The general incidence and prevalence of CHD have declined in the United States in the last several decades, and this decline has been accompanied by a decline in CHD-related mortality. These trends have been attributed to better cardiovascular risk factor control and treatment during and after acute coronary syndromes over time, primarily with the use of statin medications, blood pressure management, and antiplatelet therapies. In contrast to CHD trends, the prevalence of diabetes has been steadily increasing over time, with the disease now affecting close to a third of older US adults (65 years or older). In addition, adults with diabetes are living longer. As a result, the burden of CHD attributable to diabetes is increasing. These changes in the epidemiology of diabetes and CHD have important implications. First, strategies that mitigate the risk of CHD in patients with diabetes will be of growing importance because heart disease is increasingly a complication of diabetes. Second, these strategies will be applied to an aging population with a high comorbidity burden and at higher risk for adverse effects of therapy.

Multiple studies have assessed the relationship between various glucose parameters—fasting glucose, 2-hour glucose during an oral glucose tolerance test, or HbA1c levels—and the risk of CHD in populations with and without diabetes. Most of this work suggests a continuous relationship between measures of glycemia and CHD risk, with higher glucose associated with higher CHD risk, even for glucose levels extending well into the normal range. Results from several studies and a meta-regression analysis have shown that in populations without diabetes, there is a graded relationship between initial fasting and postprandial glucose levels and subsequent occurrence of cardiovascular events over 12 years of follow-up. The association is apparent even at levels below diabetes thresholds. However, because HbA1c is the preferred test for monitoring blood glucose control during the chronic management of diabetes, data summarized here will be predominantly based on this glycemic parameter.

In the large prospective population study of Norfolk, in the United Kingdom, HbA1c and cardiovascular risk factors were assessed from 1995 to 1997, and cardiovascular disease events and mortality were examined during the next 6 to 8 years of follow-up. The relationship between HbA1c and cardiovascular disease and total mortality was continuous and apparent even among persons without diabetes. The risk was lowest among persons with HbA1c below 5% and was higher thereafter throughout the range of nondiabetic HbA1c levels up to 6.9%. Each one percentage point higher HbA1c above 5% was associated with a 20% to 25% higher relative risk for CHD among men and women in age- and risk-factor adjusted models. Moreover, when known diabetes status and HbA1c concentration were included in the same model, diabetes was no longer a significant independent predictor of CHD, suggesting that the higher risk of CHD in dysglycemic states may be mediated through hyperglycemia per se.

The prognostic value of HbA1c was also assessed in the Atherosclerosis Risk in Communities study of US adults without a history of diabetes or cardiovascular disease and with up to 15 years of follow-up. Similar to the observations from the Norfolk study, the risk for CHD was higher with higher HbA1c values in a continuous fashion independent of classic cardiovascular risk factors. When compared with study participants with HbA1c of 5% to less than 5.5% (the reference range), the hazard ratio (HR) for CHD was 23% higher in those with HbA1c of 5.5% to less than 6%, 78% for HbA1c of 6% to less than 6.5%, and 95% for HbA1c of 6.5% or higher. The findings were similar in parallel nested case–control studies among women (Nurses’ Health Study) and men (Health Professionals Follow-up Study). Compared with participants with HbA1c of 5.0% to less than 5.5%, those with an HbA1c of 6.0% to less than 6.5% had an adjusted relative risk CHD of 1.90 in women and 1.81 in men. Although the causal role of glucose in the development of CHD could not be evaluated in either of these epidemiologic studies, the findings suggest that HbA1c, even in the nondiabetic range, can be a useful independent marker of cardiovascular risk.

