Approach

Patients with diabetes benefit from aggressive cardiovascular (CV) risk factor management.[167] One large prospective cohort study showed that patients with diabetes who met target ranges for haemoglobin A1c (HbA1c), low-density lipoproteins (LDLs), blood pressure (BP), albuminuria, and smoking had the same or only slightly increased long-term mortality compared with non-diabetic controls.[168] However, in a large US cohort study of patients with diabetes and known cardiovascular disease (CVD), only 6.9% received guideline-recommended medical therapies for CV risk reduction.[169]

Therapeutic lifestyle interventions such as medical nutrition therapy and aerobic exercise have been shown in large clinical trials to improve glycaemic, lipid, and BP control, in addition to insulin sensitivity and markers of inflammation. They are also effective in achieving sustained weight loss and improvements in fitness.[48][72][170][171][172][173] The US Preventive Services Task Force recommends behavioural counselling interventions to improve diet and increase physical activity for people with cardiometabolic risk factors to prevent longer term CV events.[174] The UK NHS has produced a free web-based structured education programme for patients with type 2 diabetes, with a focus on making and maintaining healthy lifestyle choices. NHS: ​Healthy living for people with type 2 diabetes Opens in new window

Recommendations for the management of CVD and risk in patients with diabetes include:[30][175]

  • Therapeutic lifestyle interventions (medical nutrition therapy/dietary advice, physical activity, and smoking cessation)

  • Treatment for overweight or obesity

  • Glycaemic control

  • BP control

  • Dyslipidaemia treatment

  • Antiplatelet therapy

There is substantial evidence in support of the benefit of CV risk factor management in people with type 2 diabetes; however, robust evidence to support a comparable benefit in people with type 1 diabetes is lacking. Current treatment guidelines extrapolate clinical trial evidence obtained in people with type 2 diabetes to provide similar treatment recommendations for people with both type 1 and type 2 diabetes. There is evidence, however, to support the more aggressive treatment of CV risk factors in people with type 1 diabetes, who would likely benefit from early risk stratification and comprehensive risk factor management, including aggressive lipid-lowering therapy.[176]

Medical nutrition therapy

There is no ideal amount of macronutrients that people with diabetes should consume, and studies suggest that such recommendations should be decided on an individual basis.[170][177] The Mediterranean Diet, Dietary Approaches to Stop Hypertension (DASH), vegetarian, and vegan diets have all demonstrated some efficacy in people with diabetes.[170][178][179][180][181] European guidelines recommend a Mediterranean or plant-based diet with high unsaturated fat content for lowering CV risk in people with diabetes.[7] One meta-analysis found that red meat consumption was associated with higher risk of CVD and diabetes, while another reported moderate certainty evidence that a shift from animal-based to plant-based foods is beneficially associated with cardiometabolic health and all-cause mortality.[182][183]

Reducing overall carbohydrate intake has demonstrated some evidence for improving glycaemia and one study found that among people with type 2 diabetes, greater adherence to low-carbohydrate diet patterns was associated with significantly lower all-cause mortality.[184] However, the optimal degree of carbohydrate restriction and long-term effects on CVD are still unclear.[30] Both World Health Organization (WHO) and European guidelines emphasise that carbohydrate quality, rather than quantity, is key.[133][185] The concept of carbohydrate quality refers to the nature and composition of carbohydrates in a food or in the diet, including the proportion of sugars, how quickly polysaccharides are metabolised and release glucose into the body (i.e., digestibility), and the amount of dietary fibre. It is recommended that carbohydrate intake should come primarily from high-fibre foods, such as whole grains, vegetables, whole fruits, and pulses.[133][185] Diets high in naturally occurring fibre have been shown to be protective against cardiometabolic disease and premature mortality.[133] When choosing high-fibre foods, focus should be on minimally processed and largely intact whole grains, rather than products with finely milled whole grains that may also have added sugars, sodium, and saturated fats.[133][185] Fibre-enriched foods and fibre supplements can be considered when sufficient intake cannot be obtained from diet alone.[133]

There is some evidence to suggest that reducing intake of high glycaemic index foods, and generally reducing glycaemic load, could be beneficial for preventing CVD; however, WHO guidelines do not make any recommendations on this, noting that there was a lack of consistent benefit from diets with lower glycaemic index or glycaemic load in observational studies, and little to no improvement in cardiometabolic risk factors in randomised controlled trials associated with lower glycaemic index and glycaemic load.[185][186]

