Insulin Peglispro (LY2605541): A Post-Mortem Analysis of a Novel Hepato-Preferential Insulin

Executive Summary

Insulin peglispro, also known as Basal Insulin Peglispro (BIL) or by its code designation LY2605541, was a novel, long-acting basal insulin analog developed by Eli Lilly and Company. It was bioengineered with a unique "hepato-preferential" mechanism of action, intended to more closely mimic the physiological activity of endogenous insulin. The narrative of Insulin peglispro is a compelling paradox in modern pharmaceutical development: it represents a molecule that achieved unprecedented and consistent superiority in glycemic control over the then-standard-of-care, insulin glargine, yet was ultimately terminated prior to regulatory submission. Its failure was not due to a lack of efficacy but to a complex and concerning safety profile that was inextricably linked to the very innovation that made it so effective.

Across its extensive seven-trial Phase III clinical program, named IMAGINE, Insulin peglispro consistently demonstrated statistically significant and clinically meaningful reductions in glycated hemoglobin (HbA1c​) compared to active comparators in patients with both Type 1 and Type 2 diabetes. This superior glycemic control was complemented by lower glycemic variability and significant ancillary benefits, including weight loss in Type 1 diabetes and reduced weight gain in Type 2 diabetes—outcomes that are highly desirable but often elusive in insulin therapy.

However, this remarkable efficacy was overshadowed by a constellation of adverse events that raised significant long-term safety concerns. The pivotal liabilities that ultimately derailed the program included consistent elevations in liver enzymes (alanine aminotransferase, ALT), a significant increase in serum triglycerides, and the accumulation of liver fat (steatosis) as measured by magnetic resonance imaging. Furthermore, the drug exhibited a paradoxical hypoglycemia profile, significantly reducing the risk of dangerous nocturnal events while simultaneously increasing the frequency of daytime hypoglycemia.

On December 4, 2015, Eli Lilly announced the discontinuation of the Insulin peglispro development program. This decision was not precipitated by an acute safety event but was a strategic calculation based on unresolved questions about the long-term consequences of the observed hepatic effects, the substantial time and investment required for further investigation with no guarantee of a favorable outcome, and a shifting competitive landscape with the arrival of new, second-generation basal insulins. This report concludes that Insulin peglispro serves as a critical and informative case study in drug development. It illustrates the profound challenge of balancing novel efficacy with long-term safety and underscores the systemic metabolic consequences of engineering tissue-specific drug action, providing invaluable lessons for the future of insulin therapy and metabolic drug design.

Molecular Profile and Bioengineering

Identification and Chemical Properties

Insulin peglispro is a biotech drug identified by DrugBank ID DB11567 and CAS Registry Number 1200440-65-8.[1] It was developed by Eli Lilly and Company under the internal code designation LY2605541.[4] The molecule is a derivative of insulin lispro, a rapid-acting human insulin analog where the natural sequence of proline at position B28 and lysine at position B29 of the insulin B-chain is reversed.[5] This reversal reduces the molecule's tendency to self-associate into hexamers, allowing for faster absorption and action when used as a prandial insulin.[6] In the case of Insulin peglispro, this insulin lispro base serves as the scaffold for a significant chemical modification.

The complete pegylated molecule has a molecular weight of approximately 26 kDa.[4] This is composed of the insulin lispro component (molecular weight of 5808 Da, identical to human insulin) and a covalently attached polyethylene glycol (PEG) moiety with a molecular weight of approximately 20,000 Da (20 kDa).[4] The general molecular formula is represented as

C259​H385​N65​O79​S6​[C2​H4​O]n​, where the [C2​H4​O]n​ component represents the repeating units of the PEG chain.[4]

The amino acid sequence is that of insulin lispro [8]:

• A-Chain (Chain 1): Gly-Ile-Val-Glu-Gln-Cys-Cys-Thr-Ser-Ile-Cys-Ser-Leu-Tyr-Gln-Leu-Glu-Asn-Tyr-Cys-Asn
• B-Chain (Chain 2): Phe-Val-Asn-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly-Glu-Arg-Gly-Phe-Phe-Tyr-Thr-Lys-Pro-Thr

Disulfide bonds connect the chains at A7-B7 and A20-B19, with an intrachain bond in the A-chain at A6-A11.[8]

Table 1: Insulin Peglispro - Key Identifiers and Molecular Properties

Parameter	Value	Source Snippet(s)
DrugBank ID	DB11567	1
CAS Number	1200440-65-8	2
Code Designation	LY2605541	4
Drug Type	Biotech, Hormone	2
Molecular Formula	C259​H385​N65​O79​S6​[C2​H4​O]n​	4
Molecular Weight (Total)	~26 kDa	4
Molecular Weight (Insulin Lispro)	~5.8 kDa	7
Molecular Weight (PEG moiety)	~20 kDa	4
A-Chain Sequence	GIVEQCCTSICSLYQLENYCN	8
B-Chain Sequence	FVNQHLCGSHLVEALYLVCGERGFFYTKPT	8
Site of PEGylation	Epsilon-amino group of Lysine at B28	4