Although the association between HbA1c level and CHD may be prognostically important in individuals without diabetes, to understand the effect of glucose lowering on CHD risk, data in patients with diabetes must be examined. A prospective observational study of patients with type 2 diabetes enrolled in the United Kingdom Prospective Diabetes Study (UKPDS) examined the relationship between HbA1c and cardiovascular complications. They found that each 1% higher updated HbA1c was associated with a 14% higher relative risk for myocardial infarction (MI; Fig. 10.2 ). A meta-analysis of 13 prospective cohort studies of HbA1c and cardiovascular disease in persons with diabetes (type 1 or 2) suggested that chronic hyperglycemia is associated with a higher risk for cardiovascular disease. The pooled relative risk for cardiovascular disease associated with a 1% higher HbA1c was 1.18. In a subgroup of six studies conducted in patients with type 2 diabetes, a 1% higher HbA1c was associated with a 13% higher relative risk for CHD. The inclusion criteria for the meta-analysis did not specify pharmacologic treatment for diabetes; rather, these were observational studies involving patients on both medication and diet therapy. These results suggest a moderately higher cardiovascular risk with higher HbA1c in adults with diabetes. However, the meta-analysis relied on small studies with some suggestion of heterogeneity of associations between HbA1c and outcomes that could not be explored in detail.

Epidemiologic relationship between hemoglobin A1c and cardiovascular events.

Modified from Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405–412.

One large study analyzed data from the UK General Practice Research Database (GPRD) comprising 27,965 patients with T2D whose oral monotherapy was intensified to oral combination therapy, and 20,005 whose oral therapy was intensified to include insulin. The primary and secondary outcomes for the two cohorts were all-cause mortality and major cardiovascular events, respectively, over the mean follow-up of 4.5 years. HbA1c in the study was based on the mean of any values recorded between the therapeutic switch and death or date of censor. In combined cohort analyses, the HbA1c decile with a median value of 7.5% (interquartile range 7.5%–7.6%) was associated with the lowest mortality and the lowest progression to large-vessel disease among those without history of cardiovascular events. Higher and lower HbA1c values were associated with a higher risk, and the pattern of risk was U shaped. The findings from this study differ significantly from the graded, continuous epidemiologic relationships between HbA1c and cardiovascular outcomes in individuals without diabetes. In populations without diabetes, lower HbA1c values predict better outcomes without a clear threshold, but the data from patients with treated diabetes suggest that there may be a risk associated with achieving near-normal glycemia.

Results from a US retrospective cohort study reproduced the results of the GPRD analyses. Data from 71,092 patients with T2D age 60 years or older within the Kaiser Permanente Northern California system were analyzed to examine the associations between baseline HbA1c level and subsequent nonfatal complications (metabolic, microvascular, and cardiovascular events) and mortality. The investigators found a U-shaped relationship between HbA1c level and mortality similar to that observed in the GPRD analyses, with higher risk in those with HbA1c below 6% and HbA1c ≥10% in adjusted models. In contrast, however, the relationship between HbA1c and cardiovascular events was continuous with higher risk above HbA1c of 6%. Integrating all the outcomes together, the “optimal” HbA1c range identified by this observational study was 6% to 7.9%. A third study, this one involving all adults with T2D drawn from the Kaiser Permanente Southern California system, showed a U-shaped relationship between HbA1c and cardiovascular events, with HbA1c levels of 6% or lower and HbA1c levels greater than 8% associated with a higher risk of cardiovascular events. Whether or not low HbA1c levels are a marker of sicker patients or a mediator of harm remains highly debatable. Randomized clinical trials can test the effects of interventions directly on patient outcomes and may be able to provide greater insight into the effect of glucose lowering on CHD events.

