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Dipeptydil peptidase-4 inhibitors in type 2 diabetes

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Dipeptydil peptidase-4 inhibitors in type 2 diabetes: A meta-analysis of randomized clinical trials

M. Monami, I. Iacomelli, N. Marchionni, E. Mannucci
Unit of Geriatric Medicine, Department of Critical Care Medicine, University of Florence and Azienda Ospedaliera Careggi, Florence, Italy
Nutrition, Metabolism & Cardiovascular Diseases (NMCD) May 2010; 20(4):224–235  http://dx.doi.org/10.1016/j.numecd.2009.03.015

Background and Aim

The role of Dipeptidyl Peptidase-4 (DPP-4) inhibitors in the treatment of type 2 diabetes is debated; many recent trials, which were not included in previous meta-analyses, could add relevant information.

Methods and Results

All available randomized controlled trials (RCTs), either published or unpublished, performed in type 2 diabetic patients with DPP-4 inhibitors, with a duration >12 weeks were meta-analyzed for HbA1c, BMI, hypoglycemia, and other adverse events. A total of 41 RCTs (9 of which are unpublished) was retrieved and included in the analysis. Gliptins determine a significant improvement of HbA1c in comparison with a placebo (−0.7 [−0.8:−0.6]), with a low risk of hypoglycemia. DPP-4 inhibitors show a similar efficacy in monotherapy and in combination with other agents. The risk of cardiovascular events and all-cause death with DPP-4 inhibitors is 0.76 [0.46–1.28] and 0.78 [0.40–1.51], respectively.

Conclusions

DPP-4 inhibitors reduce HbA1c, although to a lesser extent than sulphonylureas, with no weight gain and no hypoglycemic risk; further data are needed to assess their long-term safety.

 

 

Oral Dipeptidyl Peptidase-4 (DPP-4) inhibitors sitagliptin [1] and vildagliptin [2], which increase circulating levels of Glucagon-Like Peptide-1 (GLP-1), have recently been approved for use in type 2 diabetes; other molecules of the same class (such as saxagliptin and alogliptin) are under development.

The role of those new drugs in the treatment of type 2 diabetes is debated. The consensus algorithm of the American Diabetes Association and the European Association for the Study of Diabetes [[3], [4]], in its revised version [4], suggests limiting the use of GLP-1 receptor agonists and DPP-4 inhibitors only in some specific cases, without considering those agents in the mainstream (“Tier 1”) of the algorithm. Conversely, DPP-4 inhibitors are not even included as a second choice, although their use is contemplated in selected patients. The reasons for this exclusion are their perceived limited efficacy on HbA1c in comparison with other agents, their poorly defined safety profile, and their cost [[3], [4]].

Efficacy and safety need to be assessed through a comprehensive review of currently available clinical trials. Some detailed reviews of published studies have been recently published [[1], [2], [5]]; furthermore, some meta-analyses have been performed [[1], [6], [7], [8]]. However, currently available meta-analyses included only published studies, without any attempt at retrieving data from completed and publicly disclosed, although not formally published, clinical trials. Furthermore, several trials have been published in the last few months, increasing in a relevant manner the available data base for the assessment of the clinical profile of DPP-4 inhibitors.

The aim of the present study is to offer a comprehensive and updated synthesis of all available clinical data on the safety and efficacy of DPP-4 inhibitors.

The trial flow is summarized in Fig. 1, and the characteristics of the trials included in the meta-analysis are summarized in Table 1. Among the trials included, 32 were described in publications in peer-reviewed journals; results of 9 unpublished trials were disclosed on different websites. Furthermore, 10 unpublished trials, the results of which were undisclosed, could be identified (Table 2). Notably, results could be retrieved for the large majority of trials on currently available DPP-4 inhibitors (sitagliptin and vildagliptin), while only results of preliminary phase II studies were available for products currently under development (saxagliptin).