The PEGylation of Insulin Lispro: Engineering a Novel Molecule

The defining feature of Insulin peglispro is its bioengineering, specifically the process of PEGylation. This process involves the covalent and site-specific attachment of a single, large, hydrophilic 20 kDa PEG polymer to the insulin lispro molecule.[10] The attachment occurs at the epsilon-amino group of the lysine residue at position B28 of the B-chain.[4] This is achieved chemically by reacting insulin lispro with an activated PEG reagent, such as monomethoxypoly(ethylene glycol) p-nitrophenyl carbonate (mPEG-NPC), under specific pH and temperature conditions to form a stable, hydrolytically resistant urethane (carbamate) bond.[4]

The direct and most profound consequence of this modification is a massive increase in the molecule's hydrodynamic size. Dynamic light scattering analysis revealed that Insulin peglispro has a hydrodynamic diameter of 7.9 ± 0.5 nm, which is approximately four times larger than that of its parent molecule, insulin lispro, and similar in size to a ~75 kDa globular protein.[10]

This single act of chemical engineering—the addition of the 20 kDa PEG chain—is the foundational event that dictates the entirety of Insulin peglispro's unique and ultimately paradoxical clinical profile. The increase in physical size is not merely a structural change; it is the direct cause of the molecule's altered pharmacokinetics, including its slow absorption and reduced clearance. This altered pharmacokinetic profile, in turn, gives rise to its novel pharmacodynamics—the hepato-preferential mechanism of action. This mechanism is the source of both its superior glycemic efficacy and its fatal safety liabilities related to lipid metabolism and hepatic function. Therefore, the entire story of Insulin peglispro's promise and its eventual failure can be traced back to this deliberate and innovative act of PEGylation.

Pharmacological Profile: A Paradigm Shift in Exogenous Insulin Action

Mechanism of Action: The Hepato-Preferential Hypothesis

Insulin peglispro functions as an agonist of the insulin receptor (INSR).[1] However, its mechanism of action represents a significant departure from all other exogenous insulins. It was designed to be "hepato-preferential," a concept rooted in mimicking the natural physiology of endogenous insulin.[15] When the pancreas secretes insulin into the portal vein, the liver extracts 40–80% during its first pass. This results in a physiological state where the concentration of insulin acting on the liver is two to four times higher than the concentration reaching peripheral tissues like muscle and fat.[17] In contrast, conventional subcutaneously injected insulins are absorbed into the systemic circulation and are distributed equally to the liver and periphery, disrupting this natural gradient.[17]

The hepato-preferential action of Insulin peglispro is a direct consequence of its large molecular size. The prevailing hypothesis is that the large, pegylated molecule has limited ability to cross the capillary endothelium to access peripheral tissues (muscle and adipose). However, it can more readily access hepatocytes in the liver through the large fenestrae (windows) in the hepatic sinusoidal endothelium.[5]

This hypothesis was confirmed in human euglycemic clamp studies, which provide the key pharmacological evidence for its mechanism. These studies demonstrated that while Insulin peglispro was as effective as insulin glargine in suppressing endogenous glucose production (EGP) from the liver, it had a substantially and significantly reduced effect on stimulating the glucose disposal rate (GDR) in peripheral tissues.[17] This confirmed that the "hepato-preferential" action was not due to an enhanced effect on the liver, but rather a reduced effect on the periphery, thereby restoring a more physiological ratio of hepatic-to-peripheral insulin action.[17]

Receptor Binding and Mitogenic Potential

The PEGylation of insulin lispro not only altered its size but also its interaction with its target receptors. In vitro studies revealed that Insulin peglispro exhibited a reduced binding affinity and, consequently, a lower functional potency at the human insulin receptor (hIR) when compared to its parent molecule, insulin lispro.[10] This reduced potency means that higher molar concentrations of Insulin peglispro are required to achieve the same level of receptor activation as unmodified insulin.

Crucially, however, the modification resulted in a greater selectivity for the hIR over the human insulin-like growth factor 1 receptor (hIGF-1R). Binding to the hIGF-1R was markedly reduced, to the point that definitive measurements were unattainable.[10] This increased selectivity is a critical feature. Off-target activation of the hIGF-1R by insulin analogs has been a long-standing safety concern due to its potential to promote cell proliferation and mitogenicity. Furthermore, studies showed that the dephosphorylation rate of the insulin receptor after being activated and internalized was notably faster with Insulin peglispro compared to insulin lispro.[10] This rapid deactivation, coupled with the very weak binding to the hIGF-1R, was theorized to significantly reduce the overall mitogenic risk of the molecule.[10]

This profile suggests a deliberate and strategic trade-off was made during the drug's design. The engineers and chemists developing Insulin peglispro likely accepted the downside of reduced potency at the target insulin receptor in exchange for the significant safety benefit of enhanced selectivity and a minimized mitogenic risk profile. This reframes the finding of "reduced potency" from a simple liability to a calculated design choice aimed at de-risking the molecule during early development, a critical step for any new insulin analog.

Pharmacokinetic Profile: The Consequences of Increased Hydrodynamic Size

Absorption, Distribution, Metabolism, and Excretion (ADME)

The large hydrodynamic size imparted by the 20 kDa PEG moiety fundamentally alters every aspect of Insulin peglispro's pharmacokinetics, transforming the rapid-acting profile of its parent molecule, insulin lispro, into that of a long-acting basal insulin.

