The concept of glucocrinology or the relationship of glycemia with the endocrine system was emphasized during the meetings. Clinical experts arrived at a consensus for the usage of modern SUs in the presence of other endocrine dysfunction and the impact of these drugs on endocrine health. The beneficial pleiotropic and cardiovascular effects of modern SUs were also discussed.
The key discussion points were considered to develop clinical expert opinions for the use of modern SUs in persons with DM. Clinical expert opinions were developed for indications, pleiotropic benefits, cardiovascular outcomes, adherence, and safe use of modern SUs. Appropriate clinical judgement coupled with a patient-centered approach is crucial to achieve the best outcome in persons with DM. Various factors that are considered in the management of diabetes mellitus with oral medications include efficacy, safety, tolerability, and cost.
In addition to these factors, when prescribing oral medications, clinicians should also consider other endocrine and metabolic factors that could impact the clinical outcome. The latest guidelines published by the World Health Organization WHO recommend the use of metformin and SUs as preferred agents for the control of blood glucose levels in patients with DM.
But, despite their well-established efficacy profile, the clinical utility of SUs and their place in therapy have become debatable. This may be because SUs are clubbed under one group, although in reality all SUs are different. Sulfonylureas are classified on the basis of their hierarchy of development as conventional and modern and on the basis of duration of action as short-acting, intermediate-acting, and long-acting [ 1 , 2 ].
Modern SUs offer several benefits when compared to conventional SUs. Their efficacy profile is better compared to that of conventional SUs. Modern SUs also possess certain additional benefits in terms of endocrine effects, metabolic effects, and anti-inflammatory or immunomodulatory effects, which are less discussed. In the management of DM, a holistic approach encompassing vasculo-metabolic aspects and endocrine facets of diabetes is very important.
The concept of glucocrinology focuses on the association of various endocrine glands and diabetes, the role of endocrinopathic drugs in unmasking latent diabetes, and the role of antidiabetic drugs in modulating endocrine disease. The concept of glucocrinology emphasizes the consideration of endocrine aspects in the management of diabetes.
It promotes a comprehensive assessment of and aids in the quest for novel targets in the management of DM. In this context, an initiative by a multinational team of experts aimed to encourage safe and smart prescription of modern SUs while keeping the glucocrinologic aspects of these drugs in mind [ 1 ].
This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. During a 2-day international meeting, experts reviewed available literature evidence, provided their individual insights based on their experience in the management of DM with primary focus on pleiotropic effects and cardiovascular CV benefits of modern SUs, and charted out key opinions.
Important topics were discussed by panel members to arrive at expert opinion on standardization of various OADs that could be considered safe and unsafe in the management of patients with DM and CV risk or comorbidity. Drugs that could be considered safe in the use of DM patients with associated endocrinopathies were charted out.
Several endocrine glands, including adipose tissue, the gastrointestinal endocrine system, pituitary, thyroid, parathyroid, adrenals, and gonads, play an important role in the development of DM. Glucocrinology has been defined as the study of medicine that describes the correlation between glycemia and the endocrine system [ 3 ]. The important aspects of glucocrinology are listed below:. The concept of glucocrinology emphasizes the importance of endocrinology and role of endocrinologists in the management of diabetes mellitus.
It also aids in delivering a comprehensive approach to treatment of persons with diabetes mellitus. Sulfonylureas are classified into various categories on the basis of their hierarchy of development and duration of action. In terms of development, SUs are classified into conventional e. In terms of the duration of action, they are classified into short-acting tolbutamide , intermediate-acting glipizide and gliclazide , and long-acting SUs glibenclamide, glimepiride, gliclazide MR, and glipizide MR [ 1 ].
This, in turn, stimulates the exocytosis of insulin-secretory vesicle [ 1 ]. The distinct feature of modern SUs leads to a lower inhibition of K ATP channel and, hence, there is a reduced risk of hypoglycemia in comparison to conventional SUs [ 1 ]. Modern SUs may be considered as a treatment option in persons who do not respond to metformin. They are superior to conventional SUs in reducing mortality, bringing better outcomes, and preserving renal function [ 1 ].
