Silent myocardial ischemia may also contribute to the higher rates of MI seen in diabetic patients. Ischemia and subsequent angina often serves as an early warning system to patients developing obstructive CAD[ 63 ]. However, those with silent ischemia are often asymptomatic and diagnosed later into the progression of CAD, which is associated with higher rates of MI-related mortality and morbidity[ 64 ].
This disparity may be responsible for the observation seen in some angiographic studies where CAD was usually more advanced at the time of diagnosis in diabetic patients[ 65 , 66 ]. Diabetic neuropathy is one factor that may explain the increased incidence of silent ischemia in patients with DM[ 67 , 68 ]. Suboptimal glycemic control, obesity, hypertension, dyslipidemia and autonomic dysfunction are common CV risk factors among diabetic patients, placing them at heightened risk of CV complications.
Therapy that is targeted to modify these risk factors can improve CV outcomes, but this can be a challenging to achieve. The guidelines pertaining to these risk factors typically vary from the guidelines for non-diabetic patients and the recommendations often change or differ depending on what organization publishes them. In addition, the research on how these different risk factors affect the CV risk profile of diabetics can be unclear, and at times, contradictory.
The purpose of this section is to provide the most recent guidelines for the treatment of glycemic control, hypertension, dyslipidemia and autonomic dysfunction in patients with DM, and also describe the research that pertains to each of these topics. As many studies have linked poor glycemic control to worse CV outcomes, current treatment recommendations for patients with DM place a heavy emphasis on closely monitoring and controlling glycemic levels in an effort to improve cardiac outcomes.
The exact glycemic level that should be targeted for diabetics, however, is controversial and varies depending on which organization is making the guideline. For example, the current recommendation by the American Association of Clinical Endocrinologists Guidelines has a goal hemoglobin A1c HbA1c of less than or equal to 6. The recommendation also states that an A1c goal lower than the general goal of less than 7.
There have been many studies that have investigated the effect of intensive treatment of hyperglycemia on CV outcomes in patients with diabetes. The UKPDS trial was one of the first multi-center, randomized control trials to investigate the effect of intensive glycemic control in patients with recently diagnosed T2DM. In addition, the intensive therapy group trended towards a decrease in macrovascular disease although it was not statistically significant[ 72 ].
The population for this study consisted primarily of older mean age The group with the tighter glycemic control did have a significantly greater decrease in A1c levels over the course of the study 6.
This large multi-center randomized control trial recruited T2DM patients with a history of major macrovascular or microvascular disease from collaborating centers in 20 countries.
The intensive glycemic therapy group was treated to an HbA1c of less than or equal to 6. The group randomized to the tighter glycemic control did have a significantly greater reduction in HbA1c 6. The subjects were followed for an average of 3. The intensive glycemic control group had slightly lower rates of nonfatal MI, but after 3.
While it does appear that a link exists between glycemic control and CV outcomes in diabetic patients, the findings thus far on the effect of tight glycemic control on CVD are conflicting.
While there may be a small reduction in the number of microvascular events in T2D patients with the tighter glycemic control, there does not seem to be a sizeable benefit in the rates of all-cause and CV-specific mortality. In patients with T1DM, tighter glycemic control does appear to be beneficial. One potential interpretation of the studies thus far is that the concurrent CV risk factors present in diabetics may overwhelm any benefit that intensive treatment of hyperglycemia can provide in reducing risk.
Thus, diabetic patients who achieve tighter glycemic control earlier during their disease course and prior to the development of other CV risk factors may see the greatest benefit from more intensive therapy in terms of CV outcomes. For this reason, many of the new recommendations look to tailor A1c goals to the individual patient as opposed to a single A1c cutoff for all diabetic patients.
Thus, current treatment recommendations encourage weight loss in overweight and obese patients with DM to improve their CV risk profile and decrease the risk of CVD.
These recommendations were graded as high, moderate, or low on the basis of scientific methodology, scientific strength, and consistency of results[ 77 ]. As obesity is a major risk factor both for CVD and T2DM, many studies have investigated the efficacy of weight loss in reducing the development and severity of DM.
Some studies have focused on body weight reduction in pre-diabetic patients in order to decrease the incidence of subsequent DM. Of note, the diabetes prevention program DPP and finnish diabetes prevention studies evaluated the effect of behavior modification on weight loss and consequent risk of developing diabetes in pre-diabetic adults.