• Absorption: Following subcutaneous injection, Insulin peglispro is absorbed very slowly from the injection site. This delayed absorption is a primary contributor to its flat, prolonged activity profile, which lacks the distinct peak characteristic of shorter-acting insulins.[5] A significant portion of this absorption is thought to occur via the lymphatic system, a slower pathway favored by large molecules that cannot easily enter blood capillaries directly.[18]
• Distribution: Once in the circulation, the molecule's large size restricts its movement out of the vasculature. Its volume of distribution is only slightly larger than the circulating blood volume, which is considerably lower than that of regular human insulin or insulin lispro.[17] This confinement to the bloodstream is a key element of its reduced action on peripheral tissues.
• Metabolism and Elimination: The PEGylation process dramatically reduces the molecule's clearance from the body.[10] This results in a very long elimination half-life of approximately 2–3 days.[17] A practical consequence of this slow clearance is that it takes approximately 7 to 10 days of daily dosing for the drug to reach steady-state concentrations in the blood.[17]

Impact of Patient Comorbidities: Renal Impairment

A dedicated Phase 1 clinical trial was conducted to evaluate the pharmacokinetics of Insulin peglispro in subjects with varying degrees of renal impairment, from normal function to end-stage renal disease (ESRD) requiring hemodialysis.[14] The results of this study revealed a significant and unexpected clinical feature.

Unlike endogenous insulin, for which renal clearance accounts for 40–50% of its total systemic clearance, the clearance of Insulin peglispro was not significantly affected by the degree of renal impairment.[14] The pharmacokinetic profiles (including exposure and clearance rates) were similar across all groups, regardless of kidney function. Even in patients with ESRD, a single session of hemodialysis was found to eliminate only a mean fraction of 13% of the drug, indicating that its clearance is largely independent of renal pathways.[14]

This finding represented a potentially significant clinical advantage. Patients with diabetes are at high risk of developing chronic kidney disease, and for many conventional insulins, declining renal function leads to reduced clearance, drug accumulation, and an unpredictable increase in the risk of hypoglycemia, often necessitating complex and careful dose adjustments.[14] The renal-independent clearance of Insulin peglispro suggested that it could have been used in this large and vulnerable patient population with greater predictability and potentially without the need for significant dose modifications. This offered a simplification of therapy and an improved safety margin that, while ultimately rendered moot by the program's discontinuation, was a notable benefit of the drug's unique molecular design.

Clinical Efficacy: Findings from the IMAGINE Program

The clinical development of Insulin peglispro was anchored by the extensive IMAGINE program, a series of seven core Phase III trials that enrolled over 6,000 patients with Type 1 and Type 2 diabetes, with approximately 3,900 receiving Insulin peglispro.[15] The program was designed to compare the efficacy and safety of Insulin peglispro against active comparators, primarily insulin glargine (Lantus®), the standard-of-care basal insulin at the time.

Superior Glycemic Control (HbA1c Reduction)

The most striking and consistent finding across the entire IMAGINE program was the superior glycemic control achieved with Insulin peglispro. In five of the pivotal trials, Insulin peglispro demonstrated a statistically significant and clinically meaningful superiority in reducing HbA1c​ levels compared to insulin glargine in diverse patient populations.[13] This level of consistent superiority on the primary endpoint is rare for a new basal insulin, which typically aims to demonstrate non-inferiority.

This superior efficacy was evident in both Type 1 and Type 2 diabetes. For instance, in the IMAGINE-1 trial in patients with Type 1 diabetes, the mean HbA1c​ at 26 weeks was 7.06% for the Insulin peglispro group versus 7.43% for the insulin glargine group, a significant difference of -0.37% (p < 0.001).[26] This superiority was maintained at 52 and 78 weeks.[24] Similarly, in the IMAGINE-2 trial involving insulin-naïve patients with Type 2 diabetes, the mean change from baseline in

HbA1c​ at one year was -1.56% for Insulin peglispro versus -1.27% for insulin glargine (p < 0.001).[13] As a direct result of this greater glucose-lowering effect, a significantly higher proportion of patients treated with Insulin peglispro achieved the American Diabetes Association (ADA) recommended target

HbA1c​ of less than 7%.[13]

Reduction in Glycemic Variability and Fasting Glucose

Beyond lowering average blood glucose, Insulin peglispro also demonstrated benefits in the quality of glycemic control. Multiple trials reported that treatment with Insulin peglispro resulted in significantly lower between-day variability of fasting blood glucose compared to insulin glargine.[13] Lower glycemic variability is a key therapeutic goal, as wide swings in blood sugar are associated with both an increased risk of hypoglycemia and long-term complications. In line with its potent effect on hepatic glucose production, patients treated with Insulin peglispro also consistently achieved lower fasting serum glucose levels.[18]

Ancillary Clinical Benefits: Weight Management

A common and undesirable side effect of insulin therapy is weight gain. Insulin peglispro demonstrated a clear and consistent advantage in this domain. In trials involving patients with Type 1 diabetes (IMAGINE-1 and IMAGINE-3), treatment with Insulin peglispro was associated with modest but statistically significant weight loss, in stark contrast to the weight gain observed in the insulin glargine arms.[15] In patients with Type 2 diabetes, who are often already overweight or obese, Insulin peglispro treatment resulted in significantly less weight gain compared to insulin glargine.[13]

Taken together, the clinical efficacy profile of Insulin peglispro was exceptionally strong. Achieving statistical superiority over the standard of care on the primary endpoint of HbA1c​ reduction, while also demonstrating clear benefits on multiple key secondary endpoints—including glycemic variability, nocturnal hypoglycemia (discussed below), and weight management—is the hallmark of a potential best-in-class therapeutic. This context is essential for appreciating the magnitude of the subsequent disappointment when the drug's paradoxical safety profile emerged; Insulin peglispro was not a simple "me-too" drug but was poised to become a transformative treatment option based on its efficacy alone.

