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Gliptins Comparison Essay

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Comparison Essay

I read the book Uglies. and The Giver . They were both amazing books to read! There are deffinately more differences than there are similarities. The biggest similarity is that in both The Giver. and Uglies nobody is different. That is the biggest part of Uglies. is that everyone is pretty, and everyone is the same.

In The Giver and Uglies the main character rebels against their society. In Uglies Tally leaves her "perfect society" and goes to the Smoke. In The Giver Jonas turns against everyone(except for The Giver of course), and leaves his community behind with a little child named Gabe. They both leave the world behind where they grew up. Although in The Giver you don't ever find out what happens to his community, and in Uglies you do.

Uglies was an amazing book! It is about a young girl named Tally who is about to turn sixteen and become a pretty. Everyone in their world is gorgeous who is above the age of sixteen. Suddenly Tally's world turns upside down when she meets a girl the same age as her named Shay. Shay doesn't understand the big deal about being pretty, so she runs away to the Smoke, and tries to convince Tally to come with her. Tally refuses, then the Special Circumstances got involved and forces Tally to find the Smoke, as well as her friend Shay. When she gets there she meets a boy named David and falls in love with him. She then is very hesitant about calling Special Circumstances, but they end up finding the Smoke anyways. While sitting on the edge of your seat in the ending, they basically take down the entire city. It's a must read book.

The Giver is a thrilling and entertaining book. A young boy named Jonas lives in a "Perfect Society" with many rules. Jonas just got assigned to be the new "Reciever of Memory". The "Reciever of Memory" takes all of the memories from the past, and holds them all in for wisdom. Some are good memories, and some are horrible memories, but all in all Jonas is the one who has to hold them. "The Giver" then has a frightening plan that sends Jonas away to the "Elsewhere". It has a ending that keeps you wishing it would go on forever.

There are many differences between the two books. In the book Uglies. there isn't many rules, all anyone does is party. In The Giver. there are many rules, some that people don't take to seriously, and some that do. They basically have a routine they do daily, while in Uglies it changes everyday.

There are not many similarities between Uglies and The Giver. They are both "Perfect Societies", they are all the same, and nobody is different.

I really enjoyed reading both of theese books. I would recommend them to anyone, and I would deffinately read them again.

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Gliptins and Cardiovascular Outcomes: A Comparative and Critical Analysis after TECOS

Gliptins and Cardiovascular Outcomes: A Comparative and Critical Analysis after TECOS

1 Nightingale Hospital, 11 Shakespeare Sarani, Kolkata, India
2 AMRI Hospitals, JC-16/17, Salt Lake City, Kolkata 700091, India

Received 19 July 2015; Accepted 19 August 2015

Academic Editor: Shuang-Xi Wang

Copyright © 2016 Samit Ghosal and Binayak Sinha. This is an open access article distributed under the Creative Commons Attribution License. which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The issue related to macrovascular outcomes and intensive glycemic control was hotly debated after the publication of landmark trials like ACCORD, ADVANCE, and VADT. The only benefits seem to come from intervening early on in the disease process as indicated by the 10-year UKPDS follow-up. To complicate matters USFDA made it mandatory for modern drugs to conduct cardiovascular safety trials in high-risk populations after the 2008 rosiglitazone scare. This led to all the modern group of drugs designing cardiovascular safety trials (gliptins, GLP-1 agonists, and SGLT-2 inhibitors) to meet USFDA regulatory requirements. We saw publication of the first 2 randomized trials with gliptins published a year and a half back. On the face value SAVOR TIMI and EXAMINE satisfied the primary composite CV end-points. However, issues related to significant increase in heart failure and all-cause 7-day on-treatment mortality created a lot of confusion. FDA reanalysis of these data (especially SAVOR) raises a lot of doubts as far as CV safety of these groups of drugs was concerned. Hence, all eyes were on TECOS, which was published this year. We take a microscopic look at these trials trying to understand where we stand as from now on this issue.

1. Introduction

The adverse impact of oral antihyperglycemic agent on the cardiovascular system came into focus as early as 1971 with UGDP program [1 ]. The drug in question was a sulfonylurea. However, with the advent of second-generation sulfonylureas and nonusage of first-generation ones this controversy was put to rest (without proper investigation).

In early 2000 it was glitazones which came into the headlines with issues related to fluid accumulation (pedal edema and macular edema) [2 ]. Glitazone group of drugs were contraindicated in patients with NYHA Classes III and IV heart failure [3 ].