Both studies yielded similar results in that those randomized to the lifestyle intervention group had significantly greater weight loss and reduced risk of developing diabetes as compared to the control group[ 78 , 79 ]. Other studies have looked at methods for attaining weight loss and improving the CV risk profile of patients who are already diabetic. A variety of techniques including intensive lifestyle intervention, weight loss medications and bariatric surgery were effective in achieving weight loss and improving the CV risk profile of diabetic patients through improved glycemic control, blood pressure and cholesterol levels[ 80 - 82 ].
Although many studies have shown that weight loss can be achieved in diabetic patients, there is mixed evidence as to whether weight loss in these patients actually reduces subsequent CV morbidity and mortality. Thus far, there has been mixed evidence if modest weight loss in patients with DM does improve their CV risk.
Studies thus far have demonstrated that this goal is attainable both in pre-diabetic and diabetic patients through a variety of techniques including intensive behavioral modification therapy, pharmacological agents and bariatric surgery.
In addition, all of these methods of weight loss appear to either decrease the rates of incident DM in pre-diabetic patients, or improve the CV risk profile of diabetic patients[ 78 - 82 ].
However, it is unclear whether modest weight loss in diabetic patients translates to a decrease in CVD[ 83 , 84 ]. It is possible that the CV risk profile is too high in older adults with DM for modest weight loss to make a significant improvement in CV outcomes.
It might be more advantageous to focus obesity treatment efforts on pre-diabetics before they develop DM. Programs such as the DPP have demonstrated that weight loss can decrease the rate of incident diabetes, but further research is needed to determine if modest weight loss in pre-diabetic patients results in improved CV morbidity and mortality[ 78 ].
It is also possible that while modest weight loss does seem to improve the CV risk profile of patients with DM, even greater weight loss is necessary to see more definitive improvements in the rates of CV events. Since hypertension is a common comorbidity of patients with DM and a major risk factor for CVD, the current treatment recommendations strongly encourage providers to lower BP in hypertensive diabetics.
There are many studies that have investigated the effect of lowering blood pressure in patients with diabetes on CV outcomes. After 4. In addition, the intensive BP group had increased adverse events including hypotension, syncope, bradycardia or arrhythmia, hyperkalemia, angioedema and renal failure[ 86 ].
The recommendation on the type of pharmacological therapy that should be used varies in the general nonblack vs black population. For nonblack patients with DM and hypertension, initial treatment should include a thiazide-type diuretic, calcium channel blocker CCB , angiotensin-converting enzyme ACE inhibitor or angiotensin receptor blocker ARB.
For black patients with DM and hypertension, the initial treatment should include a thiazide-type diuretic or a CCB. While different antihypertensive agents used to treat hypertension have varying metabolic effects, many studies, including the ALLHAT trail, found no significant difference in the risk of coronary heart disease, nonfatal myocardial infarction, total mortality, or other clinical complications attributable to the initial antihypertensive drug therapy used to treat diabetic patients[ 88 , 89 ].
This would suggest that metabolic differences between the various antihypertensive agents do not play a major role in the subsequent development of CVD in patients with DM.
It should be noted that these recommendations have been controversial and several authors have argued that the guideline is too relaxed in the treatment of certain at-risk groups including African Americans, women and the elderly based on previous studies evaluating blood pressure control and subsequent CVD in these populations[ 90 ]. There is likely a therapeutic BP range that provides diabetic patients with a lower CV risk but also protects them from adverse events associated with hypotension.
Whether the new guidelines, particularly with the increased systolic BP threshold in adults over 60 years, match this therapeutic BP range is yet to be determined. There is also little evidence as to what the proper treatment range should be for different age groups. In addition, hypertension in different racial subgroups may have different effects on CV health. Further research is needed to investigate the ideal BP range for adults of different age groups as well as different racial groups.
Dyslipidemia is both common in patients with DM and associated with increased risk of CVD[ 91 , 92 ]. Health providers are encouraged to identify and aggressively treat patients with dyslipidemia to help diminish their risk of subsequent CV events. The current recommendation for treating dyslipidemia in diabetic patients varies by age and is in line with recognition that treatment with fixed-dose statins, rather to specific LDL target levels, is the validated approach from clinical trials.
All diabetic patients over the age of 40 are encouraged to begin statin therapy. There have been many studies conducted to determine the effect of treating dyslipidemia in diabetic patients as a means to lower CV risk. The median follow-up time was 3. The CARDS trial was stopped early to due the significant benefit demonstrated with statin therapy[ 94 ]. However, it was noted that the higher dose group did have a higher rate of adverse events myalgia, persistent elevation in alanine aminotransferase, aspartate aminotransferase, or rhabdomyolysis [ 95 ].