Major randomized clinical trials of glucose-lowering interventions are summarized in Table 10.1 . The landmark trial in the study of patients with T2D that investigated the effect of a policy of more intensive glucose lowering versus usual care on microvascular and macrovascular outcomes was the UKPDS. The trial was begun in 1977 and the results were published in 1998. In this trial, 3867 patients with newly diagnosed T2D (median age 54) were randomized to a policy of intensive treatment with sulfonylureas (chlorpropamide, glibenclamide [glyburide in the United States], or glipizide) or with insulin, versus conventional therapy with diet alone. The median HbA1c level in the intensive group during the course of the trial was 7% versus 7.9% in the conventional arm. Three separate aggregate endpoints were studied over the 10 years of follow-up. The risk in the intensive group was 12% lower for any diabetes-related endpoint ( P = 0.03), which included both macrovascular and microvascular events as well as sudden death or death due to metabolic complications and non-vascular outcomes; not significantly lower for any diabetes-related death (−10%, P = 0.34); and not significantly lower for mortality (−6%, P = 0.44), compared with patients treated with diet only. The reduction in diabetes-related endpoints was driven by a 25% relative risk reduction in microvascular events, with the effect on MI and on stroke neither reaching statistical significance (16% lower, p = 0.052; 11% higher, p = 0.52). A subgroup of UKPDS patients who had overweight or obesity at trial entry (>120% ideal body weight) were randomized either to intensive therapy with metformin ( n = 342, median achieved HbA1c 7.4%) or conventional diet therapy ( n = 411, median achieved HbA1c 8%). In this subset of patients, any diabetes-related endpoint occurred among 98/341 (29%) patients randomized to metformin versus 160/411 (39%) randomized to conventional therapy ( P = 0.002), diabetes-related death occurred among 28/341 (8%) patients randomized to metformin versus 55/411 (13%) randomized to conventional therapy ( P = 0.017), and death from any cause occurred among 50/341 (15%) patients randomized to metformin versus 89/411(22%) randomized to conventional therapy ( P = 0.011). In addition, MI occurred in 39/341 (11%) of patients randomized to metformin versus 73/411 (18%) randomized to conventional therapy, which represented a significant 39% reduction in MI ( P = 0.01) ( Fig. 10.3 ). In summary, the UKPDS trial established that intensive glucose control reduces the risk of microvascular complications in patients with newly diagnosed T2D but suggested that macrovascular benefits may be confined to patients with overweight or obesity treated with metformin therapy.

Results of the UKPDS trial with respect to myocardial infarction and coronary deaths. NS, Nonsignificant.

Data from Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes [UKPDS 34]. UK Prospective Diabetes Study [UKPDS] Group, Lancet 1998;352:854.

After the UKPDS trial was completed, study participants and their clinicians were advised to lower levels of blood glucose as much as possible, and patients returned to community or hospital-based diabetes care according to their clinical needs without any attempts to maintain previously randomized therapies. In the 10-year posttrial monitoring study of patients who survived to the end of the UKDPS trial, HbA1c levels were no longer different between the original intensive and conventional arms (approximately 8% at the end of the posttrial monitoring period). In the sulfonylurea-insulin group, relative risk reductions for diabetes-related endpoints persisted, whereas significant risk reductions for MI (15%, P = 0.010) and mortality (13%, P = 0.007) emerged over time. In the metformin group, relative risk reductions persisted for any diabetes-related endpoint, MI (33%, P = 0.005), and mortality (27%, P = 0.002). These observations suggest a modest but sustained effect of intensive glucose lowering on cardiovascular events, but only after many years of follow-up. Whether the effect is confined to patients with newly diagnosed T2D or whether it reflects the long period of time required to significantly affect subsequent atherosclerotic outcomes is not entirely clear.

