Managing Chronic Coronary Artery Disease in Patients with Diabetes

Lifestyle Intervention

The basis for risk reduction in patients with diabetes, as in nondiabetic subjects, is lifestyle intervention. Lifestyle intervention has been shown to prevent the development of CVD in primary prevention, but the benefit of lifestyle intervention including diet, physical activity, and weight loss is less well established in patients with existing chronic CAD. However, general aspects are covered by various guidelines such as the American Heart Association (AHA), American Diabetes Association, and European Society of Cardiology (ESC)/European Association for the Study of Diabetes (EASD) : these include recommendations for smoking cessation, ideally guided by structured advice or a specially developed program, as well as a Mediterranean diet with fruit, vegetables, and olive oil. To what extent weight loss reduces CV risk in patients with existing CAD has not been established. Due to the lack of evidence, current guidelines do not recommend supplementation with vitamins or micronutrients to reduce CV risk in this population. With respect to physical activity, moderate to vigorous physical activity, at least 150 min/week, is recommended to prevent vascular disease in patients that can exercise.

Glucose Control

In patients with type 2 diabetes mellitus intensive glucose control can reduce microvascular complications such as retinopathy or nephropathy. The effect on macrovascular events in patients with diabetes and chronic CAD is less well established. The United Kingdom Prospective Diabetes Study (UKPDS) was the first large study examining the effect of an intensive glucose control regimen on macrovascular events; the study compared conventional versus intensive therapy in 3867 patients with newly diagnosed type 2 diabetes and no history of CVD. Intensive therapy significantly reduced microvascular events such as nephropathy and retinopathy, but after a follow-up of 10 years only a nonsignificant reduction in macrovascular events such as MI was found. Only after an additional 10 years of follow-up did the initial intensive therapy translate into a significant decrease in macrovascular events. These results, albeit difficult to interpret because of the nature of this nonprespecified follow-up analysis, suggested that early intervention with a stringent glucose control strategy may eventually reduce macrovascular events in patients with diabetes without a history of CV disease.

Over the last decade various CV outcome trials in high-risk patients with diabetes have assessed the effect of a tight glucose control strategy compared with standard therapy on the incidence of CV events. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial examined whether an intensive glucose control with the HbA _1c target of less than 6.5% (46 mmol/mol) compared with standard therapy with an HbA _1c target of less than 7.5% (58 mmol/mol) reduced CV events in 10,251 patients with type 2 diabetes. A very aggressive glucose-lowering approach with various combination therapies including insulin and up to 5 oral antidiabetic drugs was chosen to bring the HbA _1c value to target. After 3.5 years the study was stopped prematurely due to a higher mortality in the intensive treatment arm. The primary endpoint of MI, stroke, and CV death was not significantly different between groups, despite a significant difference in HbA _1c of 7.5% in the standard therapy and 6.4% in the intensive glucose-lowering group. Increased mortality associated with intensive therapy was mainly observed in subjects with multiple CV risk factors, as well as in those subjects in whom HbA _1c lowering was very difficult.

The Action in Diabetes and Vascular Disease: PreterAx and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial included 11,140 patients and tested whether intensive glucose-lowering therapy with an HbA _1c target below 6.5% compared with standard therapy with an HbA _1c target according to local guidelines might reduce the primary combined endpoint of macrovascular (MI, stroke, or CV death) and microvascular (nephropathy or retinopathy) events. The therapeutic algorithm in this trial to reduce HbA _1c levels was less aggressive than in ACCORD, and after a follow-up of 4.3 years the two groups significantly differed with an HbA _1c of 7.3% versus 6.5%. This HbA _1c difference translated into significant 10% RR reduction for microvascular events ( p =0.013) but did not have a significant effect on the combined macrovascular endpoint. In contrast to ACCORD, there was no increase in mortality in this study.