As many studies had demonstrated that statins, particularly high-dose statins, had CV benefit in diabetic patients, the 4D study examined the effect of statins in diabetic patients receiving hemodialysis.
In the 4D trial, diabetic patients receiving hemodialysis were randomly assigned either 20 mg of atorvastatin per day or a placebo. The purpose of the study was to determine if a low-dose statin in diabetic patients with end stage renal disease lowered the rates of death from cardiac causes, nonfatal myocardial infarction, and stroke as compared to the placebo group. The group randomized to the statin therapy did have a significant reduction in their LDL-c compared to the placebo group In addition, there were significantly more cases of fatal stroke in the statin therapy group than those treated with a placebo[ 96 ].
While the previous studies had focused on reducing cholesterol in diabetic patients using statin therapy, other research groups have investigated the effect of non-statin lipid-lowering therapies on CVD in diabetic patients. In addition, since HDL has been identified in many large prospective studies to be associated with improved CV health, some research groups have investigated whether raising HDL through pharmaceutical agents reduces the risk of CV events.
These findings were similar between diabetics and nondiabetics[ 99 ]. Dyslipidemia is prevalent among diabetic patients and a major risk factor for CVD[ 91 , 92 ]. Some trials have also investigated if additional CV benefit can be achieved in patients with DM by combining a statin with other lipid-lowering therapies.
For example, the IMPROVE-IT trial found that the combination of ezetimibe a cholesterol absorption inhibitor with simvastatin was superior to simvastatin alone in reducing CV events for diabetic patients with acute coronary syndrome[ ]. The evidence thus far suggests that statin therapy in patients with DM is advantageous for CV health and that higher doses, as well as combined lipid-lowering therapy, can provide additional CV protection[ 93 ].
While some meta-analyses have suggested that statin therapy could be associated with increased incidence of DM, the absolute benefit of the therapy in diabetic patients largely outweighs the risk[ ]. Other lipid lowering agents, such as fenofibrates, have not demonstrated the same level of efficacy and reductions in CV events as statins[ 97 ]. CAN is a common complication of diabetes and places patients with DM at increased risk of CV related morbidity and mortality.
The autonomic dysfunction commonly found in diabetic patients is associated with a high risk of cardiac arrhythmias and sudden death, as well as other serious CV sequelae including silent myocardial ischemia, diabetic cardiomyopathy, stroke, and both intraoperative and perioperative CV instability.
Some of the most common clinical manifestations of CAN include heart rate variability variability in the instantaneous beat-to-beat intervals , resting tachycardia, exercise intolerance, orthostatic hypotension and abnormal blood pressure regulation[ ]. Early treatment of autonomic dysfunction can slow the pathogenesis and complications of CAN[ ].
Some studies have shown that tight glycemic control may play an important role in reducing the incidence of CAN in patients with DM. For example, the DCCT demonstrated that patients with better glycemic control, as measured by Hba1c, had significantly lower risk of developing autonomic dysfunction according to a CAN index[ ]. Lifestyle interventions that focus on improving exercise endurance and promote weight loss have also improved autonomic dysfunction.
Pharmacological therapy including ACE inhibitors, angiotensin receptor blockers and aldose reductase inhibitors also appear to help slow the progression of CAN[ 54 ].
In addition, IGF-1, ACE inhibitors and beta-blockers appear to be beneficial in the treatment of diabetic cardiomyopathy by slowing ventricular hypertrophy and normalizing the calcium homeostasis in diabetic cardiomyocytes[ - ].
Further studies are necessary, however, to validate what the best pharmacological treatment is for diabetic patients with CAN. While there have been many trials that have helped further the understanding of DM as it relates to CVD, further research is required to better identify and quantify CV risk in patients with DM.
Determining how glycemic control relates to CVD is one another area where additional research is needed. There is some evidence that improved glycemic control does in fact improve CV outcomes patients with DM[ 72 , 73 ]. One study even found that HbA1c in non-diabetic patients is an independent predictor of coronary artery disease and its severity which would suggest that glycemic control is critical to managing CV health in all patient populations[ ].
One possible explanation for the conflicting results surrounding the relationship between glycemic control and CVD is due to poor measurement tools. If glycemic control does matter, properly measuring glycemia and correlating it to CV risk is essential in order to set clinically meaningful goals for patients with DM.