Replacing saturated fats and trans-fats with unsaturated fats and carbohydrates from foods containing naturally occurring dietary fibre (such as whole grains, vegetables, fruits, and pulses) reduces LDL-cholesterol (LDL-C) and also benefits CVD risk.[170][187][188] Saturated fat should comprise <10% of total energy intake and trans-fats <1%.[133][188] Dietary fats should mainly come from plant-based foods high in mono- and poly-unsaturated fats, such as nuts, seeds, and non-hydrogenated non-tropical vegetable oils (e.g., olive oil, rapeseed/canola oil, soya bean oil, sunflower oil, linseed oil).[133]

People with diabetes who have overweight or obesity should be supported with evidence-based nutritional support to achieve and maintain weight loss.[133] European guidelines recommend that a variety of weight-loss diets can be used equally effectively, provided they can be followed and meet recommendations for protein, fat, micronutrient, and fibre intake. Neither extreme high-carbohydrate, nor very-low carbohydrate ketogenic diets are recommended, however.[133] One systematic umbrella review of published meta-analyses of studies comparing hypoenergetic diets for weight management in people with type 2 diabetes did not find evidence for any particular weight-loss diet over others (e.g., low-carbohydrate, high-protein, low-glycaemic index, Mediterranean, high-monounsaturated fatty acid, or vegetarian diets).[189]

Intermittent fasting or time-restricted eating as strategies for weight and glucose management have gained popularity.[190] They have been shown to result in mild to moderate weight loss (3% to 8% loss from baseline), but no significant difference in weight loss when compared with continuous calorie restriction.[30] The ADA advises that due to its simplicity, intermittent fasting may lend itself as a useful strategy for people with diabetes who are looking for practical eating management tools.[30] People with diabetes who are on insulin and/or secretagogues should be medically monitored during the fasting period.[30]

Evidence indicates that low- and very-low-energy diets (<3500 kJ/day [<840 kcal/day]), using total diet replacement formula diet products (replacing all meals) or partial liquid meal replacement products (replacing 1-2 meals per day) for the weight-loss phase, are most effective for weight loss and reduction of other cardiometabolic risk factors when compared with the results from self-administered food-based weight-loss diets.[133][191] Low-energy nutritionally complete formula diets with a total diet replacement induction phase also appear to be the most effective dietary approach for achieving type 2 diabetes remission.[133] One population-based cohort study found that those who achieved remission from diabetes, even for a short time, had a much lower risk of CVD events, including myocardial infarction (MI) and stroke, as well macrovascular and microvascular complications.[192]

Following the success of a pilot programme to provide a low-calorie diet treatment for people recently diagnosed with type 2 diabetes and living with overweight or obesity, the NHS has launched its Type 2 Diabetes Path to Remission (T2DR), a free one year programme to promote weight loss in those that are overweight (body mass index [BMI] of 27 kg/m² or over in people from white ethnic groups, adjusted to 25 kg/m² or over in people from black, Asian, and other ethnic groups) and recently diagnosed with type 2 diabetes, with the aim of inducing diabetes remission wherever possible.[193] Service users will follow a diet composed solely of nutritionally-complete total diet replacement products, with total energy intake of 800 to 900 kilocalories a day, for 12 weeks, followed by a period of food re-introduction and subsequent weight maintenance support, with a total duration of 12 months.

Physical activity

A sedentary lifestyle is a major risk factor for CVD.[69][70] Many individuals with type 2 diabetes do not meet the recommended exercise level per week.[30][71]

Physical activity improves glycaemic control, lipids, BP, insulin sensitivity, and markers of inflammation in type 2 diabetes.[48][72][173][194] Increased physical activity is associated with lower risk of CVD and reduced all-cause mortality in both type 1 and type 2 diabetes.[48][73][123][195]

At least 150 minutes per week of moderate- to vigorous-intensity aerobic physical activity is recommended for adults with diabetes.[7][30]​ The physical activity should be spread over at least 3 days per week, with no more than 2 consecutive days without exercise.[30] Younger and more physically fit individuals should aim for ≥75 minutes per week of vigorous-intensity exercise or interval training.[30] In the absence of contraindications, resistance training 2 to 3 times per week on non-consecutive days is also recommended.[7][30]​ The American Diabetes Association (ADA) recommends interrupting sedentary activity every 30 minutes with short bouts of physical activity.[30] Older adults may also benefit from flexibility and balance exercise 2 to 3 times per week.[30]

