Outcome trials on the effects of glycemic control on cardiovascular risk in type 2 diabetes mellitus






Lawrence A. LEITER
MD, FRCPC, FACP
Division of Endocrinology and Metabolism, St. Michael’s Hospital,
and Departments of Medicine and Nutritional Sciences,
University of Toronto – CANADA

Outcome trials on the effects of glycemic control
on cardiovascular risk in type 2 diabetes mellitus

What do we know and what will we learn from the ongoing trials?


by L . A. Leiter, Canada



Evidence from several recent large, randomized, controlled trials suggests that improved glycemic control is associated with a reduced risk for cardiovascular disease (CVD), but that this benefit may be greater in individuals with a shorter duration of diabetes and with no prior history of CVD. Although an as yet unexplained increase in mortality was observed in the ACCORD (Action to Control CardiOvascular Risk in Diabetes) trial, this was not seen in the other studies. There is still no definitive evidence that any specific antihyperglycemic agent is associated with CV benefit, although there has been a suggested benefit attributed to metformin in the UKPDS (United Kingdom Prospective Diabetes Study), gliclazide-based therapy in ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), and pioglitazone in PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events). As a result of new Federal Drug Administration regulations, a large number of ongoing studies will provide us much additional information on specific agents. These trials will certainly provide important 3- to 5-year safety data on new agents, but may or may not show benefits of specific agents to reduce CV risk. Furthermore, any difference in benefits seen with the various agents may be related not to inherent differences among the drugs, but rather to the study design or to the population studied.

Medicographia. 2013;35:40-47 (see French abstract on page 47)



There is a considerable amount of evidence demonstrating that people with diabetes have an increased risk for cardiovascular disease (CVD), that it occurs at an earlier age, and that it is associated with worse outcome.1-4 What remains less certain is whether improved glycemic control can reduce the risk of CVD and whether any specific antihyperglycemic agent reduces the risk of CVD (through glycemic or other mechanisms).

The UKPDS (the United Kingdom Perspective Diabetes Study) randomly assigned subjects with newly diagnosed type 2 diabetes (n=4209) to intensive glycemic control (sulfonylurea or insulin) or conventional control (diet) with a smaller overweight subset randomized to intensive control with metformin. Significant reduction in microvascular complications were noted in the intensively treated group, but no reduction in macrovascular risk was observed, with the exception of the metformin group that showed benefit, albeit in a small group of just 342 subjects.5,6

The ACCORD (Action to Control CardiOvascular Risk in Diabetes) trial was a large, National Health Institute (NIH)–sponsored, randomized study of 10 251 subjects with type 2 diabetes designed to determine if 3 separate strategies could reduce CV events.7 The glycemic intervention was to compare intensive therapy to target normal glycated hemoglobin (HbA1c) levels (<6.0%) with standard therapy to target an HbA1c of 7.0%-7.9%. The study was stopped prematurely because of increased mortality (hazard ratio [HR] 1.22; 95% confidence interval [CI], 1.01-1.46; P=0.04) among the intensively treated group after a mean follow-up of just 3.5 years.8 At baseline, the ACCORD subjects had a mean age of 62.2 years, median duration of diabetes of 10 years, and mean HbA1c of 8.3%. About 35% had previous CV events and 35% were already on insulin. Despite the increased mortality, intensive glucose lowering was associated with a nonsignificant 10% reduction for the primary outcome (HR 0.90; 95% CI, 0.78-1.04; P=0.16). After multiple analyses, no definitive explanation has yet been identified to explain the surprising mortality finding. Achieving a lower HbA1c was not associated with increased mortality. In fact, the mortality was higher in those patients in the intensive group who did not achieve a lower HbA1c.9 Similar adverse effects on mortality have subsequently been reported over the originally planned five years of follow-up.10

The ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN modified release Controlled Evaluation) trial11 was a factorial, randomized, controlled international trial of 11 140 subjects with type 2 diabetes, with the glycemic intervention comparing a strategy of intensive blood glucose lowering (gliclazide-modified-release based) to target an HbA1c of 6.5% or less versus a strategy of standard glucose lowering (target HbA1c based on local guidelines). The primary outcome was a composite of macrovascular (CV death, non fatal myocardial infarction [MI] or stroke) and microvascular (retinopathy or nephropathy) events. At baseline, the mean age of the participants was 66 years, duration of diabetes was 8 years, and mean HbA1c was 7.5%. About 32% had a history of macrovascular disease and 10% had microvascular disease. The primary outcome was lower in the intensively treated group (18.1%) compared with the standard group (20%) with an HR of 0.90 (95% CI, 0.82-0.98; P=0.01). However, this difference was driven by the reduction in microvascular events (HR 0.86; 95% CI, 0.77-0.97; P=0.01) and not the incidence of major macrovascular events, which was reduced by a nonsignificant 6% (HR 0.94; 95% CI, 0.85-1.06; P=032). Given the increased mortality observed in the ACCORD trial, it is important to note that there was no increase (but rather a 12% decrease; P=0.12) in mortality among the intensively treated group in ADVANCE. Interestingly, however, subsequent analyses suggest a 25% relative reduction in CV mortality and 22% relative reduction in all-cause mortality for every 1% reduction in HbA1c.12 The results of ADVANCE were surprising to some given prior concerns that sulfonylureas may not have favorable effects on CVD risk.13 In fact, several studies have now shown that gliclazide has specific properties that may be associated with potential CV benefits. Firstly, gliclazide possesses a high selectivity for the pancreatic sulfonylurea receptor 1,14 suggesting optimal CV acceptability. Indeed, it has been hypothesized that the nonselective sulfonylureas, eg, glibenclamide, may have deleterious CV effects through their blockade of KATP channels in the heart and in vascular smooth muscle, which may impair ischemic preconditioning.15 Secondly, gliclazide also has antioxidant properties,16 suggesting that it may have other additional potential advantages in preventing the pathogenesis of CV complications. It has been shown that gliclazide significantly and independently reduces the progression of the carotid artery intima-media thickness compared with glibenclamide, thus suggesting that gliclazide can attenuate the progression of atherosclerosis.17





Finally, the VADT (Veterans Affairs Diabetes Trial) was a multicenter trial that investigated the effects of intensive glycemic control (target HbA1c of 6% or less) compared with standard control (HbA1c 8%-9%) on CV outcomes among 1791 participants with type 2 diabetes.18 The choice of treatments to achieve necessary glucose targets was at the discretion of the investigator. Blood pressure and lipids were treated equally and aggressively in both groups. The primary outcome of interest was a composite of major CV events (CV death, MI, stroke, congestive heart failure, and severe inoperable coronary artery disease), amputation for ischemia, and coronary or peripheral revascularization. At baseline, the mean age was 60 years, mean duration of diabetes 11.5 years, mean HbA1c 9.4%. About 40% had a macrovascular event history. After a mean follow-up of 5 years, there was no difference in the primary outcome between the groups (25.9% intensive versus 29.3% standard; HR 0.87; P=0.12) and importantly, no difference in mortality. No difference was found in any of the various CV secondary outcomes.


Figure 1
Figure 1. Meta-analysis of more intensive vs less intensive glycemic control.

This meta-analysis was undertaken with the goal of more precisely estimating the effects of more intensive vs less intensive glucose control on the risk of major cardiovascular events in subjects with type 2 diabetes and included the four major randomized controlled trials investigating these effects (ACCORD, ADVANCE, UKPDS, and VADT). A total of 27 049 participants and 2370 events contributed to the meta-analysis. Compared with less intensive glucose control, more intensive glucose control was associated with a 9% reduced risk of major cardiovascular events (hazard ratio [HR] 0.91; 95% confidence interval [CI), 0.84-0.99). This was attributed
largely to a reduced risk of myocardial infarction (relative risk reduction 15%; HR 0.85; 95% CI, 0.76-0.94). Mortality was not significantly different between the two
groups. Thus, the increased mortality associated with intensive glucose control that was observed in the ACCORD trial was not confirmed in this meta-analysis.
Abbreviations: ACCORD, Action to Control CardiOvascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; HbA1c, glycated hemoglobin; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial.
Adapted from reference 19: Turnbull et al. Diabetologia. 2009;52:2288-2298. © 2009, Springer-Verlag.