Even before the cardiovascular benefits of intensive glucose therapy emerged in the long-term follow-up of the UKPDS trial, guidelines recommended a target HbA1c level of 7% or less in most patients. This was primarily driven by the expectation of microvascular benefits, albeit with uncertainty over the effects on macrovascular events. To settle the questions about the role of intensive glucose therapy in T2D, three randomized controlled trials were specifically designed to examine the impact of targeting near-normal glycemia on cardiovascular risk. The HbA1c targets were set low because of the continuous epidemiologic relationship of glucose with cardiovascular risk, suggesting that perhaps much lower glucose levels need to be achieved for a significant benefit to emerge. The three trials all recruited participants with T2D who had either a history of or multiple risk factors for cardiovascular disease, thus ensuring adequate event rates to study the effects of the interventions. Participants were therefore quite distinct from patients in the UKPDS trial—they were older, had a longer duration of diabetes, and had a greater comorbidity burden.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial enrolled 10,251 patients (mean age 62, median baseline HbA1c 8.1%, 35% with history of prior cardiovascular event) to intensive glucose therapy (targeting HbA1c <6%, median achieved HbA1c 6.4%) versus conventional therapy (targeting HbA1c 7%–7.9%, median achieved HbA1c 7.5%). This trial was stopped prematurely after a mean follow-up of 3.5 years because of a higher mortality rate in the intensive therapy group compared with the control arm (HR 1.22, P = 0.04). The primary endpoint of the trial, major cardiovascular events, was not significantly reduced (HR 0.90, P = 0.16), although the rate of nonfatal MI was lower in the intensive therapy group (HR 0.76, P = 0.004). To date, analyses have not identified any clear explanation for the higher mortality risk associated with the intensive glucose-lowering strategy. In the intensive therapy group, a median HbA1c level of 6.4% was rapidly achieved and maintained, but subsequent post hoc analyses implicated factors associated with persistently higher HbA1c, rather than low HbA1c, as likely contributors to the higher mortality risk. In addition, rates of serious hypoglycemia requiring medical assistance were threefold higher in the intensive group than during standard therapy (10.5% vs. 3.5%, P < 0.001). Subsequent retrospective epidemiologic analyses of ACCORD have suggested, however, that severe hypoglycemia may not, in fact, account for the difference in mortality between the two study arms. Although hypoglycemia was associated with higher mortality within each randomized group, the risk of death was actually lower in participants experiencing hypoglycemia in the intensive arm than in participants with hypoglycemia in the standard arm. Other explanations, such as the particular medication combinations or undetected medication interactions, have also been proposed, but no particular medication class has been implicated thus far. In the end, the explanation for the higher mortality may never be known, but the findings have led to a growing recognition that intensive glucose lowering may be associated with some benefits but also important risks.

Subsequent follow-up of the participants from the ACCORD trial, up to the originally planned 5 years, showed persistently higher mortality rates in the intensive therapy group (HR 1.19, P = 0.02), but still lower rates of nonfatal MI (HR 0.82, P = 0.01). Given these findings, strategies used in the ACCORD study targeting an HbA1c below 6% are not recommended for patients with advanced T2D and established macrovascular complications or multiple risk factors for cardiovascular events.

At the same time the ACCORD study was published, results from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial also became available. In this trial, 11,140 patients with T2D (mean age 66, median baseline HbA1c 7.2%, 32% with history of major macrovascular disease) were randomized to intensive therapy (preferentially with the sulfonylurea gliclazide, targeting HbA1c ≤6.5%, with mean achieved HbA1c 6.5%) or to standard therapy (HbA1c goal according to local guidelines, mean achieved HbA1c 7.3%). After a median follow-up of 5 years, there was a reduction in the primary outcome of the study, which was a composite of microvascular and macrovascular events (HR 0.90, P = 0.01), and this was almost entirely driven by effects on intermediate markers of nephropathy. There was no significant effect with respect to major cardiovascular events (HR 0.94, P = 0.32), but also no increase in mortality (HR 0.93, P = 0.28) as was observed in the ACCORD trial. The ADVANCE investigators specifically examined various subgroups at potentially increased risk of death, but none were identified. Overall, the trial findings suggest a modest improvement in markers of microvascular complications with more intensive treatment versus usual care, but no significant benefit gained with respect to CHD endpoints.

