the adverse impact of oral antihyperglycemic agent on the cardiovascular system came into focus as early as 1971 with ugdp program .
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 ) .
glitazone group of drugs were contraindicated in patients with nyha classes iii and iv heart failure .
there was another development in 2005 which brought the issue of secondary end - points into focus .
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 .
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 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 ; p < 0.0001 ) .
it was a huge disappointment . however , it was at this point that we saw the secondary end - points gaining a lot of significance .
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 ) .
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 .
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   ( table 4 ) .
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 .
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 .
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 .
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
. added to metformin , gliptins have an equivalent hba1c reducing ability compared to sulfonylurea .
subsequent data pointed at additional benefits associated with gliptins as far as cv surrogates were concerned .
all these positive effects pointed at the possibility of cv outcomes benefit with gliptins compared to placebo or other active oral comparators .
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 .
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  .
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 .
saxagliptin arm fared very well as far as the primary end - points were concerned ( table 6 ) .
the mace data indicates that both the custom and sponsor mace achieved the fda recommended cut - off value of less than 1.3 .
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 .
in a similar analysis of data with linagliptin the sponsor mace ( 0.36 [ 95% ci 0.170.78 ] ) as well as fda custom mace ( 0.34 [ 95% ci 0.150.75 ] ) met the fda cut - off criteria .
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 .
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 .
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 .
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 .
this study differed significantly from the other cv trials on the following points : 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 : 6.58.0% ) [ 15 , 17].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 .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 ( 0.891.12 ) ; p = 0.99 .
it failed the superiority test .(ii)primary safety end - point ( noninferiority ) : p < 0.001 ( passed the noninferiority test ) .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 ( p = 0.002 ) and major ( p = 0.047 ) hypoglycemic episodes in the saxagliptin arm compared to placebo .(ii)there was a statistically significant 27% increased rate for hospitalization due to heart failure ( hr 1.27 [ 1.071.51 ] ; p = 0.007 ) . 
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 .
others speculated whether the additional patients with established cvd recruited later in the trial could lead to this effect . till date
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 : 6.58.0% ) [ 15 , 17 ] .
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 . primary efficacy end - point ( superiority ) : hr 1.0 ( 0.891.12 ) ; p = 0.99 .
primary safety end - point ( noninferiority ) : p < 0.001 ( passed the noninferiority test ) .
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 ( p = 0.002 ) and major ( p = 0.047 ) hypoglycemic episodes in the saxagliptin arm compared to placebo .
there was a statistically significant 27% increased rate for hospitalization due to heart failure ( hr 1.27 [ 1.071.51 ] ; p = 0.007 ) . 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 .
others speculated whether the additional patients with established cvd recruited later in the trial could lead to this effect . till date
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% . 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 . at the end of the trial
there was a statistically significant 0.36% greater hba1c reduction ( p < 0.001 ) with alogliptin compared to placebo ( usual care ) .
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 ) . 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 : at baseline 24.2% of the recruited patient population had congestive heart failure .
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 : 0.791.46 ) .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 : 0.891.57 ) . 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 : 1.072.90 ) . at baseline 24.2% of the recruited patient population had congestive heart failure . 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 : 0.791.46 ) .
there were no significant differences between the two groups as far as the rates of hypoglycemic events were concerned .
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 .
four prominent issues were up for discussion : the issue related to heart failure.comments that were sought on all - cause mortality.issues related to renal safety.any additional safety issues.we will focus on the cv safety related issues only in this review . the issue related to heart failure .
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 .
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+ ) . both the itt ( hr : 1.00 ; 95% ci : 0.891.12 ) and the mitt ( hr : 1.00 ; 95% ci : 0.891.12 ) for primary mace satisfied the fda requirements ( upper limit of ci < 1.3 ) .
the prespecified itt secondary end - point composite ( mace+ ) had a hazard ration of 1.02 with the upper boundary of ci at 1.11 . 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 ) .
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 : 1.001.30 ) and hhf or all - cause death ( hr : 1.16 ; ci : 1.031.30 ) had the lower boundary of ci at or above 1 . 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 : 1.091.88 ) 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 : 0.941.48 ) . 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 .
although the prespecified iit analysis did not show any trend towards an increase in all - cause mortality ( hr : 1.11 ; 95% ci : 0.961.27 ) , the mitt analysis pointed at a statistically significant increase in 7-day death ( hr : 1.23 ; 95% ci : 1.021.48 ) ( table 7 ) .
once again we come across a number of speculations attempting to explain the increased rates of all - cause mortality .
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 .
nevertheless , the fda document did not consider this increased risk as a pattern happening by chance .
all eyes were on the reanalyzed heart failure and all - cause mortality data as the primary end - point was met .
a composite of mace or heart failure was looked into and the data was encouraging ( hr : 0.982 ; 95% ci : 0.8481.138 ) .
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 .
patients recruited from us and canada had a higher hazard ratio of mace ( hr : 1.28 ; 95% ci : 0.891.84 ) ( table 7 ) .
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 ) .
it was reassuring to note that all - cause mortality was not increased in this trial ( hr : 0.876 ; 95% ci : 0.7051.089 ) .
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 .
tecos recruited patients with a compact hba1c range ( 6.58.0% ) and established cardiovascular disease .
the placebo annual rate of cv events was estimated at 2.53.0% for primary composite events .
hence , it was estimated that recruiting 14,1000 patients would result in approximately 611 cv events over 6 years .
however , the end - of - study hba1c difference of 0.29% reached statistical significance ( 95% ci : 0.32 to 0.27 ; p < 0.0001 )
both pp ( hr : 0.98 ; 95% ci : 0.881.09 ) and itt ( hr : 0.98 ; 95% ci : 0.881.09 ) 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 : 0.891.10 ) .
the itt analysis of hospitalization due to heart failure did not reveal any concerns ( hr : 1.00 ; 95% ci : 0.831.20 ; p = 0.98 ) . 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 : 0.901.15 ; p = 0.74 ) .
all - cause mortality was also not adversely affected ( hr : 1.01 ; 95% ci : 0.901.14 )
. 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 .
the issue of adverse impact of oral hypoglycemic agents and adverse cv signals can be traced back to ugdp in 1971 .
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 .
however , these data were not given a lot of attention as there were issues related to trial design , analysis , and interpretation .
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 .
this study recruited patients with newly diagnosed treatment nave 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 .
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 ) . 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 .
 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
2. The Gliptin Era
3. The Polled Phase 2/3 Saxagliptin Data
4. Gliptins: CV Safety Data (SAVOR TIMI-53, EXAMINE, and TECOS)
5. FDA Analysis of SAVOR TIMI-53 and EXAMINE
6. Conclusion