The duration and onset of improved glycemic control may also contribute to the progression and severity of CVD. The UKPDS demonstrated that tight glycemic control was associated with reductions in CV outcomes in middle-aged adults median 54 years who were recently diagnosed with DM[ 72 ]. This might reveal that treating hyperglycemia aggressively in high-risk patients with longer-standing DM is too late to have a clinically significant impact, and that earlier, aggressive treatment among patients shortly after DM diagnosis may be more beneficial.
More studies are needed to better understand the relationship between glycemic control and the development of CVD and determine if the onset and duration of treatment matters in the reduction of CV events in patients with DM.
Further research is also necessary to determine what the best treatment is to decrease the risk and severity of cardiomyopathy and CAN in patients with DM.
Many studies have demonstrated that autonomic dysfunction and diabetic cardiomyopathy are disease processes that are not only common in patients with DM, but also place them at increased risk of subsequent CV complications[ ].
Lifestyle modification, tighter glycemic control and pharmacological agents appear to provide some benefit in slowing the progression of CAN and diabetic cardiomyopathy[ 54 , - ]. However, few studies have investigated what specific therapy is most effective in treating these conditions, as well as what might be done to prevent the development of these disease processes altogether.
Additional research is also needed to better understand how traditional CV risk factors including dyslipidemia, obesity and blood pressure should be monitored and managed in diabetic patients. For example, combination therapy may be the best way to treat dyslipidemia, contrary to the current recommendation that focuses primarily on statin mono-therapy. In addition, the role of HDL on CV health is complicated, and further investigation is necessary to determine if pharmacological agents designed to increase HDL can provide clinical benefit in diabetic patients.
The effect of weight loss in patients with DM is also somewhat unclear as to if, and how much, weight loss is necessary to achieve clinically significant improvements in CV outcomes. Five percent weight loss may not be sufficient for diabetic patients with other CV risk factors and comorbidities. Further studies are needed to determine what amount of weight loss is needed attain CV benefit, and what the best treatment method is to reach that weight loss goal.
Finally, follow-up regarding the new blood pressure guidelines, particularly in adults over 60 years who now fall under the higher systolic BP threshold, will need to be closely monitored moving forward. Accordingly, proper control and treatment of DM, along with aggressive treatment of associated CV risk factors is central to curbing the growing prevalence and progression of DM and CVD.
Additional research is needed to better understand the disease process and its effects on CV health in order to improve medical management and CV outcomes in diabetic patients.
Conflict-of-interest statement: Benjamin M Leon has no conflicts of interest; Benjamin M Leon is a student at the University of Colorado School of Medicine; Thomas M Maddox has no conflicts of interest relevant to this work; the views expressed in this article do not necessarily represent those of the Department of Veterans Affairs or the United States Government. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers.
Peer-review started: October 26, Cardiovascular disease represents the principal cause of death and morbidity among people with diabetes, especially in those with type 2 diabetes mellitus.
Adults with diabetes have times increased cardiovascular risk compared with adults without diabetes, and the risk rises with worsening glycaemic control. Diabetes-related macrovascular and microvascular complications, including coronary heart disease, cerebrovascular disease, heart failure, peripheral vascular disease, chronic renal disease, diabetic retinopathy and cardiovascular autonomic neuropathy are responsible for the impaired quality of life, disability and premature death associated with diabetes.
PAD is often the first sign that a person with diabetes has cardiovascular disease. Over time, high blood sugar can damage blood vessels and the nerves that control your heart. People with diabetes are also more likely to have other conditions that raise the risk for heart disease:.
None of these conditions has symptoms. Your doctor can check your blood pressure and do a simple blood test to see if your LDL, HDL, and triglyceride levels are high.
People with diabetes are also more likely to have heart failure. This can lead to swelling in your legs and fluid building up in your lungs, making it hard to breathe. Heart failure tends to get worse over time, but early diagnosis and treatment can help relieve symptoms and stop or delay the condition getting worse. Your blood pressure, cholesterol levels, and weight will help your doctor understand your overall risk for heart disease. Your doctor may also recommend other tests to check your heart health, which could include:.
These lifestyle changes can help lower your risk for heart disease or keep it from getting worse, as well as help you manage diabetes:. Your doctor may also prescribe medicines that can help keep your blood sugar, blood pressure, cholesterol, and triglycerides close to your target levels. Work with a diabetes care and education specialist for help avoiding health complications such as heart disease.
Find out more about how diabetes education can help you take the best care of yourself.
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