Hypoglycemia is one of the most common adverse reactions associated with sulfonylureas. However, modern sulfonylureas such as glimepiride differ from conventional sulfonylureas and are associated with fewer hypoglycemic episodes. This could be attributed to equivalent metabolic control and lower stimulation of insulin levels with glimepiride as compared to glibenclamide [ 4 ]. In an international prospective study, diabetic patients treated with glimepiride had fewer hypoglycemic episodes compared to those treated with glibenclamide vs.
Glipizide and modern SUs are preferred in renal failure patients and T2DM patients who are at increased risk of developing hypoglycemia. Modern SUs confer a lower risk of hypoglycemia and have favorable cost, efficacy, and safety profiles. Sulfonylureas constitute a reasonable choice among glucose-lowering medications, especially when cost is the key consideration. Patient education and use of variable dosing of modern sulfonylureas should be considered to mitigate the risk of hypoglycemia.
Glipizide, glimepiride, and gliclazide have lower risk of hypoglycemia compared to conventional sulfonylureas. Sulfonylureas should be used with great caution in patients who are at increased risk of hypoglycemia, such as those with chronic kidney disease and older patients.
Modern SUs exhibit additional benefits over conventional SUs, which guide the choice of treatment in the management of DM. A few of these benefits have been listed below:. Modern SUs cause stimulation of pancreatic insulin release [ 5 , 6 ]. Modern SUs reduce insulin clearance in the liver [ 6 ]. Modern SUs increase the levels of adiponectin [ 7 , 9 ]. Modern SUs improve insulin sensitivity and decrease insulin resistance in peripheral tissues, thereby offering a glucose-lowering effect [ 7 , 9 ].
Modern SUs exert anti-angiogenic effects by reducing plasma vascular endothelial growth factor and fibroblast growth factor-2 levels [ 7 — 9 ]. Modern SUs also lead to a significant elevation in testosterone levels, resulting in an improvement in sex drive and erectile function in men with T2DM [ 7 — 9 ]. Human chorionic gonadotropin-induced testosterone secretion by Leydig cells is inversely related to insulin sensitivity among men with varying degrees of glucose tolerance.
Thus, the lesions resulting in hypogonadism in obesity and T2DM may occur at several levels of the hypothalamic—pituitary—gonadal axis. However, the absence of an increase in gonadotropin concentrations indicates that the primary defect in T2DM and obesity is at the hypothalamo-hypophyseal level. A study evaluated the impact of sulfonylurea as an initial treatment for hypogonadism in T2DM patients.
Results indicated that as compared with the healthy control group, the middle-aged men with type 2 diabetes had significantly decreased total testosterone levels and a lower testosterone secretion index. Glimepiride, a modern SU, is cardiovascular neutral as compared to other SUs.
Another modern SU, gliclazide, has also been associated with reduced risk of hypoglycemic episodes and long-term cardiovascular safety when compared with other OADs in the treatment of DM [ 12 ]. Cardiovascular phenotype is the term used by diabetes experts to describe congenital cardiac anomalies as well as vascular and cardiac dysfunction associated with DM. It is a checklist of various clinical parameters to be assessed before therapeutic intervention for the management of DM.
The clinical parameters include pulse rate, blood pressure, weight, lipid status, systolic function, diastolic function, orthostatic hypotension, coronary health, cerebrovascular health, and peripheral arterial health [ 16 ]. The concept of cardiovascular phenotype is a useful clinical decision-making tool to help determine appropriate OAD therapy in diabetic patients with high cardiovascular risk, and allows easier assessment of the impact of such therapy on cardiovascular health [ 16 ].
Modern SUs, such as glimepiride, are found to maintain myocardial ischemic preconditioning with fewer CV side effects as compared to conventional SUs. In addition, modern SUs were not associated with all-cause or CV mortality. They are also not associated with an increased risk of myocardial infarction or stroke.