Thumbnail image of Figure 1. Opens large image

Figure 1

Trial flow diagram. RCT: randomized clinical trial.

Table 1Characteristics of the studies included in the meta-analysis.
Study (Ref.) Dose (mg/die) Comparator Add-on to Description of randomization Description of blinding Reporting of drop-out Intention-to-treat
Vildagliptin
Pan [33] 100 Acarbose None NA NA A Yes
Schweizer [28] 100 Metformin None NA NA A Yes
Rosenstock [34] 50–100 Rosiglitazone None NA NA A Yes
2329 [14] 50–100 Pioglitazone None NR NR NR Yes
Bolli [21] 100 Pioglitazone Metformin NA NA A No
  • Rosenstock [35]

  • 100

  • Pioglitazone

  • None

  • NA

  • A

  • A

  • Yes

  • 50–100

  • Placebo

  • Pioglitazone

  • NA

  • A

  • A

  • Yes

Dejager [36] 50–100 Placebo None NA NA A Yes
Scherbaum [37] 50 Placebo None NA NA A Yes
Mari [38] 50 Placebo None NA NA A NR
Scherbaum [39] 50 Placebo None NA NA A Yes
Pratley [27] 50 Placebo None NA A A Yes
Pi-Sunyer [40] 50–100 Placebo None NA NA A Yes
Ristic [41] 25–100 Placebo None NA NA NA Yes
1202 [14] 20–100 Placebo None NR NR NR Yes
Ahren [42] 50 Placebo Metformin NA NA A NR
Bosi [22] 50–100 Placebo Metformin NA NA A Yes
Garber [43] 50–100 Placebo Pioglitazone NA NA A Yes
Garber [19] 50–100 Placebo Glimepiride A NA A Yes
1302 [14] 100 Placebo Glimepiride NR NR NR Yes
Fonseca [20] 100 Placebo Insulin NA NA A Yes
1303 [14] 50–100 Placebo NR NR NR NR Yes
D’Alessio [44] 100 Placebo Metf./None NA NA A Yes
Sitagliptin
PN-036 [15] 50–100 Metformin None NA A A Yes
  • Scott [45]

  • 100

  • Rosiglitazone

  • Metformin

  • NA

  • NA

  • A

  • Yes

  • 100

  • Placebo

  • Metformin

  • NA

  • NA

  • A

  • Yes

PN-035 [15] 100 Pioglitazone Glim±Met NA NA A Yes
Nauck [17] 100 Glipizide Metformin NA NA A Yes
PN-028 [15] 25–50 Placebo/Glip. OAD/Insulin NR NR NR Yes
  • Scott [18]

  • 10–100

  • Glipizide

  • None

  • A

  • A

  • A

  • Yes

  • 10–100

  • Placebo

  • None

  • A

  • A

  • A

  • Yes

Nonaka [46] 100 Placebo None NA NA A Yes
Hanefeld [16] 25–100 Placebo None NA A A No
Raz [47] 100–200 Placebo None NA NA A Yes
Goldstein [23] 50–100 Placebo None NA A A Yes
Rosenstock [35] 100 Placebo Pioglitazone NA NA A Yes
Hermansen [24] 100 Placebo Glim±Metf NA NA A Yes
Goldstein [23] 50–100 Placebo Metformin NA A A Yes
Charbonnel [48] 100 Placebo Metformin NA NA A Yes
Aschner [49] 100–200 Placebo None NA NA A Yes
Raz [50] 100 Placebo Metformin A NA A Yes
PN-040 [15] 100 Placebo OAD/None NR NR NR Yes
PN-044 [15] 25–200 Placebo OAD/None NR NR NR Yes
Saxagliptin
Rosenstock [51] 2.5–40 Placebo None NA NA A Yes

NA: not adequate or not adequately reported; A: adequate; NR: not reported; glip.: glipizide; glim±metf: glimepiride and/or metformin; metf.: metformin; OAD: oral antidiabetic drugs; and SU/metf: sulfonylureas or metformin.