The ADA recommends assessment of the following prior to starting an exercise programme; age; physical condition; BP; and presence or absence of autonomic neuropathy or peripheral neuropathy, balance impairment, history of foot ulcers or Charcot foot, or untreated proliferative retinopathy.[30] The European Society of Cardiology (ESC) recommends that any exercise interventions be tailored according to a patient’s frailty and diabetes-associated comorbidities such as retinopathy.[7] The European Association of Preventive Cardiology recommends testing for silent myocardial ischaemia prior to initiating an exercise programme in patients with type 2 diabetes and CVD, whereas the ADA states that clinical judgement should be used in determining whether to screen asymptomatic individuals for coronary artery disease (CAD) prior to recommending an exercise programme.[30][196]

Smoking cessation

All patients with diabetes should be advised not to smoke or to stop smoking.[30] Smoking counselling and other forms of smoking cessation therapy should be incorporated into routine diabetes care.[30] Varenicline combined with nicotine replacement therapy may be more effective than varenicline alone.[197] The ADA does not support e-cigarettes as an alternative to smoking or to facilitate smoking cessation.[30]

Patients who stop smoking are prone to weight gain; therefore, it is important to have weight management strategies in place to maximise the CV benefits of smoking cessation.[48]

Weight management

In most patients with type 2 diabetes and overweight or obesity, ≥5% weight loss is recommended through diet, physical activity, and behavioural therapy.[2][30] The benefits of weight loss are progressive, and so more intensive weight loss goals (i.e., 15%) may be useful to maximise benefit.[30]

Pharmacotherapy

Obesity pharmacotherapy should be considered as an adjunct to lifestyle interventions and behavioural counselling to improve CV risk factors in people with type 2 diabetes who have overweight or obesity.[7][30][175] For those with a BMI of ≥27 kg/m² (≥25 kg/m² for Asian-Americans) who are motivated to lose weight, an initial 3-month trial of medicine should be undertaken. When weight loss is <5% after 3 months, the benefits of ongoing treatment need to be balanced in the context of the glycaemic response, the availability of other potential treatment options, treatment tolerance, and overall treatment burden.[30]

The ADA advises that agents with both glucose-lowering and weight loss effects should be used first-line; this includes glucagon-like peptide-1 (GLP-1) receptor agonists and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide.[30] Two phase 3 trials in adults with obesity demonstrated mean losses of 15% to 21% of body weight with the highest dose of tirzepatide, with adverse effects similar to those seen with GLP-1 receptor agonists.[198][199] In the larger of the two trials, over 80% of participants in all tirzepatide treatment groups lost ≥5% of body weight, compared with 35% of those assigned to placebo.[198] With higher body weight reduction, there were greater reductions in HbA1c, triglycerides, waist circumference, and BP.[200] Tirzepatide is approved for chronic weight management in adults with obesity or those who are overweight with at least one weight-related condition (such as high BP, type 2 diabetes or high cholesterol), for use in addition to a reduced calorie diet and increased physical activity.

If these medicines are not tolerated or contraindicated, other obesity treatment approaches should be considered, including phentermine, orlistat, phentermine/topiramate, or naltrexone/bupropion.[30]

The ESC recommends a GLP-1 receptor agonist or sodium-glucose cotransporter-2 (SGLT2) inhibitor as the agents of choice for glucose-lowering in patients with type 2 diabetes and overweight and obesity, in view of their proven CV benefits for these patients.[7][201]

For those not reaching goals, the ADA recommends evaluation of weight management therapies and intensification of treatment with additional approaches (e.g., metabolic surgery, additional pharmacological agents, and structured lifestyle management programmes).[30]

As well as considering specific medicines to treat obesity, healthcare professionals should carefully review the individual’s other medicines and, whenever possible, minimise or provide alternatives for medicines that promote weight gain. Examples of medicines associated with weight gain include antipsychotics (e.g., clozapine, olanzapine, risperidone), some antidepressants (e.g., tricyclic antidepressants, some selective serotonin-reuptake inhibitors, monoamine oxidase inhibitors), glucocorticoids, injectable progestins, some anticonvulsants (e.g., gabapentin, pregabalin), beta-blockers, and possibly sedating antihistamines and anticholinergics.[30]