Table 2: Summary of Efficacy Outcomes from Key IMAGINE Trials (Peglispro vs. Glargine)

IMAGINE Trial (Population)	Duration	Endpoint	Insulin Peglispro (BIL)	Insulin Glargine (GL)	Mean Difference [95% CI] / P-value	Source Snippet(s)
IMAGINE-1 (T1DM)	26 weeks	HbA1c​ (%)	7.06	7.43	-0.37% [-0.50 to -0.23], p < 0.001	24
IMAGINE-3 (T1DM)	52 weeks	HbA1c​ (%)	7.38	7.61	-0.22% [-0.32 to -0.12], p < 0.001	18
IMAGINE-2 (T2DM, Naïve)	52 weeks	HbA1c​ Change (%)	-1.56	-1.27	-0.29%, p < 0.001	13
IMAGINE-4 (T2DM, Basal-Bolus)	26 weeks	HbA1c​ (%)	6.8	7.0	-0.21% [-0.31 to -0.11], p < 0.001	25
IMAGINE-5 (T2DM, Basal Only)	26 weeks	HbA1c​ Change (%)	-0.82	-0.29	-0.52% [-0.67 to -0.38], p < 0.001	21
Across Trials	Various	Patients reaching HbA1c​ <7%	Significantly Higher	Lower	p < 0.001 in multiple trials	13
IMAGINE-3 (T1DM)	52 weeks	Weight Change (kg)	Loss	Gain	Difference: -1.8 kg [-2.3 to -1.3], p < 0.001	18
IMAGINE-2 (T2DM, Naïve)	52 weeks	Weight Gain (kg)	+2.1	+2.6	p < 0.001	13

The Safety and Tolerability Conundrum

Despite its impressive efficacy, the clinical development of Insulin peglispro was ultimately defined and derailed by a complex and concerning safety profile. The adverse events observed were not random but were mechanistically linked to the drug's unique hepato-preferential action, creating a difficult risk-benefit proposition.

The Hypoglycemia Profile: A Double-Edged Sword

The effect of Insulin peglispro on hypoglycemia was paradoxical. One of its most significant and consistent benefits was a marked reduction in the rate of nocturnal hypoglycemia. Across trials in both T1DM and T2DM, patients treated with Insulin peglispro experienced clinically relevant and statistically significant reductions in overnight low blood sugar events, with rate reductions reported between 36% and 60% compared to insulin glargine.[13] This is a major clinical advantage, as nocturnal hypoglycemia is a source of significant fear for patients and a primary barrier to achieving tight glycemic control.

However, this benefit was offset by an equally consistent finding of an increased rate of daytime hypoglycemia.[15] In patients on basal-bolus regimens (using both basal and mealtime insulin), this increase in daytime events led to a higher rate of total hypoglycemia overall. Rates of severe hypoglycemia (requiring assistance from another person) were generally similar between the Insulin peglispro and glargine groups across the program, although one open-label trial, IMAGINE-1, did report a higher rate for Insulin peglispro.[15]

Hepatic and Metabolic Adverse Events: The Program-Ending Signals

The most critical safety concerns, and the ultimate reason for the program's termination, were a cluster of adverse hepatic and metabolic events. These signals were observed consistently across the IMAGINE trials.

• Elevated Triglycerides: Treatment with Insulin peglispro was consistently associated with statistically significant increases in serum triglyceride levels from baseline. In contrast, patients treated with insulin glargine typically experienced a modest decrease or no change in triglycerides.[15]
• Elevated Liver Enzymes: Insulin peglispro treatment led to a mean increase in levels of the liver enzyme alanine aminotransferase (ALT). More concerningly, a significantly higher proportion of patients in the Insulin peglispro arms experienced ALT elevations of three times the upper limit of normal (ULN) or greater, a standard threshold for monitoring potential liver injury.[15]
• Increased Liver Fat Content (LFC): In dedicated substudies that used magnetic resonance imaging (MRI) to quantify liver fat, treatment with Insulin peglispro was associated with a statistically significant increase in LFC compared to treatment with insulin glargine.[5]

The emergence of these adverse events can be explained by a unifying theory rooted in the drug's core mechanism. The defining feature of Insulin peglispro is its reduced action in peripheral tissues. A primary role of insulin in peripheral adipose tissue is the potent suppression of lipolysis—the breakdown of stored triglycerides into free fatty acids (FFAs). By having a reduced peripheral effect, Insulin peglispro failed to fully suppress lipolysis. This failure is hypothesized to have caused an increased and sustained flux of FFAs from adipose tissue to the liver. The liver, in response to this influx of substrate, ramped up its own production and secretion of triglycerides, leading to the observed hypertriglyceridemia. A portion of this excess fat was deposited within the liver itself, causing steatosis (increased LFC), which in turn caused cellular stress and the release of liver enzymes like ALT.[5]