There have been several meta-analyses of these trials. Perhaps the most informative is that done by the Control Group.19 This analysis was performed by the investigators of these trials who were thus able to use a common end point definition and to truncate the results of the UKPDS to have a similar duration of follow-up as the other trials. Overall, intensive glycemic control was associated with significant reductions in major CV events (HR 0.91; 95% CI, 0.87-0.99), and myocardial infarctions (HR 0.85; 95% CI, 0.76-0.94) (Figure 1).19 There was no overall increase or decrease in all-cause mortality (HR 1.04; 95% CI, 0.90-1.20). Significant heterogeneity for CV events was observed based on history of macrovascular disease (Figure 2).19 A significant 16% reduction was observed in those in whom it was absent (HR 0.84; 95%CI, 0.75-0.94) while no effect (HR 1.00; 95% CI, 0.89-1.13) was observed in whom it was present. Other subgroups including age, baseline HbA1c, and duration of diabetes did not show any heterogeneity.


Figure 2
Figure 2. Effects of more intensive vs less intensive glycemic control on cardiovascular events by participant group.

Abbreviations: CI, confidence interval; HbA1c, glycated hemoglobin.
Adapted from reference 19: Turnbull et al. Diabetologia. 2009;52:2288-2298. © 2009, Springer-Verlag.



Another important recent publication was that of the post-trial follow-up of UKPDS.20 Patients were followed for an additional 10 years after completion of the randomized phase of the trial. Despite the fact that within-trial differences in HbA1c between intensive therapy and conventional therapy disappeared fairly quickly, those individuals who were originally assigned to the intensive therapy group continued to show vascular benefit, a phenomenon that has been called the “legacy effect” (Table I).20 A similar phenomenon had been previously described in patients with type 1 diabetes in the extended follow-up of the DCCT (Diabetes Control and Complications Trial) in which it was termed “metabolic memory.”21 Another lesson from the extended follow-up of the UKPDS is that the benefits of intensive glycemic control may take many years to translate into CV benefit, unlike lipid or blood pressure trials in which the benefits are typically seen within 3-5 years. Thus, there are several lessons from the CV outcome studies completed to date. Early intervention (such as what was done in the UKPDS) may be associated with greater vascular benefit and the benefits may be greater in those individuals without a prior history of CVD. Furthermore, it may take many years of good glycemic control to translate into CV risk reduction. These conclusions should be kept inmind when one considers the design of the ongoing clinical trials (as discussed below).


Table I
Table I. UKPDS: legacy effect of earlier glucose control.

After a median 8.5 years’ posttrial follow-up (intensive sulfonylurea/insulin therapy
vs conventional therapy). With more than 66 000 person-years of follow-up, this
large posttrial study showed that benefits of an intensive strategy to control blood
glucose levels in patients with type 2 diabetes were sustained for up to 10 years
after the cessation of randomized interventions. Benefits persisted despite the
early loss of within-trial differences in glycated hemoglobin levels between the
intensive-therapy group and the conventional-therapy group—a so-called legacy
effect. The trial showed the extended effects of improved glycemic control in
patients with newly diagnosed type 2 diabetes, some of whom were followed for
up to 30 years. The trial also showed that there were differences in outcomes
between an intensive glucose control strategy using sulfonylurea or insulin and
that using metformin in overweight patients.
Based on data from reference 20: Homan et al. N Engl J Med. 2008;359:
1577-1589.



Another key question is whether any specific antihyperglycemic agent reduces the risk of CVD. A substudy of the UKPDS looked at metformin in their overweight patients and, compared with the conventional policy, the use of metformin was associated with a 32% risk reduction in any diabetes-related end points, 42% risk reduction in diabetes-related deaths, 36% risk reduction in all-cause mortality, and 39% risk reduction in myocardial infarction, all of which were statistically significant.6 However, given the small number of study subjects in this group, these results, although suggestive of CV benefit of metformin, cannot be considered definitive. The PROactive (PROspective pioglitAzone Clinical Trial in macroVascular Events) study showed that overall there was no significant difference between the addition of pioglitazone versus placebo on top of background antihyperglycemic agents on a very broad composite primary end point consisting of death, nonfatal myocardial infarction, stroke, acute coronary syndrome, leg amputation, and coronary vascularization or leg revascularization.22 The so-called “principal secondary end point,” consisting of the more traditional major adverse CV events (nonfatal myocardial infarction, stroke, and CV mortality) was, however, reduced by a significant 12%. Thus, once again, the results can be considered suggestive, but not definitive for the CV benefit of an antihyperglycemic agent. In fact, the United States Food and Drug Administration (FDA) stated in 2009 that “no antihyperglycemic agent has been shown to significantly reduce the risk of vascular disease.”