There was another development in 2005 which brought the issue of secondary end-points into focus. It was the PROactive study [4 ]. The results of this study were eagerly awaited, as this was the first time type 2 diabetic individuals with high CV risk were exposed to a CV outcomes trial. All the surrogate CV markers positively influenced by pioglitazone were put to test [5 ]. The primary end-points put to test over an average of 34.5-month follow-up were time to first death, nonfatal MI, stroke, acute coronary syndrome, major leg amputation, coronary revascularization, and leg revascularization.

The key findings are summarized in Table 1 .

Table 1: PROactive primary end-point results [4 ].

The primary end-points in this study failed to achieve statistical significance in spite of a significant glycemic difference between the two arms (−0.8% pioglitazone versus −0.3% placebo;

) [4 ]. It was a huge disappointment. However, it was at this point that we saw the secondary end-points gaining a lot of significance. Instead of being a negative trial PROactive was suddenly a positive trial. However, one of the secondary end-points, that is, heart failure, was grossly underhighlighted. There were significantly higher event rates related to heart failure in the pioglitazone arm (Table 2 ).

Table 2: PROactive heart failure data [4 ].

The main blow to modern drugs seeking regulatory approval came from a meta-analysis involving rosiglitazone. Nissen and Wolski presented data analyzing 42 randomized trials with control group and of 24-week duration [6 ]. The baseline characteristics are summarized in Table 3 .

Table 3: Baseline characteristics [6 ].

There was a statistically significant 43% increase in myocardial infarction with a trend towards increased death from cardiovascular causes in the rosiglitazone arm compared to active comparators and placebo [6 ] (Table 4 ).

Table 4: Adverse outcomes [6 ].

The very next year (2008) USFDA came up with “Guidance for Industry” [7 ]. The new guidance stressed on the sponsors recruiting an independent committee looking into the cardiovascular end-points in the phases II and III study programs. The primary and secondary end-points along with the methods employed for statistical analysis should be clearly mentioned. A two-sided 95% confidence interval for each assessment of risk ratio was formulated. The cut-off values set as mandatory requirements are presented in Table 5 .

Table 5: Upper bound 2-sided 95% confidence interval cut-off for approval [7 ].

It was pointed out, however, that individuals recruited in phases II and III programs would mostly be younger with a short duration of diabetes (not the ideal population to assess CV outcomes). Hence, it was mandatory to conduct a CV safety outcomes trial even when there were no adverse signals in the phases II and III programs especially if the CV event rates were low [7 ].

The modern antidiabetic medications as a result of the abovementioned developments were exposed to a new set of laws.

Keeping in mind the USFDA CV safety requirements and the importance of secondary end-points especially heart failure, let us take an in-depth look at the recently published CV outcomes data with gliptins in focus.

2. The Gliptin Era

In mid-2000 we got a new group of antihyperglycemic agents (DPP 4 inhibitors or gliptins) for the management of type 2 diabetes. The advantages associated with this group were lack of hypoglycemia and weight neutrality [8 ]. Added to metformin, gliptins have an equivalent HBA1C reducing ability compared to sulfonylurea [9 ]. Subsequent data pointed at additional benefits associated with gliptins as far as CV surrogates were concerned [10 ]. Sitagliptin was associated with reduction in postmeal triglyceride rich apo-B levels [11 ]. Similarly, saxagliptin was associated with reduction in blood pressure in animal models [12 ].

All these positive effects pointed at the possibility of CV outcomes benefit with gliptins compared to placebo or other active oral comparators.

3. The Polled Phase 2/3 Saxagliptin Data

USFDA analyzed the pooled phases 2b and 3 saxagliptin data, which included a total of 8 studies and came out with their report in 2009 [13 ]. The primary MACE was the focus of attention. The major obstacle in the way of analyzing the data was deriving an accurate definition and terminology for the individual MACE events. Apart from the sponsor’s definition of MACE, two more definitions were included in this analysis. The first was “Broad SMQ MACE” and the second “Custom MACE” [13 ]. SMQ stands for standardized MedDRA (Medical Dictionary for Regulatory Activities) queries. The terminologies used to define a disease entity were in accordance with a standardized definition. Custom MACE was a subset of “Broad SMQ MACE” which is more specific as far as defining the end-points was concerned supervised by 3 FDA reviewers [13 ]. Saxagliptin arm fared very well as far as the primary end-points were concerned (Table 6 ).

Table 6: Saxagliptin polled phase 2b/3 MACE [13 ].

The MACE data indicates that both the custom and sponsor MACE achieved the FDA recommended cut-off value of less than 1.3 [13 ]. The ST custom MACE as a matter of fact reached statistical significance. The SMQ MACE was diluted with the use of CPK as one of the preferred terms thereby increasing the number of events and the upper limit of the two-sided confidence interval crossing 1.3 [13 ].