Metabolic (bariatric) surgery

A large number of studies have demonstrated that metabolic surgery achieves superior glycaemic management and reduction of CV risk in people with type 2 diabetes and obesity compared with non-surgical intervention.[10][202] It has also been shown to reduce microvascular complications, cancer risk, and all-cause mortality in people with obesity and type 2 diabetes.[30][203][204][205] Of note, one meta-analysis reported a 50% reduction in macrovascular complications following metabolic surgery in patients with type 2 diabetes and extreme obesity (BMI ≥40 kg/m²).[203] Another meta-analysis found that metabolic surgery reduced the risk of any CV event by 44% and yielded a risk reduction of over 55% in overall mortality and 69% in CV mortality in patients with type 2 diabetes.[206]

Vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) are the most commonly performed procedures. Both result in an anatomically smaller stomach pouch; in VSG, approximately 80% of the stomach is removed, leaving behind a long, thin sleeve-shaped pouch, whereas RYGB creates a much smaller stomach pouch (roughly the size of a walnut), which is then attached to the distal small intestine, thereby bypassing the duodenum and jejunum.[30]

The ADA recommends metabolic surgery to treat type 2 diabetes in adults with BMI ≥30 kg/m² (≥27.5 kg/m² for Asian-Americans) who are otherwise good surgical candidates.[30] The ESC recommends that metabolic surgery be considered for all patients with type 2 diabetes and BMI ≥35 kg/m² who have not achieved sufficient weight loss through lifestyle interventions and medicine.[7] Metabolic surgery is best done in a high-volume, specialised centre to reduce the risk of perioperative and longer-term complications.[30] For more comprehensive information, see Obesity in adults.

Long-term glycaemic control

Increasing severity of hyperglycaemia correlates with increasing CV risk.[48][207] One meta-analysis found that antihyperglycaemic therapies reduce major adverse cardiac events in an HbA1c-dependent manner.[208] However, three large studies, Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE), and Veterans Administration Diabetes Trial (VADT), found that very intensive glucose control (goal HbA1c <42 to 48 mmol/mol [6.0% to 6.5%] over 3-5 years) did not reduce macrovascular events in adults with type 2 diabetes.[7][209][210][211][212] In contrast, intensive glycaemic control appeared to have long-term beneficial effects on the risk of CVD in patients with type 1 diabetes.[213]

One meta-analysis found that intensive versus standard glycaemic control in patients with type 2 diabetes was associated with a reduced risk of non-fatal MI but no significant difference in the risk of major adverse CV events or other adverse CV outcomes.[214] A long-term follow-up study of intensive glycaemic control (median HbA1c 6.9% vs. 8.4%) in type 2 diabetes did show fewer major CV events per 1000 person-years, but there was no improvement in overall survival.[215] Furthermore, a follow-up of the ACCORD trial, which studied intensive versus standard glycaemic control (<6.0% vs. 7.0% to 7.9%), showed that MI, coronary revascularisation, and unstable angina were less frequent in the intensive group than the standard therapy group.[216] The reasons for the discrepancy are unclear. It appears that there may be a lag period before a benefit of glycaemic control on CV risk is realised.[217] Other possibilities that may have influenced results include the magnitude or rapidity of reductions in HbA1c in intensively treated patients; effect of specific antihyperglycaemic drugs or drug interactions; treatment-related hypoglycaemia; or age at which therapy is begun.[218]

The ADA recommends a general HbA1c goal of <7% (<53 mmol/mol) for non-pregnant adults with diabetes to optimise clinical outcomes, although this should be individualised by the physician following patient discussion.[30] If using a continuous glucose monitoring (CGM) device to assess glycaemia, a parallel goal is time in range >70% with time below range <4% and time below 3 mmol/L (<54 mg/dL) <1%.[30] Less stringent goals may be appropriate for: older adults; people with a history of severe hypoglycaemia; and those with limited life expectancies, advanced microvascular or macrovascular complications, or comorbid conditions.[30] If using a CGM device, the ADA recommends a target of >50% time in range with <1% time below range for those with frailty or at high risk of hypoglycaemia.[30]