Table 2Characteristics of the unpublished and undisclosed studies.
Study # Patients planned Comparator Add-on to Trial duration (weeks) Design Randomization Study end datea
DPP-4 inhibitors
Vildagliptin
 NCT00368134 [52] 370 Voglibose None 12 PS Double blind June 2007
 NCT00396227 [52] 2665 Glitazones Metformin 12 PS Open label October 2007
Sitagliptin
 NCT00411554 [52] 310 Voglibose None 12 PS Double blind August 2007
Saxagliptin
 NCT00327015 [52] 1396 Placebo Metformin 52 PS Double blind November 2007
Metformin None 52 PS Double blind
 NCT00121641 [52] 460 Placebo None 24 PS Double blind August 2007
 NCT00374907 [52] 36 Placebo None 12 PS Double blind October 2007
 NCT00295633 [52] 555 Placebo Glitazones 24 PS Double blind October 2007
 NCT00121667 [52] 720 Placebo Metformin 24 PS Double blind August 2006
 NCT00313313 [52] 780 Placebo Glyburide 24 PS Double blind September 2007
 NCT00316082 [52] 365 Placebo None 24 PS Double blind November 2007

PS: parallel series.

aFinal data collection date for primary outcome measure.

The Begg adjusted rank correlation test (Kendall tau: −74; p=0.13) and the Egger regression approach (intercept, −2.81 [CI, –6.91–1.27]) suggested no major publication bias.

…………….

Table 3Moderators and outcome variables in individual studies included in the meta-analysis.
Study (Ref.) # Patients (ID/C) Comparator Trial duration (weeks) >Agea(years) Duration of DMa(years) HbA1c baselinea(%) HbA1c endpoint (%, ID/C) BMI baselinea(Kg/m2) BMI endpoint (Kg/m2)
DPP-4 inhibitors
Vildagliptin
 Pan [33] 440/220 Acarbose 24 52 1.2 8.6 7.2/7.3 26.1 26.3/25.2
 Schweizer [28] 526/254 Metformin 52 53 1.0 8.7 7.7/7.3 32.4 32.5/31.8
 Rosenstock [34] 459/238 Rosiglitazone 24 54 2.5 8.7 7.6/7.4 32.5 32.1/33.5
 2329 [14] 218/55 Pioglitazone 12 52 2.0 10.0 NR NR NR
 Bolli [21] 295/280 Pioglitazone 24 56 6.4 8.4 7.5/7.5 32.1 32.1/32.8
  •  Rosenstock [35]

  • 154/161

  • Pioglitazone

24 51 2.0 8.7
  • 7.0/7.3

29.4
  • 29.9/29.4

  • 292/161

  • Placebo

24 52 2.0 8.7
  • 7.5/7.3

29.3
  • 29.5/29.4

 Dejager [36] 472/160 Placebo 24 54 2.1 8.4 7.6/8.1 32.9 NR
 Scherbaum [37] 67/61 Placebo 52 64 3.3 6.6 6.6/7.1 30.2 NR
 Mari [38] 156/150 Placebo 52 63 2.6 6.7 6.5/6.9 30.2 NR
 Scherbaum [39] 156/150 Placebo 52 63 2.5 6.7 6.5/6.9 30.2 30.2/29.9
 Pratley [27] 70/28 Placebo 12 55 4.0 8.0 7.4/8.1 29.9 NR
 Pi-Sunyer [40] 262/92 Placebo 24 51 2.1 8.4 7.7/8.4 32.2 31.9/32.2
 Ristic [41] 221/58 Placebo 12 56 3.0 7.7 7.2/7.7 31.1 31.0/31.4
 1202 [14] 219/72 Placebo 12 59 NR 7.4 6.7/7. 24.0 NR
 Ahren [42] 56/51 Placebo 12 57 5.5 7.8 7.1/7.8 29.7 NR
 Bosi [22] 349/171 Placebo 24 54 6.2 8.4 7.5/8.4 32.7 32.5/31.7
 Garber [43] 260/138 Placebo 24 54 4.7 8.7 7.6/8.1 32.4 NR
 Garber [19] 264/144 Placebo 16 58 7.1 8.5 7.9/8.6 31.4 31.8/31.2
 1302 102/100 Placebo 12 60 9.0 7.9 6.8/7.9 NR NR
 Fonseca [20] 144/152 Placebo 24 59 14.7 8.4 7.9/8.2 33.1 33.8/33.1
 1303 [14] 178/61 Placebo 12 60 6.5 7.4 6.5/7.7 NR NR
 D’Alessio [44] 20/19 Placebo 12 55 3.5 6.7 6.3/6.3 32.3 NR
Sitagliptin
 PN-036 [15] 179/176 Metformin 30 53 4.5 8.9 8.1/7.6 31.9 NR
  •  Scott [45]