In a similar analysis of data with linagliptin the sponsor MACE (0.36 [95% CI 0.17–0.78]) as well as FDA Custom MACE (0.34 [95% CI 0.15–0.75]) met the FDA cut-off criteria [14 ].

However, the number of CV events in the saxagliptin pooled data custom MACE was 40 and that in the linagliptin pooled data was 11 [13. 14 ]. This was an extremely small number to come to a definitive conclusion as far as CV safety was concerned. Hence, it was mandatory to undergo a dedicated CV safety trial. All the gliptins took to dedicated CV safety trials except vildagliptin.

4. Gliptins: CV Safety Data (SAVOR TIMI-53, EXAMINE, and TECOS)

SAVOR TIMI-53 (saxagliptin) and EXAMINE (alogliptin) were published in 2008 whereas TECOS (sitagliptin) was published in 2015. Let us take a look at the salient CV safety issues highlighted in these three landmark trials.

4.1. SAVOR TIMI-53 (Saxagliptin)

The aim of this study was to analyze primary efficacy (superiority), primary safety (noninferiority), and secondary safety issues in an intention to treat (ITT) population. It was estimated from the annual primary CV event rate with placebo (2.8%) that the study should recruit 12,000 patients and run the trial for 2 years with 3-year follow-up (total of 5 years duration) to get hold of 1,040 CV events [15 ]. This would enable the investigators to generate adequate power to test the noninferiority hypothesis. However, after 10 months after recruitment the investigators realized that the numbers recruited would not yield the anticipated event rates and additional subjects (with established CVD) were recruited to increase the study population number to 16,500 [16 ].

This study differed significantly from the other CV trials on the following points: (i) Baseline HBA1C was over a broader range (>6.5% to ≤12.0%) with a mean value of 8.0% (±1.4%) versus TECOS (HBA1C range: 6.5–8.0%) [15. 17 ]. (ii) There were patients without established CVD recruited in this trial (primary CV prevention cohort). Recruitment of this population was restricted to 25% of the whole study population [15 ]. The results were published in October 2014. The prominent primary end-point results were as follows: (i) Primary efficacy end-point (superiority): HR 1.0 (0.89–1.12);

It failed the superiority test [16 ]. (ii) Primary safety end-point (noninferiority): (passed the noninferiority test) [16 ]. The areas of concern from CV perspective are as follows: (i) Although designed as a glycemic equipoise study, the end results revealed a statistically significant difference between the two arms as far as fasting plasma glucose and HBA1C were concerned. There were significantly more episodes of both minor (

) hypoglycemic episodes in the saxagliptin arm compared to placebo [16 ]. (ii) There was a statistically significant 27% increased rate for hospitalization due to heart failure (HR 1.27 [1.07–1.51]; ) [16 ]. Although a distinctive mechanism leading to heart failure was not obvious with gliptins, several groups speculated whether it was the impact of DPP-4 inhibitors on substrates like Neuropeptide-Y (NP-Y) and Substance P (SP) that could lead to this effect [18 ]. Others speculated whether the additional patients with established CVD recruited later in the trial could lead to this effect. Till date, we do not have any answer to this phenomenon. The next logical step would be to wait for another CV safety trial.

4.2. EXAMINE (Alogliptin)

EXAMINE study group investigators recruited patients exclusively with established ACS. Since patients with established ASC were included in this trial, the placebo annual primary MACE was estimated at 3.5% [19 ]. As a result, recruiting a smaller population (5,400) followed up for approximately 40 months would generate adequate enough power to fulfill the HR cut-off [19 ].

At the end of the trial there was a statistically significant 0.36% greater HBA1C reduction ( ) with alogliptin compared to placebo (usual care) [20 ]. Once again the glycemic equipoise hypothesis was not satisfied.

The alogliptin arm achieved the primary end-point (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) noninferiority (HR 0.96; upper boundary of CI 1.16) [20 ].

With the adverse impact of saxagliptin in SAVOR TIMI-53 on hospitalization for heart failure as well as increased hypoglycemic episodes, all eyes were on EXAMINE as far as these parameters were concerned: (i) At baseline 24.2% of the recruited patient population had congestive heart failure [19 ]. However, NYHA Class IV was an exclusion criterion. EXAMINE data revealed that there was no significant trend as far as hospitalization due to heart failure as a first event was concerned (HR: 1.07; 95% CI: 0.79–1.46) [20 ]. (ii) There were no significant differences between the two groups as far as the rates of hypoglycemic events were concerned. On the one hand, the results of EXAMINE were a bit reassuring while on the other hand the absence of a clear cut answer as far as hospitalization from heart failure was concerned was discomforting. In an editorial on the post hoc analysis of heart failure, it was pointed out that there was a statistically nonsignificant increased risk for hospitalization due to heart failure (HR 1.19 CI: 0.89–1.57) [21 ]. As a matter of fact those without a background history of heart failure had a significant risk of developing it while being on alogliptin (HR 1.76; 95% CI: 1.07–2.90) [21 ].