One additional trial confirmed the lack of significant benefit of more intensive glucose lowering compared with usual care on major cardiovascular events, the Veterans Affairs Diabetes Trial (VADT). In this study of 1791 US military veterans with T2D (mean age 60, median baseline HbA1c 9.4%, 40% with history of cardiovascular events), participants were randomized to intensive glucose or standard therapy using a combination of agents, with a goal of achieving an absolute reduction in HbA1c of 1.5% in the intensive versus the standard arm. Median HbA1c levels achieved were 6.9% versus 8.4% in the intensive and standard groups, respectively, over a median follow-up of 5.6 years. There was no significant benefit with respect to the primary composite outcome, of cardiovascular events (HR 0.88, P = 0.14), the individual outcome of death from any cause, nor any difference with respect to most microvascular complications (no changes in retinopathy, new neuropathy, or doubling of creatinine, but reduction in some albuminuria-based endpoints). In this study of patients with advanced T2D, other cardiovascular risk factors were well controlled, and differences in HbA1c levels between the two groups were maintained. However, overall, the benefit of decreasing HbA1c from 8.4% to 6.9% was minimal, except in the progression of albuminuria, an intermediate marker with uncertain implications for long-term renal risk.

Multiple meta-analyses have followed the three randomized controlled trials described earlier to determine whether pooling results of existing studies will illuminate our understanding of these relationships ( Fig. 10.4 ). Although these analyses sometimes included studies of different intent (not necessarily glucose-lowering per se) and with variable patient characteristics (newly diagnosed vs. patients with advanced diabetes), they consistently show a modest, although significant, reduction of approximately 15% in the risk for nonfatal MI, but no impact on mortality or cardiovascular death. Moreover, all these studies show that the risk for severe hypoglycemia with intensive glucose therapy is more than doubled.

Relative risk and risk differences estimates (per 1000 patients over 5 years of treatment), with 95% confidence intervals ( CIs ), for the main study outcomes in the UKPDS, ACCORD, ADVANCE, and VADT.

A , Primary composite cardiovascular outcome. B , Cardiovascular mortality.

From Kelly TN, Bazzano LA, Fonseca VA, et al. Systematic review: glucose control and cardiovascular disease in type 2 diabetes, Ann Intern Med 2009;151:394–403.

Why have these large randomized controlled trials failed to show that intensive glucose lowering improves cardiovascular outcomes when the epidemiologic relationship between glycemia and cardiovascular events is so convincing? Many of the expectations for reduction in risk may have arisen from the effects of statin medications on major adverse cardiovascular events (MACEs) in early trials. A strong epidemiologic association between LDL cholesterol and CHD exists, and interventional studies show a 23% relative reduction in risk achieved for every 1 mmol/L (38 mg/dL) of LDL cholesterol lowering. Glycemia is a much weaker risk factor for CHD than cholesterol, but the assumption has been that some degree of cardiovascular (CV) risk reduction should result from glucose lowering. However, it is clear that the simple arithmetic (lower the level of a risk factor and cardiovascular events will naturally follow) does not apply in the case of glycemia. There may be a modest reduction in nonfatal MI, but overall disappointing results with respect to mortality and the composite of major cardiovascular events. Several potential explanations can be proposed: significant adverse effects of glucose therapy may counterbalance possible benefits, effects of glucose lowering applied in advanced diabetes may be too late to prevent atherosclerotic events, or the impact of glucose lowering may take a longer time to materialize than the 5 to 7 years assessed in most clinical trials. Regardless of the reasons, currently available therapies tested in these studies do not appear to constitute a “magic bullet” for the increased cardiovascular morbidity of diabetes.

Because one potential reason for the lack of benefit of intensive glucose lowering on cardiovascular disease is that it is applied too late to prevent atherosclerosis, it is worthwhile to examine studies that have investigated glucose lowering before diabetes actually develops or very early in the disease course (see also Chapters 3 and 4).