A person-centred shared decision-making approach should guide the choice of pharmacological agents for adults with type 2 diabetes, considering the effects on CV and renal comorbidities, effectiveness, hypoglycaemia risk, impact on weight, cost and access, risk of adverse reactions and tolerability, and individual preferences.[30] Medicine plan and medicine-taking behaviour should be re-evaluated at regular intervals (the ADA suggest 3 to 6 monthly) and treatment intensification, de-intensification, or modification - as appropriate - for people not meeting individualised treatment goals should not be delayed.[30]

US and European guidelines continue to recommend metformin as the first-line treatment for glycaemic control in patients with type 2 diabetes regardless of the presence or absence of established atherosclerotic CVD.[30][219][220] Evidence for the CV benefit of metformin is limited; however, it does not cause weight gain or hypoglycaemia, and is widely available relative to other agents.[48] People who are unable to take metformin due to contraindications or intolerance can either use an alternative non-insulin agent or start insulin therapy. The ADA recommends a GLP-1 receptor agonist over insulin when possible.[30]

Early combination therapy can be considered in adults with type 2 diabetes at treatment initiation to shorten time to attainment of individualised treatment goals.[30] When selecting an additional therapy, clinicians should consider the evidence of benefits, harms, patient burden, and cost of medicines in addition to performing an individualised assessment of each patient’s preferences, glycaemic control target, comorbid conditions, and risk for symptomatic hypoglycaemia.[220] The American College of Physicians (ACP) now recommends that SGLT2 inhibitors or GLP-1 receptor agonists should be the add-on therapy of choice for patients with inadequate glycaemic control.[220] It advises that sulfonylureas and long-acting insulins are inferior to these medicines in reducing all-cause mortality and morbidity but may still have some limited value for glycaemic control. Dipeptidyl peptidase-4 (DPP-4) inhibitors are not recommended as an add-on to metformin and lifestyle modifications in light of high-certainty evidence showing that this does not reduce morbidity or all-cause mortality.[220]

When considering glycaemic control in patients who have overweight or obesity, the ADA recommends that healthcare professionals should prioritise glucose-lowering medicines with a beneficial effect on weight.[30] One meta-analysis found that when glucose-lowering therapies were associated with weight loss, the risk of mortality was reduced by 22% for each 1% reduction in HbA1c.[221] In addition, concomitant reductions in HbA1c and body weight were associated with a significantly lower risk of mortality and vascular events.

  • Agents associated with clinically meaningful weight loss include GLP-1 receptor agonists, tirzepatide, SGLT2 inhibitors, metformin, and amylin analogues.[30] One network meta-analysis of 531 trials with 279,118 participants confirmed that tirzepatide is the most effective drug for reducing body weight (mean reduction 8.57 kg), followed by GLP-1 receptor agonists, SGLT2 inhibitors, and metformin.[222] DPP-4 inhibitors, bromocriptine (a centrally acting dopamine agonist), alpha-glucosidase inhibitors, and bile acid sequestrants are considered weight neutral.[30]

  • Insulin secretagogues (sulfonylureas and meglitinides), thiazolidinediones, and insulin are often associated with weight gain.[30]

See Type 2 diabetes mellitus in adults and Type 1 diabetes mellitus for further information.

Antihyperglycaemic agents with cardiovascular and renal benefit

For patients with established atherosclerotic CVD, significant CVD risk factors, established heart failure (with either preserved or reduced ejection fraction), or established chronic kidney disease (CKD), addition of a GLP-1 receptor agonist or a SGLT2 inhibitor is strongly recommended (independent of HbA1c) to reduce the risk of adverse CV or kidney events.[30][158][223]

  • The ADA and European Association for the Study of Diabetes (EASD) advise that for patients in whom atherosclerotic CVD predominates (e.g., previous MI, unstable angina, ischaemic stroke, or indicators of high CV risk present) either a GLP-1 receptor agonist or an SGLT2 inhibitor can be used.[30][219]​ While definitions of what constitutes high CV risk vary, most comprise ≥55 years of age with two or more additional risk factors such as obesity, hypertension, smoking, dyslipidaemia, or albuminuria.[219] Guidelines published by the ACP and American Heart Association (AHA)/American Stroke Association specify that GLP-1 receptor agonists should be prioritised in patients with an increased risk for stroke.[119][220]​​

  • For those patients in whom heart failure or CKD predominates, SGLT2 inhibitors should be favoured.[30][219][220]