Hence, all eyes were on the upcoming CV safety trial with gliptins and the one closest to publication after SAVOR TIMI-53 and EXAMINE was TECOS.

However, at this point FDA took note of the adverse signals emerging from these trials and conducted an analysis of their own.

5. FDA Analysis of SAVOR TIMI-53 and EXAMINE 5.1. Reanalysis of SAVOR TIMI-53

Four prominent issues were up for discussion [22 ]: (i) The issue related to heart failure. (ii) Comments that were sought on all-cause mortality. (iii) Issues related to renal safety. (iv) Any additional safety issues. We will focus on the CV safety related issues only in this review.

While reanalyzing the sponsors existing data, FDA introduced the term mITT, which differed from ITT (intention to treat) in terms of the fact that the subject must have received the drug in question even if it is for a day. This “on-treatment” analysis was further subdivided into +7 days and +30 days’ analysis (i.e. events occurring 7 days and 30 days after receiving the last dose of saxagliptin or placebo): the time-to-event analysis [22 ].

Another important point to remember at this point is that all-cause mortality was a stand-alone secondary end-point whereas hospitalization for heart failure was one of multiple secondary end-points (MACE+).

5.2. The Reanalysis Results
5.2.1. Primary MACE

Both the ITT (HR: 1.00; 95% CI: 0.89–1.12) and the mITT (HR: 1.00; 95% CI: 0.89–1.12) for primary MACE satisfied the FDA requirements (upper limit of CI <1.3) [22 ].

The individual components of primary MACE did not differ either.

5.2.2. Secondary End-Points (MACE+)

The prespecified ITT secondary end-point composite (MACE+) had a hazard ration of 1.02 with the upper boundary of CI at 1.11 [22 ].

Amongst the individual secondary end-points, it was hospitalization due to heart failure, which was pointing the wrong way. The problem FDA identified was that this was not a prespecified stand-alone secondary end-point. Since this end-point analysis ended up with a statistically significant difference, FDA went ahead and reanalyzed the data. Although those in the secondary end-point arm could continue on in the trail, those experiencing a primary event were not followed up any more. This results in crunching of the high-risk population base as we go on. Hence, FDA designed a new analytical process whereby subjects with heart failure or other high-risk composites were included in the analysis (e.g. hHF or primary MACE; hHF or CV death) [22 ]. On-study ITT population was analyzed.

Of the 3 end-points analyzed (hHF or primary MACE, hHF or CV death, and hHF or all-cause death) hHF or CV death (HR: 1.14; 95% CI: 1.00–1.30) and hHF or all-cause death (HR: 1.16; CI: 1.03–1.30) had the lower boundary of CI at or above 1 [22 ]. Hence, the issue of hHF remained significant even in the reanalysis performed.

It was thought that the detrimental by-products of DPP-4 inhibition Neuropeptide-Y (NP-Y) and Substance P (SP) clubbed with ACE inhibition could lead to increased sympathetic activity and heart failure. However, the data indicated a higher and significant hazards ratio (HR 1.42; 95% CI: 1.09–1.88) for time to first hospitalization due to heart failure in those not on ACE inhibitors compared to those who were on it (HR 1.18; 95% CI: 0.94–1.48) [22 ]. Hence, the DPP-4 inhibition induced production of adverse by-products (NP-Y and SP) could not explain this end-point.

Although a lot of effort was spent analyzing why there was an increase in hospitalization due to heart failure, none of the hypothesis generated could explain this phenomenon.

All-Cause Mortality. This was a stand-alone secondary end-point.

This was another area of concern. Although the prespecified IIT analysis did not show any trend towards an increase in all-cause mortality (HR: 1.11; 95% CI: 0.96–1.27), the mITT analysis pointed at a statistically significant increase in 7-day death (HR: 1.23; 95% CI: 1.02–1.48) (Table 7 ) [22 ]. Once again we come across a number of speculations attempting to explain the increased rates of all-cause mortality. A sizable 25% of patients in SAVOR TIMI had a baseline HBA1C below 7%. This clubbed with statistically increased rates of hypoglycemia in the saxagliptin arm was touted as one of the reasons. However, the FDA analysis on the same and other points (heart failure, increased rates of arrhythmias, etc.) could not arrive at a definitive conclusion [22 ]. Nevertheless, the FDA document did not consider this increased risk as a pattern happening by chance.