The controversy as to whether rosiglitazone was associated with increased CV risk or not, largely spurred by the metaanalysis of Nissen and Wolski published in 2007,23 prompted the FDA in 2008 to publish a new guidance for industry on evaluating CV risk in new antihyperglycemic therapies to treat type 2 diabetes.24 They declared that as part of the approval process for diabetes medicines, a postmarketing trial would generally be necessary to definitely show that the upper bound of the two-sided 95% CI for the estimated risk ratio is <1.3. Largely as a result of this guidance, a large number of CV outcome trials are currently underway testing new antihyperglycemic agents.25,26

The results of the ORIGIN study (Outcome Reduction with an Initial Glargine INtervention),27 testing the effects of insulin glargine on CV outcomes, were recently published.28 This trial included 12 537 subjects 50 years of age or older with either early type 2 diabetes or prediabetes who were randomly assigned to receive titrated basal insulin glargine with a targeted fasting plasma glucose <5.3 mmol/L or standard of care. Overall, the glargine had a neutral effect on the two coprimary composite CV end points. There are a large number of ongoing clinical trials utilizing the incretin agents (glucagon-like peptide-1 [GLP-1] receptor agonists and dipeptidyl peptidase-4 [DPP-4] inhibitors) (www. clinicaltrials.gov). There are a number of potential mechanisms by which the incretins can reduce CV risk.26 Firstly, they have beneficial effects on glycemia, body weight (more so with the GLP-1 receptor agonists than DPP-4 inhibitors), blood pressure, and lipid profile, especially postprandial lipemia. In addition, there is evidence to suggest that these drugs may have other, more direct, cardiac benefits. Although much of this is based on animal models of diabetes, there are now limited human studies that have also suggested that the incretins may also improve cardiac function and minimize ischemic damage. Although it might be expected that the GLP-1 receptor agonists which raise levels of GLP-1 to a greater degree may be associated with greater potential CV benefit, the DPP-4 inhibitors also increase a number of other substrates, including stromal cell-derived factor-1 α, that may also directly or indirectly regulate CV function, and thus may have other mechanisms by which they can reduce CV risk.

There are suggestions from clinical trials completed to date that the use of the incretin agents may, indeed, be associated with reduced CV risk. In the registration trials with the DPP-4 inhibitors linagliptin, saxagliptin, and sitagliptin, as well as the GLP-1 receptor agonists exenatide and liraglutide, the use of these agents was associated with a 30%-57% reduced risk of CV events relative to comparator. Although the number of CV events in each of these trials was not large, the consistency of the results is promising. Furthermore, recent meta-analyses by Monami and colleagues,29,30 looking at the various trials with GLP-1 receptor agonists and DPP-4 inhibitors versus all comparators as well as placebo, also suggested CV benefits. These studies cannot, however, be considered definitive.

There are four ongoing clinical trials with DPP-4 inhibitors. Three of them are comparing DPP-4 inhibitors with placebo: the EXAMINE (EXamination of cArdiovascular outcoMes: alogliptIN vs standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome) study with alogliptin, SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus—Thrombolysis InMyocardial Infarction 53)with saxagliptin, and TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) with sitagliptin. They are being conducted in somewhat different study populations. EXAMINE includes about 5400 subjects with a recent acute coronary syndrome, SAVOR-TIMI 53 includes about 16 500 subjects (about two-thirds of whom have prior history of CVD and the others two or more CV risk factors apart from their diabetes), and TECOS includes about 14 000 patients with established CVD. The CAROLINA (CARdiOvascular outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes) study is the only one of the incretin trials that has an active comparator. The potential CV benefit of linagliptin is being compared with the sulfonylurea glimepiride in about 6000 patients with known CVD or two or more risk factors.