One such study was the Diabetes Prevention Program that randomly assigned 3234 persons without diabetes at high risk for diabetes (with elevated body mass index and fasting and postload glucose values) to intensive lifestyle therapy, metformin monotherapy, or placebo. Lifestyle intervention and metformin both significantly reduced the incidence of subsequent diabetes. In follow-up studies of the trial population, the lifestyle intervention also improved cardiovascular risk factors compared with metformin or placebo treatment, but the number of cardiovascular events was too small ( n = 89 at 3 years) to allow any meaningful examination of the differences among groups. After 10 years of follow-up of the Diabetes Prevention Program, the cumulative incidence of diabetes was still lowest in the former lifestyle intervention group. Cardiovascular disease risk factors improved in all three treatment groups, but averaged over all follow-up, systolic and diastolic blood pressure and triglyceride levels were lower in the lifestyle than in the other groups (even though the use of antihypertensive medications was less frequent). However, after 21 years of follow-up, neither metformin nor lifestyle intervention reduced major cardiovascular events (nonfatal MI, stroke, or CV death). The hazard ratio for metformin versus placebo was 1.03 ( P = 0.81) and for lifestyle versus placebo was 1.14 ( P = 0.34). The effect of the intervention was unchanged after the risk factor adjustment and was not significant for an extended cardiovascular outcome. These findings suggest that metformin and lifestyle interventions may not prevent CV disease in people with impaired glucose tolerance or early T2D. Importantly, participants in the study were aggressively treated with blood pressure–lowering medications and statin therapy; in addition, out-of-study metformin use increased over time, possibly limiting the apparent effect of the interventions.

In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), investigators examined the effect of postprandial glucose lowering on the incidence of diabetes in 1429 participants with impaired glucose tolerance, elevated fasting glucose, and overweight or obesity. As a secondary outcome, investigators examined the effect of intervention on major cardiovascular events and hypertension, although the trial was not adequately powered to answer that question. The participants were randomized to receive either acarbose or a placebo and were followed for a mean of 3.3 years. The trial reported an unanticipated 49% relative risk reduction ( P = 0.03) in major cardiovascular events (including revascularization procedures, congestive heart failure, and peripheral vascular disease in addition to the conventional major cardiovascular events) associated with acarbose therapy. This composite endpoint was primarily driven by an incredible 91% reduction in MI ( P = 0.02). However, in the course of the trial, almost one-quarter of participants discontinued participation prematurely (including significantly greater numbers randomized to acarbose) and other concerns about inconsistencies, failure to follow intention-to-treat analysis methods, and changes in the trial endpoints have been raised.

A subsequent Acarbose Cardiovascular Evaluation (ACE) study randomized 3272 patients with CHD and impaired glucose tolerance to acarbose and 3250 to placebo. After a median follow-up of 5 years, there was no significant difference in the primary outcome of nonfatal MI, stroke, CV death, hospital admission for unstable angina, and hospital admission for HF (HR 0.98, P = 0.73). No significant differences were seen between treatment groups for the secondary three-point composite CV outcome, or each of the components of the composites. Given these findings, acarbose does not appear to reduce the risk of major CV events in people with impaired glucose tolerance and CHD.

Investigators of the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial decided to test an alternative postprandial glucose-lowering approach with a short-acting insulin secretagogue, nateglinide, in addition to lifestyle modification. They randomized 9306 persons (mean age 64) with impaired glucose tolerance (baseline HbA1c 5.8%) at high risk for CV disease (24% had a history of CV events) to nateglinide or a placebo and followed participants for a median of 5 years. Nateglinide did not reduce the occurrence of the three coprimary outcomes—incident diabetes (HR 1.07, P = 0.05), cardiovascular outcome (death from CV causes, nonfatal MI, nonfatal stroke, or hospitalization for HF, HR 0.94, P = 0.43), or the extended CV outcome (which in addition included unstable angina or arterial revascularization, HR 0.93, P = 0.16). The trial results confirm the results of the ACE study and show that targeting postprandial hyperglycemia in participants with impaired glucose tolerance does not lead to CV benefits.