5.3. Reanalysis of EXAMINE Trial

All eyes were on the reanalyzed heart failure and all-cause mortality data as the primary end-point was met.

5.4. Heart Failure Reanalysis Data

The same analytical method was employed as in the case of SAVOR TIMI. A composite of MACE or heart failure was looked into and the data was encouraging (HR: 0.982; 95% CI: 0.848–1.138) [23 ]. There were no signals of increased first hospitalization from heart failure. However, it should be mentioned at this point once again that EXAMINE trial excluded patients with NYHA Class IV and had the majority of individuals in the NYHA Class II category [23 ].

5.5. Mortality Signals

Patients recruited from US and Canada had a higher hazard ratio of MACE (HR: 1.28; 95% CI: 0.89–1.84) (Table 7 ) [23 ]. Although there were differences as far as baseline characteristics were concerned (longer duration of diabetes, more smokers, etc.), these factors could not explain why there was an increased mortality trend.

Increased hazard ratio for MACE was also observed in those with longer duration of diabetes (>10 years duration), moderate-to-severe renal disease, biguanide nonusers, and insulin users (Table 7 ) [23 ].

It was reassuring to note that all-cause mortality was not increased in this trial (HR: 0.876; 95% CI: 0.705–1.089) [23 ].

5.6. Post-FDA Reanalysis of Data in 2015

There were mixed reactions. Some schools of thought felt that the issue of heart failure was not replicated and hence there was some reassurance on this issue. On the other hand, the critics pointed out that there were inherent differences between the trials and hence it was not possible to come to a definite conclusion.

Hence, all eyes were on TECOS.

5.7. The TECOS Data

Baseline Characteristics in Brief. TECOS recruited patients with a compact HBA1C range (6.5–8.0%) and established cardiovascular disease. Patients with eGFR <30 mL/min were excluded from the trial [24 ].

The placebo annual rate of CV events was estimated at 2.5–3.0% for primary composite events. Hence, it was estimated that recruiting 14,1000 patients would result in approximately 611 CV events over 6 years [24 ].

5.8. The Results

Once again we are looking at a glycemic equipoise study. However, the end-of-study HBA1C difference of 0.29% reached statistical significance (95% CI: −0.32 to −0.27; ) [17 ].

Primary CV End-Points. Both PP (HR: 0.98; 95% CI: 0.88–1.09) and ITT (HR: 0.98; 95% CI: 0.88–1.09) analysis echoed the findings from SAVOR TIMI and EXAMINE [16. 17. 20 ]. Sitagliptin satisfied the FDA upper bound CI of <1.30 as far as primary CV outcomes were concerned. However, sitagliptin could not meet the superiority criteria (HR: 0.99; 95% CI: 0.89–1.10) [17 ].

5.9. The Areas under Focus

All eyes were focused on the heart failure and mortality issues.

The ITT analysis of hospitalization due to heart failure did not reveal any concerns (HR: 1.00; 95% CI: 0.83–1.20;

). What was interesting to note was that unlike the previous studies TECOS utilized the FDA pattern and analyzed hHF or cardiovascular death composite for the ITT population. Once again the results were reassuring (HR: 1.02; 95% CI: 0.90–1.15; ) [17 ].

All-cause mortality was also not adversely affected (HR: 1.01; 95% CI: 0.90–1.14) [17 ]. What was reassuring to note was that there were no adverse MACE signals as far as differing patient population, duration of diabetes, baseline HBA1C, baseline nonuse of biguanides, insulin usage, or use of ACE inhibitors were concerned [17 ]. This was in direct contrast to the findings from EXAMINE trial.

6. Conclusion

The issue of adverse impact of oral hypoglycemic agents and adverse CV signals can be traced back to UGDP in 1971 [1 ]. Similar trends were also observed in UKPDS 34 when adding metformin to sulfonylurea resulted in an increase in diabetes-related deaths and all-cause mortality [25 ].

However, these data were not given a lot of attention as there were issues related to trial design, analysis, and interpretation.

The modern trials on the contrary are well designed and analyzed. There is no running away from the fact that dedicated CV safety trials will be required for all the modern drugs to find a definitive place in treatment algorithm. With this background all the three randomized trials (SAVOR TIMI, EXAMINE, and TECOS) reassure us on the CV safety of DPP-4 inhibitors from the primary end-point perspective. What keeps the debate going are the issues related to increased hypoglycemia risk, hHF, and increased all-cause mortality in SAVOR TIMI and increased MACE risk in certain population in EXAMINE. TECOS was the picture-perfect trial pulling along the other drugs in this group towards the positive side and ruling out the fear of class effect as far as the adverse events were concerned.