The third trial, the Veterans Affairs Diabetes Trial (VADT), was a smaller trial randomizing 1791 patients with type 2 diabetes to intensive or standard glucose therapy with an HbA _1c target of 6.0% in the intensive group and 9.0% in the standard group. Despite a highly significant difference in glucose control with an HbA _1c of 8.5% in the standard group and 7.0% in the intensive group, no reduction of the combined primary endpoint of MI, stroke, CV death, CHD intervention, or amputation was achieved. Patients in these three studies had a long duration of diabetes and a large proportion had preexisting CVD and a high number of associated risk factors such as hypertension or dyslipidemia. A meta-analysis of ACCORD, ADVANCE, and VADT suggested that an HbA _1c reduction of 1% may lead to a 15% RR reduction in nonfatal MI but no benefit on stroke and all-cause mortality. Further analyses suggested that patients with a short duration of diabetes, no history of CVD, and low HbA _1c at baseline may still benefit from an intensive glucose-lowering therapy. However, lower HbA _1c targets should only be achieved without increasing the risk for hypoglycemia; in addition, weight gain and uncontrolled combination therapy of oral antidiabetic medication and/or insulin should be avoided.

Hemoglobin A _1c Targets

Current guidelines from various diabetes and heart professional associations favor an individualized strategy for HbA _1c target based on age, history, duration of diabetes, and presence of CVD as well as other comorbidities and the risk of hypoglycemia. In general, a near-normal HbA _1c level below 7% (53 mmol/L) should be achieved to decrease microvascular complications. A tighter blood glucose control with an HbA _1c target less than 6.5 might be appropriate in selected subjects with a short duration of diabetes and a low risk of hypoglycemia. For older patients with diabetes as well as those with preexisting CV disease, less stringent HbA _1c lowering to a target less than or equal to 8% is recommended.

Glucose-Lowering Agents

Most guidelines recommend metformin as the first-line therapy for glucose-lowering because of its weight-loss effect and low risk of hypoglycemia. In addition, data from the UKDPS suggested a beneficial effect on CV outcome: in the subgroup of 753 overweight patients metformin significantly reduced the risk of MI versus conventional therapy by 39%. Such data were confirmed in two meta-analyses suggesting reduced CVD in patients treated with metformin. The majority of patients with type 2 diabetes require combination therapy to achieve glycemic targets. Metformin can be combined with any other antidiabetic drug including sulfonylureas (SUs), α-glucosidase inhibitors, pioglitazone, glucagon-like peptide 1 (GLP1)-receptor agonists, dipeptidyl peptidase 4 (DPP4)-inhibitors, sodium-glucose cotransporter-2 (SGLT2)-inhibitors, and insulin. Of note, any of these agents can be used as monotherapy in subjects in whom metformin is contraindicated or not tolerated.

The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE) analyzed whether addition of pioglitazone or placebo to baseline antihyperglycemic therapy has an effect on CV events. It showed no benefit on the combined primary endpoint of all-cause mortality, nonfatal MI, acute coronary syndrome (ACS), coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI), stroke, major leg amputation, or major leg revascularization. However, because this endpoint included non-CV composites such as reduction of leg amputation or revascularization—events that are unlikely to be reduced by medical therapy alone—a principal secondary endpoint was predefined. Pioglitazone significantly reduced this secondary outcome of MI, stroke, and CV mortality (HR 0.84; 95% CI, 0.72–0.98; p = 0.027) versus placebo. For another thiazolidinedione, rosiglitazone, no such effects have been observed. However, PROACTIVE showed an increase in heart failure, a class effect of these insulin-sensitizing agents. The Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM) showed a 49% RR reduction of CV events by acarbose versus placebo in patients with impaired glucose tolerance. Still, this was not the primary endpoint of this study and the study population did not have manifest diabetes. Therefore, the effect of acarbose on CV events is currently being tested in a large CV outcome trial in China, the Acarbose Cardiovascular Evaluation (ACE), enrolling patients with established type 2 diabetes.