  • 94/87

  • Rosiglitazone

18 55 5.0 7.7
  • 7.0/6.9

30.2
  • 30.1/30.9

  • 94/92

  • Placebo

18 55 5.0 7.7
  • 7.0/7.5

30.1
  • 30.1/29.8

 PN-035 [15] 91/68 Pioglitazone 30 56 8.7 8.2 7.6/8.0 31.2 NR
 Nauck [17] 576/559 Glipizide 52 57 6.3 7.7 7.2/7.0 31.2 30.7/31.7
 PN-028 [15] 65/26 Placebo/Glip 54 68 13.5 7.7 7.0/7.6 NR NR
  •  Scott [18]

  • 595/123

  • Glipizide

12 55 5.0 7.9
  • 7.5/7.1

30.8
  • NR

  • 595/125

  • Placebo

12 55 5.0 7.9
  • 7.5/8.1

31.0
  • NR

 Nonaka [46] 75/76 Placebo 12 55 4.0 7.6 6.9/8.1 25.2 NR
 Hanefeld [16] 444/111 Placebo 12 56 3.7 7.7 7.4/7.8 31.7 NR
 Raz [47] 411/110 Placebo 18 55 4.6 8.0 7.7/8.2 32.1 31.8/32.3
 Goldstein [23] 179/176 Placebo 24 53 4.5 8.7 8.2/8.9 31.9 NR
 Rosenstock [35] 175/178 Placebo 24 56 6.1 8.1 7.2/7.8 31.5 32.6/31.5
 Hermansen [24] 222/219 Placebo 24 56 8.7 8.3 7.8/8.6 31.0 31.5/31.2
 Goldstein [23] 372/364 Placebo 54 53 4.4 8.8 7.1/7.8 32.2 NR
 Charbonnel [48] 429/206 Placebo 24 54 6.3 8.0 7.3/7.9 31.3 NR
 Aschner [49] 488/253 Placebo 24 54 4.4 8.0 7.3/8.2 30.5 30.3/30.5
 Raz [50] 96/94 Placebo 30 55 8.0 9.2 8.3/9.1 30.2 NR
 PN-040 [15] 352/178 Placebo 18 NR NR 8.7 NR NR NR
 PN-044 [15] 290/73 Placebo 12 NR NR 7.6 NR NR NR
Saxagliptin
 Rosenstock [51] 271/67 Placebo 12 53 1.0 7.9 7.1/7.7 31.0 30.7/30.7

ID/C: investigational drug/comparator; DM: diabetes mellitus; and glip.: glipizide.

aMean values.
Thumbnail image of Figure 2. Opens large image

Figure 2

Standardized differences (with 95% CI) of mean HbA1c at endpoint.

……………………….