However, it would be premature to say that the issue has been settled once and for all.

There are a couple of interesting studies lined up either to simplify the contentious issues or to complicate matters even further. CARMELINA with linagliptin would add on to the increasing experience with usage of DPP-4 inhibitors in high CVD risk diabetic population [26 ]. Another data would probably help put a lot of unanswered questions in perspective.

However, things might get a bit complicated with CAROLINA [27 ]. This study recruited patients with newly diagnosed treatment naïve diabetes or early on in the disease process with high CV risks profile. Patients were randomized to either glimepiride or linagliptin and would be followed up for 5 years. This would be the first in kind head-to-head comparison between a sulfonylurea and a gliptin on high CV risk patients. The duration of this trial is too short to answer this question, as we saw CV benefits appearing after 20 years in those with newly diagnosed type 2 diabetes [28 ]. However, the patient population in this trial is unique as they are newly diagnosed but already have established CVD (similar to the ORIGIN trial population [29 ]).

Overall, sitagliptin in TECOS trial came up with the most impressive results (pending FDA reanalysis). We need to keep at the back of our minds the issues related to saxagliptin and alogliptin in some special situations.

Abbreviations

Action to Control Cardiovascular Risk in Diabetes

Cv safety of gliptins

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    Gliptins comparison essay

    Emerging gliptins for type 2 diabetes.

    The dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are novel oral hypoglycemic drugs which have been in clinical use for the past 7 years. The drugs are safe, weight neutral and widely prescribed. There are currently eight gliptins registered worldwide with several more in advanced stages of development.
    The place of the gliptins in the treatment algorithm of type 2 diabetes is discussed as well as unique features of the individual drugs. The gliptins may possess cardiovascular protective effects and their administration may promote β-cell survival; claims currently being evaluated in clinical and preclinical studies. The global market revenues and future prospects of the gliptins are discussed and the gliptins in Phases II and III of development are reviewed.
    The gliptins are an optional second-line therapy after metformin; they are generally well tolerated with low risk of hypoglycemia. The various compounds differ with respect to their pharmacokinetic and pharmacodynamic properties; however, their clinical efficacy appears to be similar. The clinical differences between the various compounds stem from effects other than hypoglycemic effects, their safety and side effects profile. The currently registered compounds appear to have maximized the clinical potential of DPP-4 inhibition, and the new compounds in the companies' pipelines seem to be as effective as the ones presently in use. There are two gliptins in advanced stages of development which will be registered for once-weekly dosing, possibly increasing patient adherence to therapy. Several individual gliptins are being evaluated for treatment in diabetes subpopulations such as type 1 patients or adolescents.

    Affiliation

    Hadassah Hebrew University Medical Center, The Diabetes Research Center, Jerusalem, Israel.

    The dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are novel oral hypoglycemic drugs which have been in clinical use for the past 7 years. The drugs are safe, weight neutral and widely prescribed. There are currently eight gliptins registered worldwide with several more in advanced stages of development.
    The place of the gliptins in the treatment algorithm of type 2 diabetes is discussed as well as unique features of the individual drugs. The gliptins may possess cardiovascular protective effects and their administration may promote β-cell survival; claims currently being evaluated in clinical and preclinical studies. The global market revenues and future prospects of the gliptins are discussed and the gliptins in Phases II and III of development are reviewed.
    The gliptins are an optional second-line therapy after metformin; they are generally well tolerated with low risk of hypoglycemia. The various compounds differ with respect to their pharmacokinetic and pharmacodynamic properties; however, their clinical efficacy appears to be similar. The clinical differences between the various compounds stem from effects other than hypoglycemic effects, their safety and side effects profile. The currently registered compounds appear to have maximized the clinical potential of DPP-4 inhibition, and the new compounds in the companies' pipelines seem to be as effective as the ones presently in use. There are two gliptins in advanced stages of development which will be registered for once-weekly dosing, possibly increasing patient adherence to therapy. Several individual gliptins are being evaluated for treatment in diabetes subpopulations such as type 1 patients or adolescents.