Simultaneously, the reduced peripheral action in muscle tissue meant less stimulation of glucose uptake. This likely contributed to the higher rates of daytime hypoglycemia, as the doses of prandial (mealtime) insulin—intended to cover glucose from food—became relatively oversized and more potent in a system where the basal insulin was not driving as much glucose into the periphery. The drug's strong and stable suppression of hepatic glucose production throughout the night, however, remained intact, explaining the profound reduction in nocturnal hypoglycemia. Thus, the single, innovative mechanism of "reduced peripheral action" was the common origin of the drug's entire complex and contradictory clinical profile, giving rise to both its greatest therapeutic strengths and its fatal flaws.

It is critical to note that despite these concerning signals, no cases of severe, acute drug-induced liver injury that met the criteria of Hy's Law (a regulatory standard indicating a high risk of fatal liver failure) were observed in the entire clinical program.[15] The concern was not about acute toxicity but about the unknown long-term consequences of inducing chronic hypertriglyceridemia and hepatic steatosis in a patient population already at high risk for metabolic and cardiovascular disease.

Other Notable Adverse Events

Other adverse events associated with Insulin peglispro included:

• Injection Site Reactions: A significantly higher frequency of injection site reactions, primarily lipohypertrophy (a thickening of subcutaneous fat tissue), was reported with Insulin peglispro compared to insulin glargine.[15]
• Lipid Profile: Beyond triglycerides, some trials also reported small but statistically significant increases in LDL cholesterol and decreases in HDL cholesterol.[17]
• Blood Pressure: Small but statistically significant increases in both systolic and diastolic blood pressure (mean difference <2 mmHg) were observed in some studies.[18]
• Cardiovascular Safety: Despite the negative changes in lipids and blood pressure, integrated analyses of major adverse cardiovascular events (MACE) across the program showed that the rates were similar between patients treated with Insulin peglispro and those on comparator insulins, providing some reassurance on short-term cardiovascular safety.[18]

Table 3: Comparative Safety and Adverse Event Profile from IMAGINE Trials (Peglispro vs. Glargine)

Adverse Event	Parameter	Insulin Peglispro (BIL)	Insulin Glargine (GL)	Relative Rate / Difference	Source Snippet(s)
Hypoglycemia	Nocturnal Rate	Significantly Lower	Higher	36-60% reduction	13
Hypoglycemia	Daytime Rate	Higher	Lower	Rate increased	15
Hypoglycemia	Total Rate (Basal-Bolus)	Higher	Lower	~11-29% increase	18
Hypoglycemia	Severe Rate	Generally Similar	Generally Similar	No significant difference in blinded trials	15
Hepatic	ALT Change from Baseline	Increased	Decreased or Stable	Mean difference ~6.5-7.4 IU/L	18
Hepatic	Patients with ALT ≥3x ULN	2.03 - 4.4%	0.62 - 1.5%	Significantly Higher	23
Metabolic	Triglyceride Change	Increased	Decreased or Stable	Significantly Higher (p < 0.001)	15
Metabolic	Liver Fat Content Change	Increased	Decreased or Stable	Mean difference 2.2-5.3%	21
Local Tolerability	Injection Site Reactions	Higher Incidence	Lower Incidence	Significantly more frequent	15

Comparative Assessment and Strategic Context

Head-to-Head Analysis: Insulin Peglispro vs. Insulin Glargine

The clinical data from the IMAGINE program presents a clear and stark trade-off when comparing Insulin peglispro to the first-generation basal insulin, insulin glargine. On one hand, Insulin peglispro offered a compelling suite of efficacy benefits that were consistently superior to the standard of care. These included greater HbA1c​ reduction, lower glycemic variability, a profound reduction in nocturnal hypoglycemia, and a favorable impact on body weight.

On the other hand, these benefits came at a significant cost. The safety and tolerability profile was considerably worse, marked by an increase in daytime hypoglycemia, frequent injection site reactions, and most critically, a constellation of adverse metabolic signals: elevated triglycerides, increased liver fat content, and elevated liver enzymes. For a physician and patient, the choice would have been to accept a known, albeit poorly understood, long-term metabolic and hepatic risk in exchange for superior glycemic control and less fear of overnight hypoglycemia.