In light of this, modern SUs can be considered cardiac-friendly [ 1 , 14 ]. Since modern SUs such as gliclazide MR and glimepiride are associated with a lower risk of all-cause and CV-related mortality compared to conventional SUs in T2DM patients, the clinical expert group opinion suggests that the modern SUs can be safely used in T2DM patients with CV risk, myocardial infarction, or stroke.
A nationwide registry comprising DM patients with acute myocardial infarction revealed that the mortality was lower in patients previously treated with modern SUs when compared to those treated with other oral medications or insulin [ 1 , 17 ]. A study conducted by Romero et al. However, it was not associated with an improved prognosis of HF patients [ 19 ]. A study conducted by Scirica et al. However, subsequent mortality or morbidity was not increased in patients with serious HF treated with pioglitazone [ 23 ].
Benefits were found to be greater in those patients with a history of HF at baseline [ 24 ]. A study conducted by Kosiborod et al. Hospitalizations due to HF were found to be rare with dapagliflozin 0. Point estimates for hazard ratios of composite cardiovascular outcomes also favored dapagliflozin vs.
A retrospective cohort study conducted by Pantalone et al. From these trial reports, it is evident that rates of non-fatal stroke in patients treated with OADs, including alogliptin, sitagliptin, and liraglutide, were non-significantly lower than in those treated with placebo [ 21 , 22 , 26 ].
A meta-analysis conducted by Lee et al. The median duration of follow-up was 5 years. The primary outcome is time to the first occurrence of any of the following adjudicated components of the primary composite endpoint: CV death including fatal stroke and fatal MI , non-fatal MI excluding silent MI , or non-fatal stroke.
Linagliptin was non-inferior to glimepiride for time to first major adverse CV event in adults with type 2 diabetes at high CV risk. To date, detailed results are awaited [ 30 ]. Despite the growing understanding of diabetes and the availability of new medications and technologies for the management of DM, a substantial number of individuals are not able to achieve their glycemic goals [ 28 , 29 , 43 , 44 ].
This proportion has not improved through , despite the development of many new medications [ 28 , 29 , 43 , 44 ]. The key contributing factor for the inadequate glycemic control in a real-world setting is poor medication adherence. Adherence to and persistence with antidiabetic medications are crucial in patients with DM to achieve optimal clinical benefits.
Increased adherence to medications is associated with a decrease in HbA 1c , decreased mortality rates, fewer all-cause hospitalizations, and lower healthcare expenditure. Adherence to medications is important to achieve an effective therapeutic outcome. A retrospective cohort study conducted by Ho et al. It was found that the non-adherent patients had higher all-cause hospitalization and all-cause mortality when compared to adherent patients [ 32 , 47 ].
Compliance to and non-persistence with prescribed medication regimens also resulted in increased morbidity and mortality as well as increased healthcare costs [ 33 , 48 ]. Communication contributes to a better understanding among patients about the illness and the risks and benefits of treatment. Support, empathy, understanding, collaborative partnerships, and patient-centered interviewing are essential for improving effective communication and enhancing adherence [ 34 ].
In a meta-analysis conducted by Haskard Zolnierek et al. Non-adherence was found to be more than 1. The odds ratio of a patient adhering is 2. A study conducted by Kurlander et al. Modern SUs offer superior glycemic efficacy and are also available at a reasonable cost. Treatment with modern SUs is associated with a lower economic burden, and hence they are an effective alternative to other newer antidiabetic drugs.
Sulfonylureas have an oral route of administration vs. The once-daily dosing ensures better patient adherence to the medication, unlike its comparator drugs [ 1 ]. Sulfonylureas are an asset in diabetes care. Owing to their safety, efficacy, extra-pancreatic benefits, and low cost of therapy, modern SUs could be considered as drugs of choice for the treatment of diabetes.
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Based upon the time needed to achieve the endpoint, subsequent studies may be designed to better understand the dynamics of response and the relationship to concentration. An important goal of such studies is to be able to differentiate compounds based upon the results. A mechanistic hypothesis as to why some compounds showed a response vs. One may consider a dose fractionation approach or altered dosing regimen help to define the pharmacokinetics needed to achieve the endpoint.
