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The Burden of Cardiovascular Disease in Patients with Diabetes
Brooke Hudspeth, PharmD, CDE
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The Burden of Cardiovascular Disease in Patients with Diabetes

Brooke Hudspeth, PharmD, CDE
Numerous studies have demonstrated the link between elevated glucose levels and ASCVD. Furthermore, the research shows that control of this risk factor positively impacts ASCVD. The Framingham Heart Study was the first study to show that patients with T2D are more susceptible to heart disease. The study reported a 2-to-3–fold increased risk of atherosclerotic disease in T2D.48 In a retrospective look at the achieved A1Cs in the United Kingdom Prospective Diabetes Study (UKPDS), a 14% reduction in the risk of MI for each percentage point decrease in A1C in patients with recent-onset T2D was seen.49 In the UKPDS, early intensive treatment with sulfonylureas or insulin versus diet alone showed that intensive therapy is associated with a 25% lower risk of developing macrovascular complications. There was a trend toward a reduction of MI in the intensive therapy group at 10 years after follow-up, but it was not statistically significant.50 In another arm of the UKPDS, patients with obesity and T2D were randomized to receive either metformin or conventional therapy (primarily diet alone). In this arm, there was lower all-cause mortality in the metformin-treated group.51 Although the median A1C level between the groups was 7.4% (metformin) versus 8.0% (control), metformin also lowered diabetes-related deaths and all-cause mortality at the 10-year follow-up with newly diagnosed patients.51 Metformin was less effective in lowering A1C levels compared with intensive regimens with sulfonylurea or insulin. However, it was associated with a lower risk of death and stroke as well as lower risks for hypoglycemia.51 Note that this was before statins, tighter hypertension control, and frequent aspirin use in patients with CAD.

In contrast to the UKPDS, the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Veterans Affairs Diabetes Trial (VADT), and the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) failed to show an overall reduction in cardiovascular events with aggressive glucose control.52-55 The authors noted that this could be attributed to a longer mean duration of T2D or a shorter length of follow-up.40 After 3.5 years, the ACCORD trial showed significant higher all-cause mortality in patients with T2D who received more intensive glycemic control compared with conventional controls. As a result, the glycemic control portion of the trial was stopped early.52 A detailed scrutiny of the ACCORD data reveals that higher A1C levels predicted increased risks for death in the intensive arm of the trial. Most of the deaths occurred in the subgroup of patients whose A1C levels remained high despite intensive glycemic control.56 Additionally, in a subgroup of patients who did not have documented CVD at baseline, a subanalysis showed that intensive glycemic control in this group was associated with a reduced risk for cardiovascular death as well as nonfatal cardiovascular events.40,57

The VADT compared intensive and standard treatment in patients with T2D. After a median follow-up of 5.6 years, the intensive control group achieved an A1C of 6.9% compared with 8.4% in the control group. There was no statistically significant difference in the incidence of major cardiovascular events.53 However, in a subset analysis, patients without significant coronary atherosclerosis had a decrease in cardiovascular events with intensive therapy.55 Both the VADT and ACCORD studies suggest that intensive glucose control may reduce cardiovascular events in patients who have a shorter duration of T2D as well as in those who do not have any significant preexisting CVD.51,58

The ADVANCE trial looked at patients after 5 years of intensive versus standard glycemic control. The results of the ADVANCE trial were similar to ACCORD and VADT. In patients who did not have established CVD, the rate of microvascular and macrovascular events was significantly lower in the intensive glucose control group.59 ACCORD, ADVANCE, and VADT also had a shorter study duration than the UKPDS, and most of the patients had a longer duration of T2D.60

The benefits of early glycemic control may only be seen after several years.40 Trials with longer durations, such as the UKPDS, Epidemiology of Diabetes Interventions and Complications (EDIC), and Steno-2, show greater benefit with aggressive glucose control than trials that have a shorter duration.33,56 The cumulative data suggest that the benefits or harms from intensive glucose therapy may be determined by the presence of significant atherosclerosis at the time of therapy initiation.40 A less aggressive A1C (7%-7.5%) may be preferred for patients with a limited life expectancy or those with established CVD or long-term T2D.40 Pooled data from UKPDS, ACCORD, ADVANCE, VADT, and Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) studies demonstrate that there is an association between cardiovascular death in the intensive therapy arms and severe hypoglycemia.40,61  Therefore, younger patients with shorter durations of T2D and no established CVD may be better candidates for more intensive glycemic control.40