There are also four ongoing clinical trials with GLP-1 receptor agonists. All are compared with placebo as add-on to background antihyperglycemic agents. ELIXA (Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010) is utilizing lixisenatide, EXSCEL (EXenatide Study of Cardiovascular Event Lowering) is using once-weekly exenatide, LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results) is using liraglutide, and REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) is using dulaglutide. While ELIXA is being carried out in patients with a recent acute coronary syndrome, the other studies are being done in individuals with known vascular disease or multiple risk factors in addition to diabetes. The sample sizes of these trials are expected to range from 6000-10 000.

Treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitors has been associated with reductions in blood pressure and body weight in addition to glucose lowering,31 and therefore their use may also be expected to potentially reduce CV risk. The CANVAS study (CANagliflozin cardioVascular Assessment Study) is looking at the effects of canagliflozin in about 4300 individuals with type 2 diabetes and a history of or who are at high risk for CVD, and C-SCADE 8 (BI 10773 Add-On to Usual Care Compared With Usual Care Alone in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk) is comparing empagliflozin with usual care alone in patients with type 2 diabetes and known vascular disease.

The dual peroxisome proliferator-activated receptor agonist aleglitazar has been shown to have beneficial effects on both glucose levels and lipids. In the 16-week SYNCHRONY study (Effect of the Dual Peroxisome Proliferator-Activated Receptor- α/γAgonist Aleglitazar on Risk of Cardiovascular Disease in Patients With Type 2 Diabetes),32 the 0.15-mg dose was associated with a 0.85% reduction in HbA1c, 43.4% reduction in triglycerides, 15.5% reduction in low-density lipoprotein cholesterol, and a 20.7% increase in high-density lipoprotein cholesterol. Therefore, in a phase 3 study called ALECARDIO (Cardiovascular Outcomes Study to Evaluate the Potential of Aleglitazar to Reduce Cardiovascular Risk in Patients With a Recent Acute Coronary Syndrome (ACS) Event and Type 2 Diabetes Mellitus), the addition of aleglitazar 0.15 mg versus placebo added to standard of care is being compared in about 6000 subjects with diabetes post–acute coronary syndrome.

Finally, in the STOP NIDDM trial (Study TO Prevent Non-Insulin- Dependent Diabetes Mellitus),33 acarbose was associated with a significant reduction in CV events and new-onset hypertension, although the number of events was very small. The ongoing ACE (Acarbose Cardiovascular Evaluation) study is testing the addition of acarbose versus placebo in patients with established coronary heart disease or acute coronary syndrome in about 7500 subjects with impaired glucose tolerance over the age of 50.

Conclusion
There is evidence from large randomized controlled trials that improved glycemic control may be associated with a reduced risk for CVD, but that this benefit may be greater in individuals with a shorter duration of diabetes and with no prior history of CVD. At the same time, there is no definitive evidence that any specific antihyperglycemic agent is associated with CV benefit, although there has been a suggestion of benefit for metformin in the UKPDS, gliclazide-based therapy in ADVANCE, and pioglitazone in PROactive.

As a result of new FDA regulations, a number of ongoing studies will provide us much additional information on specific agents. These trials will certainly provide important 3- to 5-year safety data on new agents, which should be sufficient to rule out CV harmandmay also provide data on unanticipated safety issues (eg, the neutral effect of glargine on cancer observed in ORIGIN). The exposure will likely not be sufficient (not enough subjects entered and/or inadequate duration of follow-up) to rule out less common adverse effects. These studies may or may not show benefits of specific agents to reduce CV risk. Furthermore, any difference in benefits seen with the various agents may be related not to inherent differences among the drugs, but perhaps to differences in the duration of follow-up, protocol design, comparator, or study population (presence versus absence of known CVD). These studies may also provide other novel information about diabetes. Finally, although the cost of these large studies is significant, this does not appear to have hampered the development of new antihyperglycemic agents, notwithstanding initial concerns to the contrary.

Acknowledgment: The editorial assistance of Hwee Teoh, PhD is greatly appreciated.



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Keywords: antihyperglycemic agent; cardiovascular disease; DPP-4 inhibitor; GLP-1 receptor agonist; glycemic control; insulin; metformin; SGLT2 inhibitor; sulfonylurea; type 2 diabetes mellitus