  • Combination therapy with a GLP-1 receptor agonist and an SGLT2 inhibitor may be appropriate for some patients to provide additive reduction in risk of adverse CV and kidney outcomes (e.g., if HbA1c remains above target and the patient is taking either an SGLT2 inhibitor or a GLP-1 receptor agonist).[30]

SGLT2 inhibitors and GLP-1 receptor agonists have been shown to reduce CV events and mortality in outcome trials and in real-world studies, regardless of baseline HbA1c values and concurrent use of CV medicines.[48][224][225][226][227][228][229][230][231][232] One Cochrane meta-analysis concluded that SGLT2 inhibitors and GLP-1 receptor agonists reduce CVD and all-cause mortality with high certainty.[233] High-certainty evidence supported use of SGLT2 inhibitors to reduce risk of hospitalisation for heart failure, with moderate-certainty evidence supporting use of GLP-1 receptor agonists to reduce fatal and non-fatal stroke.[233] Another meta-analysis found that in patients with type 2 diabetes, the hypotensive effects of SGLT2 inhibitors and GLP-1 receptor agonists were significantly associated with a reduction in mortality and cardiorenal events, suggesting that this BP-lowering effect could be seen as an additive indicator of the CV protective effects of these agents.[234]

SGLT inhibitors

  • SGLT2 inhibitors reduce the risk for all-cause mortality, major adverse CV events, progression of CKD, and hospitalisation due to congestive heart failure.[220][235][236] They have been shown to improve CV outcomes in patients with heart failure regardless of left ventricular ejection fraction, and irrespective of type 2 diabetes status.[222][237][238][239][240][241][242][243][244]

  • The SGLT2 inhibitors with the strongest evidence for CVD risk reduction are dapagliflozin, canagliflozin, and empagliflozin.[121][219][245][246][247][248][249][250][251] Only empagliflozin and canagliflozin have shown reduction in major adverse cardiac events (MACE) in patients with type 2 diabetes.[252]

  • CV outcome trials in patients with type 2 diabetes:

    • The EMPA-REG OUTCOME trial evaluated CV outcomes with empagliflozin in patients with established CVD. Empagliflozin was superior to placebo in reducing the risk of the primary composite outcome of 3-point MACE (non-fatal MI, non-fatal stroke, and CV mortality; MACE-3) and unexpectedly yielded a 35% relative risk reduction in hospitalisation for heart failure. All-cause mortality was also significantly reduced by 32% compared with placebo.[250]

    • Similar findings were seen for canagliflozin in the CANVAS Programme trial.[251][253]

    • The DECLARE-TIMI 58 trial found that dapagliflozin did not significantly reduce MACE-3, but resulted in a 27% reduction in heart failure-related hospitalisation compared with placebo.[121] However, it decreased CV outcomes in a subanalysis of the primary trial confined to participants with prior MI.[254]

    • In the VERTIS-CV trial, ertugliflozin was not found to be superior to placebo in reducing MACE-3 or CV mortality; however, a significant reduction in heart failure hospitalisations was reported in the ertugliflozin arm.[255][256]

    • The CREDENCE trial primarily evaluated kidney-related outcomes with canagliflozin and found a significant 31% reduction in the secondary composite outcome of CV death and heart failure hospitalisations with canagliflozin compared to placebo.[246]

    • One pooled meta-analysis of these trials revealed a significant reduction in MACE (most apparent in patients with established atherosclerotic CVD), all-cause mortality, CV deaths, and heart failure hospitalisations. The greatest magnitude of benefit was for reduction in risk for hospitalisation for heart failure and kidney disease progression.[257]

  • On the basis of these findings, SGLT2 inhibitors are recommended in the management of heart failure, regardless of diabetes status.[158][258][259] SGLT inhibitors, particularly empagliflozin, have been shown to significantly reverse cardiac remodelling in patients with heart failure.[260][261][262][263][264]

  • One meta-analysis looked at the efficacy of SGLT2 inhibitors in older people with type 2 diabetes and heart failure and found they were associated with a significant reduction in all-cause mortality, cardiac death, and hospitalisation for heart failure, confirming that their cardioprotective advantages extend to the frail/older population. However, they did not demonstrate a significant effect in reducing the risk of macrovascular events (acute coronary syndrome or stroke).[265]

  • The ESC recommends dapagliflozin or empagliflozin for all patients with type 2 diabetes and CKD to reduce risk of heart failure hospitalisation or CV death, regardless of whether they have a pre-existing heart failure diagnosis.[259]

  • SGLT2 inhibitors also reduce the risk of serious hyperkalaemia in people with type 2 diabetes at high CV risk without increasing the risk of hypokalaemia, allowing the titration of guideline-directed medical therapy in patients with heart failure.[266]

  • An initial decline in estimated glomerular filtration rate (eGFR) is commonly observed after initiating an SGLT2 inhibitor but this decline is not associated with subsequent risk of CV or kidney events.[267] Thus, SGLT2 inhibitors should not be interrupted or discontinued in response to an initial eGFR decline.