Retrospective data demonstrate that the risk of macrovascular complications increases with the severity of hyperglycemia, suggesting that there is a linear relationship between metabolic disturbance and vascular damage. With concerns of increased cardiovascular disease risk associated with some diabetes medications, the FDA issued guidance that all new medications for T2D must undergo cardiovascular outcomes trials. Since this time, several glucose-lowering agents have been tested for their efficacy and safety in lowering CVD in patients with T2D. Although some agents that carry risk for hypoglycemia have not been successful in lowering CVD, clinical trials have demonstrated improved ASCVD outcomes with empagliflozin, canagliflozin, and liraglutide, with potential benefit with metformin and pioglitazone.40,51,60-68

Healthcare professionals also need to balance the benefits of A1C lowering with the risk of hypoglycemia when considering glucose-lowering therapies. Hypoglycemia is proinflammatory and can increase the chances for plaque inflammation, rupture, and cardiovascular events.40,69,70 Therefore, therapies that minimize hypoglycemia risk may be optimal, particularly in patients with preexisting CVD.

Screening and Treatment Recommendations for CVD Risk Factors in Patients With T2D

The current T2D treatment guidelines recommend a more comprehensive approach that includes the management of CVD risk factors, such as hypertension and dyslipidemia.5,16 The 2018 ADA guidelines emphasize that CVD risk factors need to be assessed annually in all patients with T2D. These include both traditional and nontraditional risk factors, such as hypertension, dyslipidemia, smoking, a family history of premature coronary disease, CKD, and the presence of albuminuria. The ADA recommends that modifiable risk factors should subsequently be treated.7 The ADA guidelines recommend that in patients with T2D and established ASCVD, antihyperglycemic therapy should begin with lifestyle therapy and metformin, with subsequent therapies including agents that have been proven to reduce major cardiovascular events and cardiovascular mortality, such as empagliflozin, canagliflozin, and liraglutide.16,71

The 2018 AACE/ACE consensus statement for the treatment of T2D algorithm also provides specific recommendations for blood pressure and lipid control, which the AACE/ACE deems to be the

2 most important risk factors for CVD.16 The guidelines emphasize evaluating CVD risk and stratifying risk in patients. Lipid targets also must be stratified in patients with elevated blood glucose or T2D. The use of statins to treat dyslipidemia is emphasized by the ADA and the AACE/ACE.5,16 The AACE/ACE guidelines also emphasize lifestyle therapy as well as the use of metformin and weight-loss therapies in patients with prediabetes to reduce ASCVD risk factors.16 The AACE/ACE guidelines include algorithms to modify ASCVD risk factors as well as an algorithm to control hyperglycemia. A1C goals need to be individualized based on hypoglycemia risks.16

Conclusions

Numerous trials have demonstrated that, over time, poorly controlled diabetes leads to damage of the heart and blood vessels, and patients with T2D tend to develop CVD at a younger age than individuals without diabetes. Additionally, adults with T2D have a 2-to-4–fold higher risk of cardiovascular morbidity and mortality than adults without diabetes.7 Managed care professionals need to acquire an understanding of and become familiar with the risk factors for CVD in T2D and the burden that diabetes inflicts on patients. Control of these risk factors, as well as an understanding of the link between hyperglycemia and CVD risk, is essential for the optimal management of T2D. Recent trials have demonstrated improved CVD outcomes with several novel glucose-lowering agents. Managed care professionals must evaluate these trials and results to provide optimal care to their patients with T2D. 

Author affiliation: Adjunct Assistant Professor, University of Kentucky College of Pharmacy, Lexington, KY.
Funding source: This activity is supported by an independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc. and Lilly USA, LLC.
Author disclosure: Dr Hudspeth does not have any relevant financial relationships with commercial interests to disclose.
Authorship information: Concept and design, acquisition of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.
Address correspondence to: brooke.hudspeth@uky.edu.
Medical writing and editorial support provided by: Ruwaida Vakil, MSc.
 
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