    Health Technol Assess

    Health Technol Assess 2010 Jul;14(36):1-248

    In May 2008, the National Institute for Health and Clinical Excellence (NICE) issued an updated guideline [clinical guideline (CG) 66] for the management of all aspects of type 2 diabetes. This report aims to provide information on new drug developments to support a 'new drugs update' to the 2008 guideline.
    To review the newer agents available for blood glucose control in type 2 diabetes from four classes: the glucagon-like peptide-1 (GLP-1) analogue exenatide; dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin; the long-acting insulin analogues, glargine and detemir; and to review concerns about the safety of the thiazolidinediones.
    The following databases were searched: MEDLINE (1990-April 2008), EMBASE (1990-April 2008), the Cochrane Library (all sections) Issue 2, 2008, and the Science Citation Index and ISI Proceedings (2000-April 2008). The websites of the American Diabetes Association, the European Association for the Study of Diabetes, the US Food and Drug Administration, the European Medicines Evaluation Agency and the Medicines and Healthcare Products Regulatory Agency were searched, as were manufacturers' websites.
    Data extraction was carried out by one person, and checked by a second. Studies were assessed for quality using standard methods for reviews of trials. Meta-analyses were carried out using the Cochrane Review Manager (RevMan) software. Inclusion and exclusion criteria were based on current standard clinical practice in the UK, as outlined in NICE CG 66. The outcomes for the GLP-1 analogues, DPP-4 inhibitors and the long-acting insulin analogues were: glycaemic control, reflected by glycated haemoglobin (HbA1c) level, hypoglycaemic episodes, changes in weight, adverse events, quality of life and costs. Modelling of the cost-effectiveness of the various regimes used the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model.
    Exenatide improved glycaemic control by around 1%, and had the added benefit of weight loss. The gliptins were effective in improving glycaemic control, reducing HbA1c level by about 0.8%. Glargine and detemir were equivalent to Neutral Protamine Hagedorn (NPH) (and to each other) in terms of glycaemic control but had modest advantages in terms of hypoglycaemia, especially nocturnal. Detemir, used only once daily, appeared to cause slightly less weight gain than glargine. The glitazones appeared to have similar effectiveness in controlling hyperglycaemia. Both can cause heart failure and fractures, but rosiglitazone appears to slightly increase the risk of cardiovascular events whereas pioglitazone reduces it. Eight trials examined the benefits of adding pioglitazone to an insulin regimen; in our meta-analysis, the mean reduction in HbA1c level was 0.54% [95% confidence interval (CI) -0.70 to -0.38] and hypoglycaemia was marginally more frequent in the pioglitazone arms [relative risk (RR) 1.27, 95% CI 0.99 to 1.63]. In most studies, those on pioglitazone gained more weight than those who were not. In terms of annual drug acquisition costs among the non-insulin regimes for a representative patient with a body mass index of around 30 kg/m2, the gliptins were the cheapest of the new drugs, with costs of between 386 pounds and 460 pounds. The glitazone costs were similar, with total annual costs for pioglitazone and for rosiglitazone of around 437 pounds and 482 pounds, respectively. Exenatide was more expensive, with an annual cost of around 830 pounds. Regimens containing insulin fell between the gliptins and exenatide in terms of their direct costs, with a NPH-based regimen having an annual cost of around 468 pounds for the representative patient, whereas the glargine and detemir regimens were more expensive, at around 634 pounds and 716 pounds, respectively. Comparisons of sitagliptin and rosiglitazone, and of vidagliptin and pioglitazone slowed clinical equivalence in terms of quality-adjusted life-years (QALYs), but the gliptins were marginally less costly. Exenatide, when compared with glargine, appeared to be cost-effective. Comparing glargine with NPH showed an additional anticipated cost of around 1800 pounds. Within the comparison of detemir and NPH, the overall treatment costs for detemir were slightly higher, at between 2700 pounds and 2600 pounds.
    The UKPDS Outcomes Model does not directly address aspects of the treatments under consideration, for example the direct utility effects from weight loss or weight gain, severe hypoglycaemic events and the fear of severe hypoglycaemic events. Also, small differences in QALYs among the drugs lead to fluctuations in incremental cost-effectiveness ratios.
    Exenatide, the gliptins and detemir were all clinically effective. The long-acting insulin analogues glargine and detemir appeared to have only slight clinical advantages over NPH, but had much higher costs and did not appear to be cost-effective as first-line insulins for type 2 diabetes. Neither did exenatide appear to be cost-effective compared with NPH but, when used as third drug after failure of dual oral combination therapy, exenatide appeared cost-effective relative to glargine in this analysis. The gliptins are similar to the glitazones in glycaemic control and costs, and appeared to have fewer long-term side effects. Therefore, it appears, as supported by recent NICE guidelines, that NPH should be the preferred first-line insulin for the treatment of type 2 diabetes. More economic analysis is required to establish when it becomes cost-effective to switch from NPH to a long-acting analogue. Also, long-term follow-up studies of exenatide and the gliptins, and data on combined insulin and exenatide treatment, would be useful.