Positioning Against Second-Generation Basal Insulins

The strategic context of Insulin peglispro's development cannot be understood without considering the concurrent evolution of the basal insulin market. During the same period that the IMAGINE trials were being conducted, a new generation of basal insulins was emerging, most notably Insulin Degludec (Tresiba®) and a more concentrated formulation of insulin glargine, U300 (Toujeo®).[5]

These second-generation insulins were also designed to have flatter, more prolonged activity profiles than first-generation glargine. Insulin degludec, in particular, demonstrated an ultra-long duration of action (up to 40 hours) and, critically, also showed a significant benefit in reducing the risk of hypoglycemia, especially nocturnal hypoglycemia, when compared to insulin glargine.[11]

This placed Insulin peglispro in a competitive vise. One of its key differentiating advantages over insulin glargine—the reduction in nocturnal hypoglycemia—was being matched by a new competitor, insulin degludec. However, insulin degludec achieved this benefit without the baggage of adverse hepatic and metabolic signals. The risk-benefit calculation for Insulin peglispro therefore became increasingly unfavorable. A physician or payer would be faced with a difficult question: why accept the risks of elevated liver fat and triglycerides associated with Insulin peglispro to gain a benefit (reduced nocturnal hypoglycemia) that could be achieved with another new, safer alternative? This intense competitive pressure severely eroded the potential market niche and unique value proposition for Insulin peglispro, becoming a major, albeit unstated, factor in the strategic decision to terminate its development.

Table 4: Pharmacokinetic and Pharmacodynamic Comparison of Basal Insulins

Parameter	Insulin Glargine U100 (1st Gen)	Insulin Degludec (2nd Gen)	Insulin Peglispro (Investigational)
Onset of Action	~1-2 hours	30-90 minutes	Not Determined
Peak	Relatively flat, slight peak	Flat, no peak	Flat, no peak
Duration of Action	Up to 24 hours	>24 hours (up to 40 hours)	>24 hours
Half-life	~12 hours	~25 hours	~2-3 days
Key PK/PD Feature	pH-dependent precipitation	Subcutaneous multi-hexamer depot	Large hydrodynamic size, reduced peripheral action
Key Clinical Advantage	Established standard of care	Reduced hypoglycemia vs. glargine, flexible dosing	Superior HbA1c​ reduction, reduced nocturnal hypoglycemia, weight benefit vs. glargine
Key Clinical Disadvantage	Higher hypoglycemia risk vs. newer agents		Elevated liver fat, triglycerides, ALT; increased daytime hypoglycemia

Program Discontinuation and Lessons Learned

The Regulatory Trajectory and Eli Lilly's Decision

The development trajectory of Insulin peglispro shifted abruptly from promising to problematic in early 2015. Following the completion of the successful Phase III program, Eli Lilly had initially planned to submit the drug for regulatory review to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) by the end of the first quarter of 2015.[28]

However, in February 2015, the company announced a significant delay in these submissions. The stated reason was the need to generate additional clinical data to "further understand and characterize the potential effects, if any, of changes in liver fat observed with BIL treatment in the Phase III trials".[36] This public acknowledgment signaled that the hepatic safety signals were a major point of concern for regulators.

After several months of engagement with regulatory authorities and external experts to assess potential paths forward, Eli Lilly made the definitive announcement on December 4, 2015: the company was ceasing the development program for Insulin peglispro entirely.[5] In its official statement, the company emphasized that the decision was informed by these regulatory conversations and was not prompted by any new safety signals. The rationale was framed as a strategic business decision, citing the "significant amount of time and investment" that would be required to further investigate the liver data, with "no assurance that we would find conclusive answers".[33] The company opted instead to focus its R&D efforts on other assets in its portfolio. The discontinuation resulted in a fourth-quarter charge to R&D expenses of an estimated $55 million (pre-tax).[33]

Post-Mortem Analysis: The Rationale for Failure

The termination of the Insulin peglispro program was not the result of a single, catastrophic event, such as a patient death or a definitive finding of hepatotoxicity. Rather, it was a "death by a thousand cuts," a confluence of scientific, regulatory, and commercial factors that made continuing the program untenable.

• Factor 1: The Unresolved Safety Signal: The primary driver was the inability to adequately explain or mitigate the long-term risks associated with the observed increases in liver fat and triglycerides. While no acute liver injury was seen, the prospect of marketing a drug that induced hepatic steatosis in a diabetes population already at high risk for nonalcoholic fatty liver disease (NAFLD) and cardiovascular events was a major hurdle. Regulators were clearly unwilling to approve the drug without a much deeper understanding of these long-term consequences.[5]
• Factor 2: The Prohibitive Cost of Further Investigation: The clinical trials required to prove that these hepatic effects were benign over the long term (e.g., 5-10 years) would have been extraordinarily large, lengthy, and expensive. As Lilly's statement implied, the cost of this undertaking, coupled with the high probability of an inconclusive or unfavorable result, created an unacceptable return-on-investment profile.[33]
• Factor 3: The Shifting Competitive Landscape: As previously discussed, the arrival of second-generation basal insulins like insulin degludec, which offered a key benefit of Insulin peglispro (reduced nocturnal hypoglycemia) without the associated hepatic risks, critically weakened its commercial case. The drug was caught between a first-generation standard it could beat on efficacy but not safety, and a second-generation competitor that offered a safer path to similar benefits.[5]

Ultimately, the decision to discontinue was a pragmatic and strategic one, reflecting a sober assessment of the diminishing probability of regulatory approval and commercial success weighed against the high and certain costs of continued development.

Expert Synthesis and Future Outlook

The story of Insulin peglispro should not be viewed as a simple failure, but rather as a highly informative and pivotal scientific endeavor in the field of diabetology. The program successfully and unequivocally validated the principle that the physical properties of an insulin molecule can be engineered to achieve tissue-specific action. The creation of a truly hepato-preferential insulin was a remarkable scientific achievement.