Modeling behavioral pharmacology of psychotropic drugs is often complicated by the fact that non-continuous pharmacodynamic endpoints are reported on a categorical scale Geldof et al. Proportional odds models have been successfully applied to data from analgesic trials in which severity of pain, albeit a continuous measurement, is recorded on a categorical scale and used at the pharmacodynamic measure Nestorov et al.
On a quest to discover and develop a new class of anti-malaria drugs, Novartis scientists studied efficacy in a malaria infected mouse model Meister et al. The team used measurements of parasitemia reduction and days of survival as pharmacological endpoints. By rank ordering compounds according to percent parasite reduction and survival length at multiple dose and exposure levels, the team was able to identify an anti-malaria drug candidate for clinical development. Parasitemia reduction and survival in a Plasmodium Berghei mouse model of Malaria infection Meister et al.
In preclinical models of Hepatitis C viral replication, the endpoint in the study is a 1-log reduction in viral replication. This integrative process provides a better understanding of the mechanism of drug action, suggests improved animal models to evaluate drug targets and drug-disease interactions, and helps to design animal experiments that provide more clinically useful information.
Furthermore, it allows investigators to predict drug class liability with respect to safety, and generate exposure-response relationships for efficacy and safety which can be extrapolated from animals to humans. Translation to the clinic with binary data should be made with caution, especially in the absence of robust dose response.
Access to a well characterized drug target and biological pathway s involved in modulation of disease is a tremendous advantage when selecting biomarker s. When presented with several potential biomarkers, teams are asked to qualify the validity of one biomarker over another and select the most appropriate PD endpoint for analysis Vaidya et al. Although this may aid in a more comprehensive capture of the biological response, it may also complicate the data analysis and provide limited additional insight toward subsequent study design.
A consideration of the experimental question being asked e. Scientists from Astra-Zeneca have outlined a biomarker classification e. It is known that normal cells can convert to cancer cells when mutations occur in genes that control kinase signaling cascades and thus regulate cell proliferation and differentiation. For example, more than 40 different mutations have been identified in the BRAF gene in human cancer.
Pharmaceutical scientists have relatively recently developed anti-cancer agents that target specific kinase signaling pathways relevant to tumorigenesis. The BRAF VE pathway includes multiple biomarkers whose direct or indirect response could be indicative of efficacy. When presented with multiple biomarker data, it is important to identify the rate-limiting steps that might be driving the response of a given biomarker. The closeness of the drug target to the biomarker in a signaling cascade will impact the data interpretation.
Based upon these results, the model to describe the effect-concentration relationship between p-ERK and plasma vs. Assuming the goal of the study is to understand target engagement in BRAF, the phospho-MEK:plasma analysis could enable subsequent study design around better understanding of the duration of response and decline of the phospho-MEK signal. Alternatively, if one attempts to understand the relationship to the potential for tumor shrinkage in a follow up efficacy study, the phospho-ERK:plasma analysis might better enable this.
A single oral dose was administered to tumor bearing mice. Plasma and tumor tissue were collected from the same mice to simultaneously obtain plasma PK and biomarker response of phospho-MEK and phospho-ERK in tumors. When fitting a model to pharmacokinetic and pharmacodynamic data, variability associated with PK and PD data within each study is a possible concern.
In other cases it may be valuable to understand the reason for variability in the PK e. When assessing the impact of variability in a dataset, it is important to consider the dosing and sampling strategy used for PK and PD measurements. If the PK and PD were collected from different animals within the same study e. In any of these cases data analysis can still be conducted.
However, it is important to identify when discussing and presenting the data that the results reflect multiple studies, and to interpret such data with the caveats of the study design. If data from multiple studies and animal models are combined to support the modeling, the resulting parameter values may not be single point estimates but rather a distribution of parameter values generated from the uncertainty in the parameters estimated from the preclinical data Chien et al.
