Inhibitors of Dipeptidyl Peptidase 4 (DPP-4)
Drugs

Commentary on T2DM characterisation and personalized therapy

T2DM and patient genetic singularity

Since 2000, genetic association studies have provided incontrovertible levels of statistical evidence that many loci contribute to the development of type 2 diabetes. Several methods of discovery have been utilized to identify such loci as PPARG, KCNJ11, TCF7L2, SLC30A8, JAZF1, CDC123-CAMK1D, ADAM30, MTNR1B, and many others. The transcription factor 7-like 2 (TCF7L2) has the strongest evidence demonstrating a genetic link to type 2 diabetes. Many of these loci are currently being studied for their usefulness in diagnosis, prediction, prevention, and treatment. However, results have not demonstrated a clear role in the clinical care of type 2 diabetes today, Although research is ongoing.
Diabetes treatment is complicated by the vast number of treatment options available and, possibly even more, by the varied inter-patient responses to each treatment option. Treatment response heterogeneity is seen in patients with various characteristics including varied metabolic capabilities, diverse socioeconomic and environmental issues, and varying degrees of illness severity.
Race and ethnicity have long been recognized as a significant risk factor for type 2 diabetes and related complications. Minorities tend to have much higher rates of diabetes-related complications and death, in some instances as much as 50% more than the total population. In one study, Hispanics and African Americans were less likely to have A1C, glycated hemoglobin levels <7% (35-37%) compared to Caucasians (49%). Other studies have also shown increased insulin resistance and beta-cell dysfunction in Hispanics and African Americans. Recently, pooled data from 11 multinational clinical trials showed that race/ethnicity was associated with statistically significant differences in outcomes compared to Caucasians for each insulin regimen. This study demonstrated that Hispanics and African Americans have different metabolic responses to insulin therapy than Caucasians, dependent upon insulin type and regimen intensity. These findings should thus be taken into consideration when clinicians are tailoring treatment plans to meet the individual needs of their patients.
New Directions and revolutionary approaches in the personalized treatment of type 2 diabetes, 2011

Usage of incretinic therapy depending on patient therapy aim

Now let's consider the example of incretinic therapy as an instrument in choosing personalized T2DM treatment. The medication consists in the administration of subcutaneous infusion of GLP-1 (glucagon-like peptide 1) or gliptins (DPP-4 inhibitors). GLP-1 (7-36) amide has turned out as not very useful for treatment of type 2 diabetes mellitus. In fact the need of continous infusion has limited the use of this medication, forcing the research to develop some long lasting analogs, having the same insulinotropic activity like exenatide and liraglutide.The rapidity of the deactivation by DPP 4 of GLP 1 and GIP has driven the research to find some Dipeptidil peptidase inhibitors, Therefore sitagliptine has appeared as a good instrument in enhancing incretins and reducing their deactivation both. The competitive advantages of incretins in treatment of T2DM stand in the lack of ponderal effects (in the case of gliptins), or possibly the positive weight control (ARGLP 1) in contrast with the ponderal increment caused by use of insuline and secretagogs and the low incidence of collateral effects (gliptins) or limitaded GI affections(ARGLP1). In addition HbA1C levels reduction (0.8-1.5% ARGLP1 , 0.6-0.8 gliptins) is comparable with the traditional medications like metphormine , secretagogs and insuline. These peculiarities of incretin therapy have positive effects on the patient's life-style and self confidence, on his metabolic compensation and longlasting glycemic control. It results though a significant posticipation in insuline care introduction.

Some guide line suggests to use this therapy as a second or third line medication , after the failure of metphormine, or the association metphormine+ sulphonyluree , others to use it in some selected patients that need to control ponderal augmentation or ipoglycemical events.This because the high cost of the therapy would be absorbed, and considered economically convenient by the sanitary sistem or by the patient's own wallet only if the reduction of patient's weight, comorbidity, secondary effects to be cured and cronic disease development prevented, was granted. Surely the cost of the introduction of a new medication in national pharmacopea is to be considered as a disadvantage of incretinic therapy.This has caused the limited application of this therapy in Italy, with a percentage of daycare of 1.1, compared to the use in Germany(8.6),France(6.9) and Spain (10.0).The cost gap will be filled with the variety of future missed costs of cardiovascular disease prevention, and ponderal augmentation(+1 BMI = +2-4% sanitary costs).
The National Institute for Health and Clinical Excellence suggests that targets of this kind of therapy should be: obese patients, due to the need to control ponderal augmentation, aged/ fragile people, interested in reducing secondary effects often found in classical therapy, patients presenting high risk of hypoglycemic crisis, relatively reduced with incretins, and subjects with moderate kidney failure.Seen the lack of evidence of different response to incretinic therapy depending on ethnicity, and the amount of differences in insulinic therapy respones race linked, the incretinic therapy seems to grant a possibility to level off the spread between races in T2DM treatment.

h3. Final considerations

Eventually incretins , due to the features of easy calibration on patient’s age, weight, medication response, socio-economical characteristics, will find a place in the individualisation of treatment of T2DM.Infact considering the first type of developed incretin, the GLP-1 analogs, we can see that the appetite reduction, that can avoid the clear bynomius diabetes-obesity without imposing a strict diet regimen, is a great instrument in treating great-obese and compulsive eaters T2DM patients. Still this medication requires a daily subcutaneous infusion, that can inficiate patient life quality like insulin in insulin dependent Diabetes 1, and may be disadvantaging even for elder patients. The second generation of incretins therapy medication is based on DPP-4 inhibitors. Great adventages are granted using this oral medication simply by its way of administration, and sometime ponderal control effect are comparable with GLP-1 analogs. Nonetheless during clinical trials GI secondary effects and cefalea have turned out followed by one of the most undesirable collateral effects of classical T2DM therapies: Ipoglycemia. The differences in between GLP-1 and DPP4 inhibitors, regarding therapeutic and collateral effects both, lead us to considerate the two medications equally valuable in T2DM treating, inviting us to base our choice of incretinic medication on patient need and capability of tolerating the differents undesired effects. This makes of incretin the remarkable example of a therapy choice to be personalized on patient needs. We can't consider easily and superficially both positive (less collateral effects, comparable glycemic effects) and negative (costs, GI disease still presenting) implications that follow the introduction of this new therapy; but in the ability to choose a specific medication depending on patient peculiarity stands the probability to improve his way of living the disease and tollerate the treatment.
Position and statement AMD-SID sulla terapia incretinica, 2011"