Another potential approach is to test whether early provision of basal insulin to normalize fasting plasma glucose may reduce CV outcomes in persons with mildly elevated glucose levels or early diabetes. This strategy does not specifically target postprandial hyperglycemia, but rather postulates that insulin, which has been demonstrated to have antiinflammatory effects, may be cardioprotective and may preserve pancreatic beta-cell function over time. The Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial randomized 12,537 people (mean age 64; 82% with early diabetes, 6% with new diabetes, and 12% with impaired fasting glucose or impaired glucose tolerance; median baseline HbA1c 6.4%; 59% with prior CV disease) to insulin glargine or standard care. The target in the insulin group was to achieve a fasting glucose level of 95 mg/dL or lower. After a median 6 years of follow-up, HbA1c levels were 6.2% versus 6.5% in the insulin and standard arms, respectively. The trial found no significant reduction in two coprimary outcomes: major CV events (HR 1.02, P = 0.63) and major CV events plus revascularization and HF (HR 1.04, P = 0.27). However, there was an increased risk of hypoglycemia with insulin therapy and some weight gain (+1.6 kg vs. −0.5 kg in the two groups). Although diabetes incidence was decreased (a finding of questionable clinical application), the trial findings were generally disappointing. The ORIGIN trial did not support the original hypothesis that normalizing glucose with early insulin therapy would lead to better CV outcomes.

These studies illustrate the impact of glucose lowering with a variety of different approaches in persons with prediabetes or early diabetes on cardiovascular outcomes. With the exception of the STOP-NIDDM study, which had important limitations and was not confirmed by the subsequent ACE trial, the studies to date have not supported the notion that glucose lowering is beneficial for CV outcomes at the prediabetic stage. Despite the epidemiologic association of glucose with CV events that extends well into the nondiabetic range, interventions targeting glycemia have thus far failed to deliver an effective strategy to reduce this risk.

Perhaps one of the most important lessons in CV risk reduction in T2D has been the growing recognition that the exact strategy used to reduce glucose may actually matter with respect to outcomes. The early UKPDS experience, albeit based on a small subgroup ( n = 342) of patients, has given metformin a preferred place in the antihyperglycemic regimen for T2D. In the subsequent glucose-lowering trials (ACCORD, ADVANCE, VADT), combinations of various medications, including insulin, had to be used to lower glucose levels, and there was no particular advantage to one strategy versus another. However, these glucose-lowering trials were not designed to test the effects of specific medications on outcomes.

Interest in the effects of specific antihyperglycemic medications on outcomes was boosted by the publication of a meta-analysis by Nissen and colleagues in 2007 that showed an adverse effect of the thiazolidinedione rosiglitazone on MI risk. In the analysis of 42 trials that was performed, there were 86 MI events in the rosiglitazone group compared with 71 in the comparator arm (including placebo, metformin, sulfonylurea, or insulin), resulting in an odds ratio of 1.43 ( P = 0.03). Although the methodology and the results of this meta-analysis have been debated, and some have noted no increase in risk associated with rosiglitazone use, there is no doubt that the study provided a cautionary tale for glucose lowering. Most important, the study suggested that even though a medication may reduce glucose levels, and thus appear to treat diabetes effectively, it may in fact increase the risk of clinical events that are the target of glucose lowering in the first place. After the rosiglitazone experience, however, the US Food and Drug Administration (FDA) mandated that novel glucose-lowering medications must have data that support their safety with respect to cardiovascular events before they are approved for use in diabetes.

The FDA guidance led to a proliferation of multiple large cardiovascular outcomes trials (CVOTs), which substantially differ in their design from glycemic control trials. CVOTs include participants with established atherosclerotic CV disease, or at high risk for CV events, to ensure accrual of sufficient events in a timely manner. The trials randomize participants to either receive placebo with other diabetes treatments per usual care, or to receive a specific drug being tested with other diabetes treatments as background therapy. Since clinicians are blinded to the intervention, they can adjust participants’ glucose-lowering therapies to achieve HbA1c levels according to standards of care. As a result, the study arms differ in the use of the specific study drug but generally achieve similar levels of glycemic control, albeit the active comparator arm is typically associated with reduction in HbA1c levels by ~0.3%.

