Primary prevention
Primary prevention of cardiovascular disease (CVD) in people with diabetes
Lifestyle modifications
A major component of primary prevention for CVD in people with diabetes is lifestyle modification.[106] Most of the major CVD risk factors can be altered by aggressive lifestyle changes.[29] Lifestyle modification focusing on weight loss (if indicated); application of a Mediterranean or Dietary Approaches to Stop Hypertension (DASH) eating pattern; reduction of saturated fat and trans fat; increase of dietary omega-3 fatty acids, viscous fiber, and plant stanol/sterol intake; smoking cessation or noninitiation; and increased physical activity should be recommended to improve the lipid profile and reduce the risk of developing CVD in people with diabetes.[29]
Evidence suggests that patients with type 2 diabetes who achieve remission of their diabetes at any point in time have a substantially lower incidence of CVD compared with those who do not achieve remission. The greater the duration of remission, the greater the reduction in CVD risk.[107]
Alcohol consumption should be limited, with one study suggesting that alcohol abstinence may prevent new-onset atrial fibrillation in patients with type 2 diabetes.[47][108]
Aspirin
The routine use of aspirin for primary prevention of diabetic CVD is not generally recommended. However, in patients with diabetes ages ≥50 years who have at least one additional risk factor (e.g., hypertension, hyperlipidemia, family history of premature coronary artery disease, current or past smoker, or chronic kidney disease [CKD]/albuminuria) with no indicators of high bleeding risk (e.g., older age, anemia, renal disease, or prior significant bleeding episodes), the American Diabetes Association (ADA) advises that aspirin therapy may be considered as a primary prevention strategy following discussion of the benefits versus increased risk of bleeding.[29]
Coronary calcium score can be used to assess CVD risk and therefore help determine an indication for aspirin therapy.[29][76][109]
For patients ages >70 years the risk of bleeding increases, and ADA guidelines state that aspirin is generally not recommended for primary prevention in this population.[29][110]
The US Preventive Services Task Force recommends against the use of aspirin for the primary prevention of CVD in adults ages 60 years or older.[111]
Blood pressure (BP) control
It is well accepted that BP control reduces cardiovascular (CV) risk. There is a lack of high-quality evidence regarding optimal treatment of hypertension in people with diabetes.[60] However, guidelines recommend a BP treatment goal of <130/80 mmHg for all patients with diabetes, providing this can be safely attained.[29][60][61]
For more information on BP control, see Management approach.
Lipid management
Low-density lipoprotein cholesterol (LDL-C) is the most extensively studied modifiable risk factor associated with atherosclerotic CVD. There is strong evidence that LDL-C is a causal factor in the pathophysiology of CVD, and CVD risk reduction is proportional to the absolute and relative LDL-C reduction achieved.[112]
Statins are the first-line medication for LDL-C lowering and cardioprotection.[29] Moderate-intensity statin therapy is defined as therapy that generally lowers LDL-C level by 30% to 50%, while high-intensity statin therapy lowers it by ≥50%.[113] Low-dose statin therapy is generally not recommended in people with diabetes, but it is sometimes the only dose of statin that an individual can tolerate; for individuals who do not tolerate the intended intensity of statin, the maximum tolerated statin dose should be used.[29]
A lipid profile should be checked: at time of diagnosis of diabetes; at initiation of statins or other lipid-lowering therapy; 4-12 weeks after initiation or a change in dose; and annually thereafter.[29]
For certain patients at intermediate or borderline risk, coronary artery calcium (CAC) measurement may be useful to support shared decision-making for statin therapy.[76] A CAC score ≥100 Agatston units or in the ≥75th age/sex/race percentile can reclassify CV as being increased.[76]
For primary prevention of CVD in adults with diabetes without established CVD, ADA guidelines recommend:[29]
Consideration of statin therapy in patients ages 20 to 39 years with additional atherosclerotic CVD risk factors (being mindful that statins are contraindicated in pregnancy).
Moderate-intensity statin therapy in people ages 40 to 75 years.
High-intensity statin therapy in people ages 40 to 75 years at higher CV risk, including those with one or more CVD risk factors, to reduce LDL-C by ≥50% of baseline and to target an LDL-C goal of <70 mg/dL (<1.81 mmol/L).
