduces carbohydrate intake and improves glycemia. These studies support the ADA’s recommendation to use a GLP-1 receptor agonist in patients with type 2 diabetes who have eating disorders.

The patient in our case 1 was using substantial doses of both basal and mealtime insulin. The addition of a GLP-1 receptor agonist allowed a drastic reduction in insulin doses while still lowering A1C. This pair of findings has been documented in other literature. Sheffield et al. (26) observed that 134 patients after 1 year of using immediate-release exenatide and insulin had an A1C reduction of 0.87%. These authors noted that 45% of the patients were able to completely discontinue mealtime insulin doses. Additionally, there was a 9-unit reduction in mean mealtime insulin dose and a reduction in the median number of daily insulin injections. In a similar study by Balena et al. (27), the researchers observed the impact of adding immediate-release exenatide to insulin. They found a mean A1C reduction of 0.51%, a mean reduction in insulin dose of 42 units/day, and discontinuation of insulin in 16.6% of patients.

The impact of initiating a GLP-1 receptor agonist to replace insulin is substantial. This strategy avoids the weight gain and hypoglycemia associated with insulin use while also promoting weight loss. The burden of multiple daily injections is also reduced, which positively influences adherence and patient satisfaction. Liraglutide is generally well tolerated, with primary complaints consisting of mild-to-moderate gastrointestinal effects (18). Although the average wholesale price is high ($425.85 per pen or $1,277.55 per box), most patients can acquire a GLP-1 receptor agonist at more reasonable out-of-pocket costs through private insurance, Medicaid, or manufacturer assistance programs.

The cases presented here demonstrate the potential for robust A1C lowering with the use of liraglutide in patients with type 2 diabetes who overeat. Other benefits of GLP-1 receptor agonist use include resolution of overeating, potential weight loss, and cardiovascular and renal protection. The use of liraglutide in lieu of insulin in patients with A1C levels >9–10% must be weighed against the risks and benefits of insulin use on an individual basis. However, consideration of liraglutide before or in addition to insulin therapy should be considered in the presence of overeating to reduce the risks of insulin and gain the benefits of a GLP-1 receptor agonist. Liraglutide provides an alternative to insulin for patients with grossly elevated blood glucose levels. More studies are needed to confirm and solidify these observations.

No potential conflicts of interest relevant to this article were reported.

M.A.P. identified references and wrote the manuscript. R.H.G. and M.R.H. summarized cited studies and contributed to the discussion section. M.S.T. contributed to the introduction and case summaries. J.L.J. identified the cases and contributed to writing and editing the manuscript J.L.J. is the guarantor of this work and, as such, had full access to all the information reported and takes responsibility for the integrity of the content.