Although CVOTs were mainly designed to rule out unacceptable cardiovascular risk, many were powered to estimate superiority as well as noninferiority. The results of these trials for SGLT-2 inhibitors and GLP-1 receptor agonists, two classes of antihyperglycemic medications with robustly proven efficacy for cardiovascular and kidney outcomes, are described in detail in Chapters x and y. Below, the evidence for the other antihyperglycemic drug classes including the FDA-mandated CVOTs with DPP-4 inhibitors is summarized (see also Table 10.2 ).

Metformin

Metformin, which works primarily by reducing hepatic glucose production, effectively reduces HbA1c levels, is weight neutral, and does not lead to hypoglycemia when used as monotherapy. It is also inexpensive, has a favorable safety profile, and may have potential benefit with respect to CV disease, based on the UKPDS substudy. However, despite the many advantages of metformin, the evidence generated from large CVOTs with SGLT2i and GLP1RA has not been matched by large-scale CVOTs with metformin, partly because of its pervasive and entrenched use as first-line therapy in T2D.

As noted above, existing data with respect to CV risk reduction with metformin are relatively sparse. In addition to the UKPDS substudy, only one prior randomized controlled trial was conducted on this subject. In the trial, 390 patients treated with insulin were randomized to receive either metformin or placebo as add-on therapy. The primary endpoint, an aggregate of microvascular and macrovascular outcomes, did not differ between the two groups after 4.3 years of follow-up (HR 0.92, P = 0.33), but there was a significant reduction in the secondary endpoint of macrovascular events (HR 0.60, P = 0.04). In addition, metformin use was associated with beneficial effects on body weight and insulin requirements.

In observational studies, metformin use (either as monotherapy or in combination with another oral agent) has been associated with reduced mortality, CV deaths, and CV events. Because metformin is generally the preferred initial agent for diabetes treatment and remains contraindicated in patients with advanced chronic kidney disease, patients who are not treated with this medication in an observational study may differ in important ways from those who are. These analyses either adjusted for potential confounders or matched patient populations for the propensity to be prescribed metformin versus another medication (usually a sulfonylurea). However, these investigations were observational in nature, so unmeasured factors may potentially still have contributed to the differences in outcomes.

Alongside the evidence that supports the safety and effectiveness of metformin, there are data that provide a less reassuring picture. Although the UKPDS substudy showed benefits of metformin in participants with overweight or obesity, the trial also reported an increased death rate in nonoverweight patients who took metformin and a sulfonylurea compared with those who took a sulfonylurea alone (relative risk 1.60, P = 0.04). Combined analyses of the two UKPDS studies did not reveal an increased risk for mortality in patients treated with this combination, and the increased mortality in the UKPDS substudy has not been fully explained. In a subsequent meta-analysis of 13 randomized controlled trials involving more than 13,000 patients with T2D, compared with other treatments, metformin therapy had no significant effect on the risk for mortality (relative risk 0.99 with wide 95% confidence intervals that could not exclude a 25% reduction or 31% increase in risk), CV mortality (relative risk 1.05), or rates of MI (relative risk 0.90 with 95% CIs that could not exclude 26% risk reduction or 9% harm). Similar findings were reported in a meta-analysis that specifically examined the effects of metformin with insulin compared with insulin alone in 23 trials with over 2000 participants. The study found that metformin added to insulin did not significantly change mortality risk (relative risk 1.30, with 95% CIs 0.57–2.99) or cardiovascular mortality risk (relative risk 1.70, with 95% CIs 0.35–8.30) but provided little reassurance with regard to each of these endpoints given the wide confidence intervals. Finally, in a meta-analysis of 301 clinical trials of nine major classes of glucose-lowering medications (metformin, sulfonylureas, thiazolidinediones, meglitinides, alpha-glucosidase inhibitors, DPP-4i, SLGT2i, GLP1RA, and basal insulin), there were no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with the odds of CV or all-cause mortality.

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