For more than a century, oral insulin has been considered one of the most compelling goals in diabetes drug development. The idea is clear: replacing injections with a more convenient oral option could significantly improve treatment experience for people with diabetes. Yet despite decades of research, oral insulin remains a major scientific and clinical challenge.
This article explores where oral insulin development stands today, why progress has been so difficult, and why the glucose clamp technique remains the gold standard for evaluating insulin action in clinical development.
The first attempts to develop an oral insulin were made more than 100 years ago with a paper that concluded that "oral [insulin] administration in alcohol would be so uncertain and so expensive as to be of little or no therapeutic value in diabetes mellitus in man". While many scientists worked on oral insulins ever since, no full success has been reported as of today.
The form of oral insulin itself leads to hurdles that are currently easier overcome by subcutaneous insulins:
Absorption variability: The absorption of oral insulin has been proved feasible with absorption enhancers. However, both high intraindividual and interindividual variability complicate accurate dosing [1].
Gastrointestinal degradation: Due to the stomach’s acidity, proteins are degraded and absorbed as amino acids. While absorption enhancers improved overall absorption of oral insulin, bio availability usually stays below 2%. Such low values would require high dosing, making the real-world application unfeasible.
Hepatic first-pass effects: The first pass effect of insulin is estimated around 50%. While the first pass effect influences both pancreatic and oral insulin, adding an additional barrier in reaching adequate systemic insulin concentration after oral administration of insulin, it also offers the chance of achieving more natural and physiological insulin levels by going a similar pathway. Compared to subcutaneous insulin which results in higher peripheral insulin levels, oral insulin might have positive effects like less weight gain and lower peripheral (hyper)insulinemia.
Delayed or inconsistent onset of action: In human physiology, insulin secretion is matched with food intake. The absorption of oral insulin being affected when taken together with a meal is known as the food effect. The effect of insulin might vary between 10 to 30 minutes, making it impractical for many patients and may result in pre-prandial hypoglycemia.
Why the euglycemic clamp remains the gold standard
The euglycemic clamp is the FDA and EMA accepted reference method to establish the time-action profile of new insulins (as for example documented in EMA guideline CPMP/EWP/1080/00 Rev. 2) [2].
The fully automated euglycemic glucose clamp that Profil offers, allows for controlled and precise quantitative assessment of the pharmacodynamic (PD) properties of novel glucose lowering compounds like insulins across different target populations. Important parameters for this assessment are the time until a candidate begins to act, how strong the glucose lowering effect is and how long the effect is maintained. Alternative ways of studying mealtime insulins of postprandial glucose lowering and related PD values are less precise due to variable absorption of the meals, both as to energy content and composition (for example due to rapidly and slowly absorbed carbohydrates, fat, protein, starch, etc.).
Glucose clamp endpoints
A central pharmacodynamic measure in a glucose clamp study is the glucose infusion rate, or GIR. It describes the amount of glucose that must be infused to maintain a stable blood glucose level after administration of the investigational compound, providing a precise measure of its glucose-lowering effect.
Beyond the overall glucose infusion rate, several additional pharmacodynamic parameters can be derived from the GIR profile to describe the compound’s metabolic effect in more detail.
The maximum glucose infusion rate (GIRmax) indicates the point of peak metabolic activity, or peak action. The time to maximum glucose infusion rate (tGIRmax) shows how quickly this peak activity is reached. Early and late t50% values describe the time points at which 50% of GIRmax is reached during the ascending and descending parts of the GIR profile, helping to characterize both the onset and decline of action.
Another important parameter is the area under the GIR curve (AUCGIR,0–xxh) over a defined time interval. This reflects the overall metabolic effect of the compound over time and provides valuable information on the total glucose-lowering activity during the clamp.
Depending on the pharmacological profile of the investigational compound, further parameters may also be assessed. For ultra-short-acting insulins, for example, the onset of action is particularly relevant, while for ultra-long-acting formulations, the duration of action becomes a key parameter. Other predefined time points or intervals may be evaluated depending on the intended clinical profile of the compound.
In parallel, pharmacokinetic parameters are derived from measured compound concentrations using validated, compound-specific analytical assays. Common PK parameters include baseline and maximum concentrations, such as Cbasal and Cmax, as well as the time to maximum concentration (tmax). Together, PK and PD assessments provide a comprehensive picture of the compound’s exposure-response relationship.
The interpretive scope of early-phase clamp data
Glucose clamp studies play a central role in insulin development because they provide a precise and standardized way to characterize how an insulin product acts over time. The euglycemic clamp methodology is recognized by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as the reference standard for establishing the time-action profile of new insulin products. As a result, clamp data are an important component of regulatory submissions and can also support the pharmacodynamic information included in product labeling.
A clear example is the pharmacodynamic characterization of Fiasp®, described by Tim Heise and colleagues in Clinical Pharmacokinetics in 2017 [3]. The respective study was conducted at Profil, and glucose clamp data are also shown in the Fiasp® prescribing information, Section 12.2 “Pharmacodynamics”, where they are used to describe the product’s onset and duration of action.
However, the value of early-phase clamp studies goes beyond generating a single pharmacodynamic profile. Clamp-based studies can define the pharmacokinetic and pharmacodynamic characteristics of new insulin formulations with high precision. They can also provide an early understanding of safety and tolerability. Positive early-phase results can then support the rationale for subsequent Phase 2 and Phase 3 programs, where clinical dosing regimens, long-term glycemic effects such as HbA1c reduction, hypoglycemia rates and the broader safety profile are evaluated in larger patient populations.
At the same time, clamp data must be interpreted carefully and within the right translational context. Early pharmacodynamic findings can be highly informative, but they do not replace the need for robust clinical outcome data in later-stage development. The importance of disciplined interpretation in translational insulin research is illustrated by Tim Heise’s article “Oral insulin: A history of ambition, failure and data torturing” (Diabetes, Obesity and Metabolism, 2023;25:940–942) [4], as well as by the later discontinuation of ORMD-0801, an oral insulin candidate that failed to meet its primary endpoint in a large Phase 3 study.
Many pivotal clamp studies supporting regulatory submissions to the FDA and EMA have been conducted at Profil, which is internationally recognized for its expertise in automated glucose clamp methodology. With the recent addition of an early-phase clinical trial site in Houston, Texas, Profil is further expanding its ability to provide specialized glucose clamp studies for sponsors seeking to conduct insulin and metabolic clinical research in the United States.
If you are planning an insulin development program, our experts would be happy to discuss how Profil’s specialized glucose clamp methodology can support your next clinical study in Europe or the United States. Reach out now.