Consider addition of ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to maximum tolerated statin therapy in people ages 40 to 75 years at higher CV risk, especially those with multiple CVD risk factors and LDL-C ≥70 mg/dL (≥1.81 mmol/L). PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events Opens in new window
For adults ages >75 years already established on statin therapy, it is reasonable to continue statin treatment. It may be reasonable to initiate moderate-intensity statin therapy in this age group following discussion of the potential benefits and risks.
In people intolerant of statin therapy, treatment with bempedoic acid is recommended as an alternative cholesterol-lowering therapy.
European guidelines recommended a more aggressive target for LDL-C of <55 mg/dL (<1.42 mmol/L) in very high-risk patients (again, aiming for at least a 50% reduction in LDL-C).[6] This includes patients with diabetes with severe target end-organ damage or a 10-year CVD risk of 20% or more using the SCORE2-Diabetes risk calculator.[6]
Role of other lipid-lowering pharmacotherapies
Icosapent ethyl can be considered in patients with additional CV risk factors who are on a statin and have controlled LDL-C but elevated triglycerides (135 to 499 mg/dL [1.53 to 5.64 mmol/L]).[29] It has been shown to modestly reduce CV events.[114][115]
Fibrates are effective for lowering very high triglyceride levels (i.e., >500 mg/dL [>5.65 mmol/L]) to reduce the risk of pancreatitis.[114] They are most often added to statin therapy, although the ADA notes that this approach is generally not recommended due to a lack of evidence of improvement in atherosclerotic CVD outcomes.[29] Furthermore, caution is recommended as combination statin and fibrate therapy can increase the risk of myositis and rhabdomyolysis. To lower the risk, fenofibrate is recommended over gemfibrozil.[47]
Supplementation with omega-3 fatty acids has not been found to reduce the rate of CV events in patients with diabetes at high risk for these events.[116]
For more information about these lipid-lowering treatments, see Management approach.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists
Beyond their role in the treatment of established CVD, SGLT2 inhibitors and GLP-1 receptor agonists may also have a role in primary prevention.
One retrospective study of patients with type 2 diabetes and no existing CVD found treatment with these agents to be beneficial in preventing major adverse cardiac and cerebrovascular events and heart failure.[117]
Based on evidence from randomized controlled trials (RCTs), the American Heart Association and American Stroke Association advise that for patients with diabetes who have high CV risk and HbA1c ≥7% (53 mmol/mol), treatment with a GLP-1 receptor agonist is effective for reducing the risk of stroke.[118] They note that RCT evidence to support a similar role for SGLT2 inhibitors in primary prevention is lacking, however.[118]
Canagliflozin was shown to reduce a composite of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke in patients with type 2 diabetes and elevated CV risk; however, it did not reduce overall mortality, and led to an increase in lower extremity amputation in certain patient subgroups.[119]
Dapagliflozin has failed to show reduction in CV outcomes in patients with diabetes without overt CVD.[120][121]
One meta-analysis found that SGLT2 inhibitors significantly reduced atherosclerotic major adverse cardiac events in patients with type 2 diabetes and coexisting CKD without established CVD; however, this benefit was not observed in patients without CKD.[122]
Further large-scale randomized clinical trials investigating SGLT2 inhibitors for the primary prevention of diabetic CVD are warranted.[117]
Primary prevention of CVD in people with prediabetes
People with prediabetes are at increased risk of major adverse CV events, and often have other CV risk factors, including hypertension and dyslipidemia; it is therefore important to screen for and address CV risk factors in this population as well as in those with established type 2 diabetes.[29][123]
Of note, statin therapy may increase the risk of developing type 2 diabetes in those already at high risk.[124] For these patients, the ADA recommends regular monitoring of glucose status alongside the reinforcement of diabetes prevention approaches.[29]
In people with a history of stroke, and insulin resistance and prediabetes, the ADA recommends that clinicians consider offering pioglitazone (a thiazolidinedione medication) to lower the risk of future stroke and myocardial infarction, noting that the benefit of lower CV risk with pioglitazone must be balanced against the associated increased risks of weight gain, edema, and fracture.[29] Pioglitazone has also been linked to an increased risk of bladder cancer, although this association is controversial, with studies yielding conflicting results; nonetheless, it should be avoided in patients with active bladder cancer and used with caution in those with a history of the disease.[125][126][127][128][129]
Primary prevention of type 2 diabetes
Primordial prevention