Conflicting data exist with respect to the effects of SUs on CV events. The University Group Diabetes Program (UGDP) was the first study conducted in the 1960s that raised concerns about the safety of the first-generation SU tolbutamide. It showed a significant increase of overall and CV mortality in subjects receiving tolbutamide versus placebo. Still, this study was not designed or powered to test CV safety, and it has been criticized because the results were not corrected for higher preexisting CV risk in the tolbutamide group versus the placebo group. In addition, it is unclear to what extent the findings of this study can be applied to current clinical practice, given the fact that modern diabetes management including a multifactorial approach was not applied. It is also unclear whether these findings apply to modern SUs. In contrast to the findings in UGDP, UKPDS demonstrated that tolbutamide, glyburide, and glimepiride were not associated with adverse CV events. Other trials of longer-term duration also indicated that SUs are not associated with an increased CV risk when compared head-to-head with other agents, such as thiazolidinediones, DPP4-inhibitors, metformin, or GLP1-analogs. In addition, a large meta-analysis of 40 randomized controlled trials of glucose-lowering drugs found no increased risk of macrovascular events and all-cause mortality in second-generation SUs versus other oral agents or placebo. However, most of the trials included in this meta-analysis were not designed or powered to examine CV events. Moreover, the inconsistent reporting of adverse events and the short-term duration of these studies make it difficult to make final conclusions on the effect of SUs on CV events. Interestingly several observational studies have shown higher rates of all-cause and CV mortality associated with SU monotherapy or in combination with metformin compared with metformin monotherapy, but this was not confirmed in other studies. Overall, there is an absence of conclusive outcome data on the impact of SUs on CV events. The ongoing Cardiovascular Outcome Trial of Linagliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA) trial may shed more light on this issue.

Newer Treatment Options

Over the last years, multiple novel antidiabetic therapies have come to the market and the Food and Drug Administration (FDA) and Europe, the Middle East, and Africa (EMEA) requirements have made it mandatory for the industry to perform CV outcome trials to show safety. The FDA required a demonstration of noninferiority of these agents versus placebo with regard to CV events, utilizing a noninferiority margin of 1.3. This has led to carrying out and publishing results of large CV outcome trials in patients with type 2 diabetes and high CV risk. So far, three large CV outcome trials with DPP4-inhibitors, three large trials with GLP1-receptor agonist, and the first outcome trial for an SGLT-2-inhibitor have been published. The three DPP4-inhibitor trials, SAVOUR (saxagliptin), EXAMINE (alogliptin), and TECOS (sitagliptin), examined in a high-risk population of patients with a long duration of diabetes, prior CVD, and/or various risk factors whether the addition of the given drug increases CV risk versus placebo ( Table 24.1 ).

These trials were designed as noninferiority trials and did not show an increased CV risk of any of these DPP4-inhibitors. Of note, they were designed to achieve glycemic equipoise between groups, not to examine whether a difference in HbA _1c levels in the two treatment arms translates into a reduction of CV events. Interestingly, SAVOUR-TIMI showed a significant increase in hospitalization for heart failure in patients treated with saxagliptin versus placebo, whereas such a significant signal was not found in the two other trials of DPP4-inhibitors. Three similar trials were performed with GLP-1 receptor agonists. The ELIXA trial confirmed CV safety of lixisenatide versus placebo without showing a portenial benefit with respect to CV events.

In contrast, the LEADER cardiovascular outcome trial testing the effect of the long acting GLP1 receptor agonist Liraglutide showed a significant reduction of the primary endpoint of cardiovascular death, myocardial infarction and stroke and the results were mainly driven by a significant reduction of cardiovascular death. In addition Liraglutide reduced overall mortality in a population of 9340 patients with diabetes and high cardiocardiovascular risk.

Most recently SUSTAIN 6 was reported. This study examined once weekly Semaglutide in 3297 patients with type 2 diabetes and high cardiovascular risk. Compared to placebo Semaglutide significantly reduced the combined cardiovascular endpoint of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Interestingly this result was mainly driven by a significant 39% reduction of non-fatal stroke. The trend for myocardial infarction was statistically not significant NEJM 2016 inline). A similar trial with the GLP-1 receptor agonist lixisenatide versus placebo confirmed this drug’s safety, without showing a potential benefit with respect to CV events.