However, the program's downfall provides an equally important lesson: the profound and perhaps underappreciated importance of peripheral insulin action. While the concept of mimicking the high hepatic-to-peripheral ratio of endogenous insulin was physiologically sound in theory, Insulin peglispro demonstrated in practice that peripheral insulin signaling, particularly the suppression of lipolysis in adipose tissue, is not a secondary function that can be safely diminished. Disrupting this critical peripheral action, even in the pursuit of a more "physiological" hepatic effect, unleashed a cascade of unintended and ultimately unacceptable metabolic consequences.

The legacy of Insulin peglispro is the massive dataset it generated, which continues to inform our understanding of integrated insulin physiology. It serves as a cautionary tale for future drug development, highlighting that targeting one aspect of a complex metabolic pathway can have far-reaching and unpredictable effects on others. Future innovations in insulin therapy may need to be more nuanced, perhaps aiming to subtly modulate the hepato-peripheral balance rather than drastically shifting it. The data from the IMAGINE trials remains an invaluable resource for scientists and clinicians, a detailed map of a promising therapeutic road that led to an unforeseen and impassable clinical obstacle.

Works cited

1. Protein Annotation DataBase - Search - ASpdb, accessed September 13, 2025, https://biodataai.uth.edu/ASpdb/gene_search_result.cgi?page=page&type=quick_search&quick_search=3643
2. Insulin peglispro | MedPath, accessed September 13, 2025, https://trial.medpath.com/drug/52d48a09a5c3c1f5?page=2
3. Insulin peglispro | ChemScene, accessed September 13, 2025, https://www.chemscene.com/product-life-science/1200440-65-8.html
4. INSULIN PEGLISPRO, accessed September 13, 2025, https://searchusan.ama-assn.org/usan/documentDownload?uri=/unstructured/binary/usan/insulin-peglispro.pdf
5. Lessons From Peglispro: IMAGINE How to Improve Drug Development and Affordability, accessed September 13, 2025, https://diabetesjournals.org/care/article/39/4/499/29236/Lessons-From-Peglispro-IMAGINE-How-to-Improve-Drug
6. Insulin lispro: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 13, 2025, https://go.drugbank.com/drugs/DB00046
7. humalog - accessdata.fda.gov, accessed September 13, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020563s082lbl.pdf
8. Insulin peglispro (BIL) - MedchemExpress.com, accessed September 13, 2025, https://www.medchemexpress.com/insulin-peglispro.html?locale=ko-KR
9. Basal insulin peglispro(Eli Lilly) - Drug Targets, Indications, Patents - Patsnap Synapse, accessed September 13, 2025, https://synapse.patsnap.com/drug/9cd8948568d845e3a1f53f38d85a50ab
10. In Vivo and In Vitro Characterization of Basal Insulin Peglispro: A Novel Insulin Analog | Request PDF - ResearchGate, accessed September 13, 2025, https://www.researchgate.net/publication/299494197_In_Vivo_and_In_Vitro_Characterization_of_Basal_Insulin_Peglispro_A_Novel_Insulin_Analog
11. Insulin degludec n Insulin peglispro | PPTX - SlideShare, accessed September 13, 2025, https://www.slideshare.net/slideshow/insulin-degludec-n-insulin-peglispro/52170221
12. US20090312236A1 - Pegylated insulin lispro compounds - Google ..., accessed September 13, 2025, https://patents.google.com/patent/US20090312236A1/en
13. EASD: PEGlispro – the new standard for basal insulin? - MDEdge, accessed September 13, 2025, https://www.mdedge.com/endocrinology/article/103710/diabetes/easd-peglispro-new-standard-basal-insulin
14. Pharmacokinetics of the Long‐Acting Basal Insulin LY2605541 in ..., accessed September 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5071690/
15. Basal insulin peglispro: Overview of a novel long-acting insulin with ..., accessed September 13, 2025, https://pubmed.ncbi.nlm.nih.gov/27723228/
16. investor.lilly.com, accessed September 13, 2025, https://investor.lilly.com/news-releases/news-release-details/lillys-basal-insulin-peglispro-shows-superiority-insulin#:~:text=About%20Basal%20Insulin%20Peglispro&text=BIL%20is%20a%20hepato%2Dpreferential,with%20a%20conventional%20activity%20profile.
17. Basal Insulin Peglispro Demonstrates Preferential Hepatic Versus ..., accessed September 13, 2025, https://diabetesjournals.org/care/article/37/9/2609/28932/Basal-Insulin-Peglispro-Demonstrates-Preferential
18. Randomized, double‐blind clinical trial comparing basal insulin ..., accessed September 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5096008/
19. Insulin peglispro (BIL) - MedchemExpress.com, accessed September 13, 2025, https://www.medchemexpress.com/insulin-peglispro.html
20. New Long-Acting Basal Insulins: Does Benefit Outweigh Cost? | Diabetes Care, accessed September 13, 2025, https://diabetesjournals.org/care/article/39/Supplement_2/S172/30337/New-Long-Acting-Basal-Insulins-Does-Benefit