Prevention of cardiometabolic disease begins at the primordial stage and involves targeting potential behaviors that put the population, especially youth, at risk for insulin resistance and adiposity. Such population-level interventions include community-based education around healthy eating patterns, improving nutrition during pregnancy to optimize fetal development, and regulating the marketing and taxation of sugar-sweetened beverages.[130][131]
Lifestyle changes
Progression from prediabetes to overt type 2 diabetes can itself be prevented with lifestyle changes, including increased physical activity, healthy diet, and weight loss/prevention of weight gain. People with overweight or obesity are at increased risk of type 2 diabetes, and should aim for at least 5% weight loss by adopting an intensive lifestyle intervention involving an energy-restricted diet and increased physical activity.[132]
Other dietary patterns and food-based approaches that do not primarily target weight loss have also been associated with reduced type 2 diabetes risk. These include Mediterranean, Nordic, and vegetarian dietary patterns, or diets high in vegetables, fruit, wholegrains and fiber, or low in glycemic index and load.[132]
Diets rich in magnesium (e.g., wholegrains, nuts, and green leafy vegetables) have also been shown to reduce risk of type 2 diabetes and stroke in a dose-dependent manner.[133] One large US cohort study found that total ultra-processed food consumption was associated with higher risk of developing type 2 diabetes.[134]
Pharmacologic preventive treatment
People at high risk of type 2 diabetes may also benefit from pharmacotherapeutic preventive treatment. However, no pharmacologic agent has been approved for prevention of type 2 diabetes, and it is not clear whether prevention of overt diabetes translates into eventual reduced CV risk. The risk versus benefit of each medication in support of person-centered goals must be weighed, in addition to cost and burden of administration.[29]
Metformin, alpha-glucosidase inhibitors, GLP-1 receptor agonists, thiazolidinediones, and insulin have been shown to lower the incidence of diabetes in specific populations.[29]
Dapagliflozin (an SGLT2 inhibitor) reduced the incidence of new-onset type 2 diabetes in patients with CKD or heart failure compared with placebo, although no improvement in glycemic control was observed.[135]
In people with impaired glucose tolerance and CVD or risk factors, nateglinide (a meglitinide medication) for 5 years did not reduce the incidence of diabetes or composite CV outcomes.[136]
Treatment of hypertension
One study investigating the effect of BP lowering on the risk of new-onset type 2 diabetes found that reducing systolic BP by 5 mmHg decreased the risk of type 2 diabetes by 11%.[137] Antihypertensive treatment with ACE inhibitors and angiotensin-II receptor agonists led to more favorable outcomes than treatment with beta-blockers, thiazide diuretics, or calcium-channel blockers.[137]
Another study found that valsartan plus lifestyle modification produced a reduction in the incidence of diabetes but did not reduce the rate of CV events.[138]
Secondary prevention
Risk factors for atherosclerotic cardiovascular disease (CVD) should be elicited and appropriate treatment given. See Management approach.
A large international trial showed that 29% of patients studied could attain all 5 common secondary prevention parameters (smoking cessation, lipid reduction, blood pressure control, aspirin use, and ACE or angiotensin-II receptor antagonist use) with intensive risk factor modification, while 71% of patients studied could achieve 4 out of the 5 parameters.[419] However, in a large US cohort study of patients with diabetes and known CVD, only 6.9% received guideline-recommended medical therapies for cardiovascular risk (CV) reduction.[172] Although diet and exercise are commonly recommended, one study found no significant reduction in CV events in patients with type 2 diabetes and overweight or obesity who underwent an intensive diet and exercise program when compared with a control group.[420]
Sodium-glucose cotransporter-2 (SGLT2) and glucagon-like peptide-1 (GLP-1) receptor agonist therapy can play a significant role in reducing future risk in individuals with established atherosclerotic CVD, heart failure, or chronic kidney disease, and use of one these agents should be strongly considered, if not contraindicated, for the secondary prevention of macrovascular complications.[221][421] The American Heart Association and American Stroke Association advise that in patients with diabetes who have established CVD and hemoglobin A1c ≥7%, treatment with a GLP-1 receptor agonist is effective for reducing the risk of stroke.[118] Despite the overwhelming evidence of CVD benefit from large CV outcome trials, the number of patients receiving these drugs remains low. Several reasons have been proposed for this: clinical inertia, a lack of knowledge in healthcare practitioners about the results of CV outcome trials, uncertainty in prescribing these agents, and concerns about potential side effects.[422] An analysis of patients in the Swedish National Diabetes Register estimated that giving semaglutide to people with a very high CVD risk who have already had a CV event may prevent around 803 CV events each year.[423]
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