Although the model fit of the data shows a very good representation of the mean values in the study, the appropriate use of error bars indicates to the reader that there is variability associated with the predicted response. Based upon these data, a log-linear relationship may have also well described the PD.
In this case, additional data points at both higher and lower concentrations might better refine selection of the appropriate model in future studies. Consideration of statistical significance is helpful when interpreting data sets. This statistical analysis will not only aid in the selection of an appropriate model, but also help to guide subsequent study design.
Variability in PK and PD data. Dose-dependent suppression of biomarker response in rats following administration of a drug candidate. The error bars represent variability in both plasma AUC and biomarker response. Understanding species differences in the biological target, pharmacokinetics, protein binding, and physiology can all aid in more robust translation of preclinical data into the patient population.
When human dose predictions were required, a Novartis project team used an approach much like the one illustrated below. Assuming that there were no differences in the target pharmacology between monkey and human, corrections for PPB and intrinsic potency across species were made to predict what type of response might be observed in vivo in the clinic over a given concentration range.
Pharmacokinetics were scaled to humans in using allometric scaling Mahmood, ; Sinha et al. Equipped with this information, the team could make predictions regarding human dose requirements and anticipated duration of action in the clinic. Translation of preclinical PD data to humans. A Illustrates the ex vivo incubation data of a drug molecule in whole blood from Cynomolgus monkey when used to determine concentration dependent changes in the desired PD effect.
B Shows how the model fit of PD parameters from the incubations were used to predict the in vivo efficacy. Allometric scaling of PK parameters enabled simulations of plasma concentrations in humans. Effective translation of preclinical data is critical to the design of appropriate and successful clinical trials. This iterative process offers a rational approach to both better understand the mechanism of action of a drug as well as select the optimal compounds for further profiling.
The dataset should adequately capture the following: the entire concentration vs. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Front Pharmacol. Published online Jul Prepublished online Jun Author information Article notes Copyright and License information Disclaimer.
This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology. Received May 2; Accepted Jul 5. The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
This article has been cited by other articles in PMC. Abstract Characterizing the relationship between the pharmacokinetics PK, concentration vs. Establish effective partnerships of pharmacology and DMPK A core drug discovery team in the pharmaceutical industry e. Open in a separate window. Figure 1. Figure 2. Figure 3. Unbound concentrations in plasma and tissue It is desirable that PK concentrations and PD readouts are obtained from the same samples and animals, or matrix if using satellite animals.
Figure 4. Plasma protein binding assessments Good experimental designs will take into consideration that unbound concentrations of compound may be responsible for driving the pharmacodynamic response. Simulating the exposure—effect relationship Observations of PK exposure after a specific single dose can be utilized to predict the exposure after administration of a different dose or after repeated dosing. Figure 5. Dose fractionation studies The observed pharmacodynamic effect in a given preclinical model system is associated with a specific pharmacokinetic driver such as parameters AUC, C max , or C min compared to the in vitro potency measure.
Figure 6. Correlation of concentration and effect The initial approach to evaluate the correlation of the concentration vs. Figure 7. Temporal delays in effects Hysteresis Relative to the time course of pharmacokinetics, the pharmacodynamic effect can be delayed or shifted for several reasons. Figure 8. Figure 9. Table 1 Parasitemia reduction and survival in a Plasmodium Berghei mouse model of Malaria infection Meister et al. Multiple biomarker data Access to a well characterized drug target and biological pathway s involved in modulation of disease is a tremendous advantage when selecting biomarker s.
Figure Variability in PK and PD When fitting a model to pharmacokinetic and pharmacodynamic data, variability associated with PK and PD data within each study is a possible concern. Concluding remarks Effective translation of preclinical data is critical to the design of appropriate and successful clinical trials. Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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A well designed PK/PD study offers a rational approach to efficient and informative drug development and can help the project team to understand the mechanism. Federal law permits the use of marketed products in wider circumstances, however. Physicians may prescribe drugs and devices in situations not covered by the. The staff and experts of the European Medicines Agency (EMA) publish articles on the Expert Opinion on Drug Safety, DOI: /