21. Randomized Clinical Trial Comparing Basal Insulin Peglispro and Insulin Glargine in Patients With Type 2 Diabetes Previously Treated With Basal Insulin: IMAGINE 5, accessed September 13, 2025, https://diabetesjournals.org/care/article/39/1/92/31362/Randomized-Clinical-Trial-Comparing-Basal-Insulin
22. Insulin lispro (intravenous route, subcutaneous route) - Side effects & dosage - Mayo Clinic, accessed September 13, 2025, https://www.mayoclinic.org/drugs-supplements/insulin-lispro-intravenous-route-subcutaneous-route/description/drg-20064334
23. Basal Insulin Peglispro Studies Demonstrate Superiority to Insulin Glargine Across Multiple Measures in People with Type 1 Diabetes - Eli Lilly Investors, accessed September 13, 2025, https://investor.lilly.com/static-files/6261d963-31dc-4b2b-bf35-bc54cb012a1a
24. Lilly's Basal Insulin Peglispro Demonstrated HbA1c Superiority against Lantus® in Phase III Trials in Patients with Type 1 Diabetes, accessed September 13, 2025, https://investor.lilly.com/news-releases/news-release-details/lillys-basal-insulin-peglispro-demonstrated-hba1c-superiority
25. Lilly's Basal Insulin Peglispro Shows Superiority to Insulin Glargine in Reducing HbA1c in People with Type 2 Diabetes | Eli Lilly and Company, accessed September 13, 2025, https://investor.lilly.com/news-releases/news-release-details/lillys-basal-insulin-peglispro-shows-superiority-insulin
26. A randomized clinical trial comparing basal insulin peglispro and ..., accessed September 13, 2025, https://pubmed.ncbi.nlm.nih.gov/27393697/
27. Randomized, Double-Blind Clinical Trial Comparing Basal Insulin Peglispro and Insulin Glargine, in Combination With Prandial Insulin Lispro, in Patients with Type 2 Diabetes: IMAGINE 4 - ResearchGate, accessed September 13, 2025, https://www.researchgate.net/publication/303634626_Randomized_Double-Blind_Clinical_Trial_Comparing_Basal_Insulin_Peglispro_and_Insulin_Glargine_in_Combination_With_Prandial_Insulin_Lispro_in_Patients_with_Type_2_Diabetes_IMAGINE_4_Basal_insulin_pegli
28. Lilly's Peglispro Superior To Lantus In Phase 3 Trials - Clinical Leader, accessed September 13, 2025, https://www.clinicalleader.com/doc/lilly-s-peglispro-superior-to-lantus-in-phase-trials-0001
29. Lilly's Basal Insulin Peglispro Shows Superiority to Insulin Glargine in Reducing HbA1c in People with Type 2 Diabetes - PR Newswire, accessed September 13, 2025, https://www.prnewswire.com/news-releases/lillys-basal-insulin-peglispro-shows-superiority-to-insulin-glargine-in-reducing-hba1c-in-people-with-type-2-diabetes-300095203.html
30. Basal Insulin Peglispro Studies Demonstrate Superiority to Insulin Glargine Across Multiple Measures in People with Type 1 Diabetes | Eli Lilly and Company, accessed September 13, 2025, https://investor.lilly.com/news-releases/news-release-details/basal-insulin-peglispro-studies-demonstrate-superiority-insulin
31. Lipid Changes During Basal Insulin Peglispro, Insulin Glargine, or ..., accessed September 13, 2025, https://pubmed.ncbi.nlm.nih.gov/27486125/
32. Lilly's Basal Insulin Peglispro Demonstrated HbA1c Superiority against Lantus® in Phase III Trials in Patients with Type 1 Diabetes, accessed September 13, 2025, https://investor.lilly.com/static-files/9da321bb-dbbd-4de4-947b-1bf082b9e93a
33. Lilly Ends Basal Insulin Peglispro Development Program | Eli Lilly ..., accessed September 13, 2025, https://investor.lilly.com/news-releases/news-release-details/lilly-ends-basal-insulin-peglispro-development-program
34. Lilly Discontinues Development of Liver-Selective Basal Insulin Peglispro - diaTribe.org, accessed September 13, 2025, https://diatribe.org/diabetes-medications/lilly-discontinues-development-liver-selective-basal-insulin-peglispro
35. Efficacy and safety of insulin glargine 300 units/mL vs insulin degludec in patients with type 1 and type 2 diabetes: a systematic review and meta-analysis - Frontiers, accessed September 13, 2025, https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1285147/full
36. Development of new basal insulin peglispro (LY2605541) ends in a disappointing result, accessed September 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6224905/
37. Eli Lilly delays US, EU filings for basal insulin peglispro until after 2016 - FirstWord Pharma, accessed September 13, 2025, https://firstwordpharma.com/story/2422265
38. Lilly Announces Update on Regulatory Submission Timing for Basal Insulin Peglispro, accessed September 13, 2025, https://investor.lilly.com/news-releases/news-release-details/lilly-announces-update-regulatory-submission-timing-basal
39. Eli Lilly to end development of basal insulin peglispro - FirstWord Pharma, accessed September 13, 2025, https://firstwordpharma.com/story/3317876
40. Eli Lilly to End Peglispro Diabetes Research - CHEManager Online, accessed September 13, 2025, https://chemanager-online.com/en/news/eli-lilly-to-end-peglispro-diabetes-research