DPP-4 inhibitors have been proposed as an alternative to currently available therapies (sulphonylureas, thiazolidinediones or insulin), mainly as an add-on treatment in patients failing with metformin monotherapy. However, even the most recent version of the ADA–EASD consensus algorithm does not consider these drugs a viable option, except for selected cases [4]. The reasons for exclusion from the main treatment algorithm are scarce efficacy, limited amount of available evidence and high cost. With respect to available evidence, it should be recognized that several trials, which had not been included in previous meta-analyses [6], have been recently published [[19], [21], [22], [23], [24], [25]]. Furthermore, there are a relevant number of unpublished trials, the results of which have been disclosed on different websites, and are therefore available. The decision to publish a trial is, in most instances, performed by the sponsor which has a specific interest in pursuing the greater safety and tolerability of the new drug. This bias is unfortunate and limits the reliability of this and other meta-analysis, often based only on data provided from manufacturers; however, the retrieval of all available information should always be attempted, although the possibility of including some information of poorer methodological quality should be taken into account. The overall amount of evidence from randomized clinical trials which can be retrieved using this comprehensive approach is relevant, and probably sufficient for a reliable assessment of the clinical profile of this new class.

The overall efficacy on HbA1c of DPP-4 inhibitors in placebo-controlled trials is similar to that reported in previous meta-analyses [[1], [6], [7], [8]]. However, the greater number of available studies allowed separate analyses of trials in which DPP-4 inhibitors were used either as monotherapy or as an add-on to other agents. In fact, most currently available hypoglycemic treatments show a smaller additional effect on HbA1c when used as an add-on to metformin, in comparison with monotherapy trials [26]. Conversely, DPP-4 inhibitors produce a similar placebo-subtracted reduction of HbA1c either in monotherapy or as an add-on to other agents. This pattern resembles that of other drugs specifically active on post-prandial glucose, such as acarbose or glinides [26]. In fact, DPP-4 inhibitors, as well as GLP-1 receptor agonists, show a relevant effect on post-prandial hyperglycemia. Although data on post-prandial glucose measured through self-monitoring were not available, the results obtained in many trials with meal tests [[7], [27]] support the hypothesis of a specific action of DPP-4 inhibitors on post-prandial hyperglycemia.

Based on the considerations reported above, DPP-4 inhibitors, when used in combination with other drugs, should not be expected to be less effective on HbA1c than other agents (such as sulphonylureas, thiazolidinediones or insulin). Unfortunately, only a small number of head-to-head comparisons with other drugs are currently available. The efficacy of DPP-4 inhibitors on HbA1c, either in monotherapy or in combination with metformin, appears to be somewhat smaller than that of sulphonylureas, and similar to thiazolidinediones; the only two available comparisons with metformin, both in monotherapy, one with vildagliptin [28] and one with sitagliptin (PN-036 on www.merck.com/mrl/clinical_trials/results.html) suggest a smaller effect on HbA1c. It should be considered that most trials are of a relatively short duration and it is possible that sulphonylureas, which are known to produce a less durable effect on glucose than other available agents, [29] could provide less favorable results in the long-term.

Taken together, the present results on efficacy do not support the use of DPP-4 inhibitors in monotherapy as an alternative to metformin. On the other hand, these drugs appear to be effective as add-on treatments in patients failing with metformin monotherapy, with a specific effect on post-prandial glucose, although the short-term efficacy of sulphonylureas on HbA1c could be greater than that of DPP-4 inhibitors.

With respect to body mass index, this meta-analysis confirms the neutrality of DPP-4 inhibitors [[1], [6], [7], [8]]. In direct comparison, DPP-4 inhibitors appear to have an advantage in this respect over thiazolidinediones.