    Expert Opin Pharmacother

    Expert Opin Pharmacother 2012 Jan;13(1):81-99

    Dipeptidylpeptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes (T2DM).
    This paper is an updated review, providing an analysis of both the similarities and the differences between the various compounds known as gliptins, currently used in the clinic (sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin). This paper discusses the pharmacokinetic and pharmacodynamic characteristics of gliptins; both the efficacy and safety profiles of gliptins in clinical trials (compared with classical glucose-lowering agents), given as monotherapy or in combination, including in special populations; the positioning of DPP-4 inhibitors in the management of T2DM in recent guidelines; and various unanswered questions and perspectives.
    The role of DPP-4 inhibitors in the therapeutic armamentarium of T2DM is evolving, as their potential strengths and weaknesses become better defined. Future critical issues may include the durability of glucose control, resulting from better β-cell protection, positive effects on cardiovascular outcomes and long-term safety issues.

    Pharmacotherapy 2015 Mar 10;35(3):277-97. Epub 2015 Mar 10.

    The dipeptidyl peptidase-IV (DPP-IV) inhibitors, also known as gliptins, are widely used in clinical practice either as monotherapy or in combination with other agents for the management of type 2 diabetes mellitus (T2DM). The gliptins are effective, safe, well tolerated, and conveniently administered once/day. Moreover, these agents have a low risk for drug interactions and do not require initial dosage titrations to lessen adverse effects. They are not only clinically desirable, having the most favorable side-effect profile of all available antihyperglycemic medications, but they can also be used in any stage of renal or hepatic impairment. The antihyperglycemic effects of gliptins are attributed to inhibition of the DPP-IV enzyme, thereby prolonging the half-life (t1/2 ) of incretin hormones (substrates) to promote glucose-stimulated insulin secretion. Beyond their glucose-lowering effects, gliptins may also reduce the risk of cardiovascular disease by improving endothelial function, lowering blood pressure, reducing inflammation, and delaying the progression of atherosclerosis. Although the vascular protective effects of gliptins depend on incretins, the contributions of other biologically important endogenous vasoactive substrates of DPP-IV are worthy of consideration from a therapeutic standpoint. Future and ongoing studies should help determine whether these vascular protective effects contribute to improved cardiovascular outcomes in patients with T2DM. The experimental and clinical evidence supporting the vascular protective effects of gliptins is reviewed.

    Diabetes Metab 2012 Apr 22;38(2):89-101. Epub 2011 Dec 22.

    Dipeptidyl peptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes. Direct comparisons with active glucose-lowering comparators in drug-naive patients have demonstrated that DPP-4 inhibitors exert slightly less pronounced HbA(1c) reduction than metformin (with the advantage of better gastrointestinal tolerability) and similar glucose-lowering effects as with a thiazolidinedione (TZD; with the advantage of no weight gain). In metformin-treated patients, gliptins were associated with similar HbA(1c) reductions compared with a sulphonylurea (SU; with the advantage of no weight gain, considerably fewer hypoglycaemic episodes and no need for titration) and a TZD (with the advantage of no weight gain and better overall tolerability). DPP-4 inhibitors also exert clinically relevant glucose-lowering effects compared with a placebo in patients treated with SU or TZD (of potential interest when metformin is either not tolerated or contraindicated), and as oral triple therapy with a good tolerability profile when added to a metformin-SU or pioglitazone-SU combination. Several clinical trials also showed a consistent reduction in HbA(1c) when DPP-4 inhibitors were added to basal insulin therapy, with no increased risk of hypoglycaemia. Because of the complex pathophysiology of type 2 diabetes and the complementary actions of glucose-lowering agents, initial combination of a DPP-4 inhibitor with either metformin or a glitazone may be applied in drug-naive patients, resulting in greater efficacy and similar safety compared with either drug as monotherapy. However, DPP-4 inhibitors were less effective than GLP-1 receptor agonists for reducing HbA(1c) and body weight, but offer the advantage of being easier to use (oral instead of injected administration) and lower in cost. Only one head-to-head trial demonstrated the non-inferiority of saxagliptin vs sitagliptin. Clearly, more trials of direct comparisons between different incretin-based therapies are needed. Because of their pharmacokinetic characteristics, pharmacodynamic properties (glucose-dependent glucose-lowering effect) and good overall tolerability profile, DPP-4 inhibitors may have a key role to play in patients with renal impairment and in the elderly. The role of DPP-4 inhibitors in the therapeutic armamentarium of type 2 diabetes is rapidly evolving as their potential strengths and weaknesses become better defined mainly through controlled clinical trials.

    Affiliation Details
    • Hadassah Hebrew University Medical Center, The Diabetes Research Center, Jerusalem, Israel.
    • Hadassah Hebrew University Medical Center

    Hadassah Hebrew University Medical Center, The Diabetes Research Center, Jerusalem, Israel.

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