GLP-1 stimulates insulin secretion and inhibits glucagon production in a glucose-dependent manner, i.e. its effects are blunted when blood glucose reaches the lower limits of the normal range [30]. Therefore, DPP-4 inhibitors are expected to reduce glycemia with a low hypoglycemic risk. In fact, DPP-4 inhibitors do not induce any additional risk, in comparison with a placebo, either in monotherapy or in combination with sulphonylureas or insulin. This confirms the results of a recent meta-analysis performed on patient-level data from randomized clinical trials with sitagliptin [31]. Interestingly, in the only trial performed in insulin-treated patients, vildagliptin reduced the incidence of hypoglycemia in comparison with a placebo [20]. The mechanisms underlying this phenomenon need to be further elucidated. As expected, DPP-4 inhibitors do not increase the incidence of hypoglycemic episodes when compared with insulin-sensitizing drugs; on the other hand, they show a markedly reduced risk of hypoglycemia in head-to-head comparisons with sulphonylureas. This difference, which could be partly determined by a marginally greater efficacy of sulphonylureas on HbA1c, is consistent with the different mechanisms of action of the classes of drugs.

No patient experienced severe hypoglycemia during vildagliptin therapy. Unexpectedly, episodes of severe hypoglycemia occurred in five patients treated with sitagliptin, either in monotherapy or in combination with metformin, in three different trials [[16], [17], [18]]. Notably, two of those trials [[16], [18]], although published, did not report those events but since those trials were included in the registration data for drug approval in the US, the information on severe hypoglycemia can be retrieved from the FDA website. Furthermore, episodes of severe hypoglycemia were not considered in a recent meta-analysis of trials with sitagliptin, although a greater number of such events had occurred in comparator groups, which included sulphonylureas [31]. It should also be considered that some of the trials did not report any information on severe hypoglycemia, raising the possibility of a selective reporting bias. The occurrence of cases of severe hypoglycemia with DPP-4 inhibitor monotherapy is difficult to explain on the basis of the current knowledge of the mechanism of action of those drugs, and deserved further investigation.

Among other expected adverse events, the previously reported increased incidence of some infections during DPP-4 inhibitor therapy [[6], [8]] is confirmed, with sitagliptin, but not vildagliptin, associated with nasopharyngitis, and with a nonsignificant trend toward an increased risk of urinary tract infections. These results are consistent with those of a recent meta-analysis on patient-level data from trials with sitagliptin, which included only a fraction of the studies summarized in the present meta-analysis, and which showed a similar trend toward the increase of risk of nasopharyngitis with the DPP-4 inhibitor, although it failed to reach statistical significance [31]. It should be considered that DPP-4 is involved in the interaction between immune cells and that it could therefore modulate immune responses [32]; however, there is no evidence from mechanistic studies that inhibition of DPP-4 with currently available agents has an immunodepressant effect. Consistently, treatment with DPP-4 inhibitors does not appear to increase the risk of infections other than nasopharyngitis and urinary tract infections.

The introduction of a new class of drugs which are designed for long-term use always raises some concerns about safety during prolonged treatment. The possibility of rare, unexpected serious adverse events, which could not be detected in registration trials, should be considered. The number of reported deaths in available trials is still very small; however, there is no evidence suggesting an increase in mortality during treatment with DPP-4 inhibitors. The number of cardiovascular events registered in clinical trials is remarkably greater, although still inadequate to detect minor differences between groups. The two drugs which have been more thoroughly studied (sitagliptin and vildagliptin) do not seem to be associated with increased cardiovascular risk; in fact, the actual risk is lower than with comparators, although differences do not reach statistical significance. In fact, available data do not rule out the possibility of an increase of cardiovascular risk up to 28%, or of a reduction up to 54%. It should be considered that the duration of the available trials (up to one year) is insufficient to detect any effect of treatment (either detrimental or beneficial) on atherogenesis.

The addition of unpublished trials does not substantially modify the estimates of efficacy of DPP-4 inhibitors. However, the retrieval of unpublished, but publicly disclosed, information allowed the identification of some potentially interesting phenomena, such as cases of severe hypoglycemia with DPP-4 inhibitor monotherapy, which could not be detected in published papers.

The limitations of the present meta-analysis should be recognized and considered when interpreting the results. The analysis was performed on summary data, therefore lacking the accuracy of assessment which can be obtained when using patient-level data. For the very same reason, a time-to-event analysis for categorial outcomes (including cardiovascular events) could not be performed; the proportion of patients experiencing at least one event during the trial, which was used for meta-analysis, approximates the actual incidence of events only if this incidence is assumed to be constant throughout the duration of the trial. Furthermore, the number of subject studies and the duration of trials performed is insufficient to draw any definitive conclusion on the long-term cardiovascular safety of DPP-4 inhibitors.

In conclusion, DPP-4 inhibitors are effective in reducing HbA1c and post-prandial glucose; when used as an add-on to metformin, they show a medium-term efficacy on HbA1c similar to thiazolidinediones and marginally inferior to sulphonylureas, with a reassuring short- and medium-term safety profile. In fact, the hypoglycemic risk is low, and there is no evidence of detrimental effects on cardiovascular disease. In comparison with sulphonylureas or insulin, which have been proposed as first-choice agents in patients failing with metformin [4], DPP-4 inhibitors exhibit, at least in the short- and medium-term, a lower hypoglycemic risk and a more favorable action on body weight, at the price of a somewhat smaller efficacy and higher cost. The choice of the drugs to be used as add-ons to metformin in monotherapy failure largely depends on the relative weight attributed to each of these three components (safety, efficacy on HbA1c and cost).

 

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Atherosclerosis Risk and Highly Sensitive Cardiac Troponin-T Levels in European Americans and Blacks: Genome-Wide Variation Association Study

Reporter: Aviva Lev-Ari, PhD, RN

Association of Genome-Wide Variation With Highly Sensitive Cardiac Troponin-T Levels in European Americans and Blacks

A Meta-Analysis From Atherosclerosis Risk in Communities and Cardiovascular Health Studies

Bing Yu, MD, MSc, Maja Barbalic, PhD, Ariel Brautbar, MD, Vijay Nambi, MD, Ron C. Hoogeveen, PhD, Weihong Tang, PhD, Thomas H. Mosley, PhD, Jerome I. Rotter, MD,Christopher R. deFilippi, MD, Christopher J. O’Donnell, MD, Sekar Kathiresan, MD,Ken Rice, PhD, Susan R. Heckbert, MD, PhD, Christie M. Ballantyne, MD, Bruce M. Psaty, MD, PhD and Eric Boerwinkle, PhD on behalf of the CARDIoGRAM Consortium

Author Affiliations

From the Human Genetic Center, University of Texas Health Science Center at Houston, Houston, TX (B.Y., M.B., E.B.); Deptartment of Medicine (A.B., V.N., R.C.H., C.M.B.), and Human Genome Sequencing Center (E.B.), Baylor College of Medicine, Houston, TX; Department of Epidemiology, University of Minnesota, Minneapolis, MN (W.T.); Division of Geriatrics, University of Mississippi Medical Center, Jackson, MS (T.H.M.); Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA (J.I.R.); School of Medicine, University of Maryland, Baltimore, MD (C.R.D.); National Heart, Lung, and Blood Institute and Framingham Heart Study, National Institutes of Health, Bethesda, MD (C.J.O.D.); Center for Human Genetic Research & Cardiovascular Research Center, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA (S.K.); Department of Biostatistics (K.R.), and Cardiovascular Health Research Unit & Department of Epidemiology (S.R.H.), University of Washington, Seattle, WA; and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington & Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.).

Correspondence to Eric Boerwinkle, PhD, Human Genetic Center, University of Texas School of Public Health, 1200 Herman Pressler E-447, Houston, TX 77030. E-mailEric.Boerwinkle@uth.tmc.edu

Abstract

Background—High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels.

Methods and Results—We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374;P=9.06×10−9) near the nuclear receptor coactivator 2 (NCOA2) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P=4.73×10−8) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P=0.004).

Conclusions—We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.

SOURCE:

Circulation: Cardiovascular Genetics.2013; 6: 82-88

Published online before print December 16, 2012,

doi: 10.1161/ CIRCGENETICS.112.963058

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