  • SGLT2 inhibitors are generally well-tolerated; however, some serious adverse reactions have been documented, including a higher rate of diabetic ketoacidosis, acute kidney injury, fracture, and/or amputation. The European Medicines Agency (EMA) warns of the potential increased risk of toe amputation.[268] The Food and Drug Administration (FDA) states that the risk of amputation, while increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.[269] One large network meta-analysis estimated that treatment with SGLT-2 inhibitors in 1000 patients for 5 years probably results in three additional amputations.[222] The FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA) warn of cases of necrotising fasciitis of the perineum (also known as Fournier gangrene) observed in post-marketing surveillance of SGLT2 inhibitors.[270][271] Thus, SGLT2 inhibitors should be avoided in patients with conditions that increase the risk for limb amputations, and in patients prone to urinary tract or genital infections.

  • Sotagliflozin is the first dual SGLT inhibitor.[272] It inhibits both renal SGLT2 (promoting significant excretion of glucose in the urine, in the same way as other already available SGLT2 selective inhibitors) and intestinal SGLT1 (delaying glucose absorption and therefore reducing postprandial glucose).[272] It has been approved in people with heart failure (both with and without diabetes) and in patients with type 2 diabetes who have CKD or high risk of/established CVD, to reduce the risk of hospitalisation for heart failure.[30] The approval was based on two randomised, double-blind, placebo-controlled phase 3 CV outcome trials: SOLOIST-WHF (Effects of Sotagliflozin on Clinical Outcomes in Haemodynamically Stable Patients with Type 2 Diabetes Post Worsening Heart Failure) and SCORED (Effects of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes Mellitus, Cardiovascular Risk Factors and Moderately Impaired Renal Function).[273][274] It is not currently approved for glycaemic management of type 1 or type 2 diabetes.

  • One concern with expanded use of SGLT inhibition is the infrequent but serious risk of diabetic ketoacidosis (DKA), including the atypical presentation of euglycaemic ketoacidosis.[30] Of note, the studies that led to the approved indication of sotagliflozin for heart failure excluded individuals with type 1 diabetes or a history of DKA.[273][274] In clinical trials of sotagliflozin in people with type 1 diabetes, results showed improvements in HbA1c and body weight; however, its use was associated with an eightfold increase in DKA compared with placebo.[30][275] The risks and benefits of SGLT inhibitors in this population continue to be evaluated, with consensus statements providing guidance on patient selection and precautions.[30][276]

GLP-1 receptor agonists

  • Reduce the risk for all-cause mortality and major adverse CV events.[220][277] The GLP-1 receptor agonists with the strongest evidence for atherosclerotic CVD risk reduction are injectable semaglutide, liraglutide, and dulaglutide.[219][278][279][280][281][282]

  • In addition to their beneficial effects on coronary artery disease, GLP-1 receptor agonists are the only drug class that has been shown to convincingly reduce non-fatal stroke.[220][222][283][284][285][286]

  • The addition of semaglutide to standard care has been shown to be associated with an important gain in life-years free of new/recurrent CVD events and a decrease in 10-year CVD risk.[287] It is the only GLP-1 receptor agonist that is available in both oral and injectable formulations. However, unlike for injectable semaglutide, conclusive evidence for the CV benefit of oral semaglutide has not yet been established in clinical studies.[279] For more information on oral semaglutide, see Emerging treatments.

  • Unlike for SGLT2 inhibitors, the evidence for GLP-1 receptor agonists in reducing heart failure or improving CV outcomes in patients with heart failure has been inconsistent across trials.[288] One meta-analysis found that they may prevent new-onset heart failure and mortality in patients with type 2 diabetes; however, they did not reduce heart failure hospitalisations and mortality in those patients with pre-existing heart failure.[289]

  • Data from retrospective studies and meta-analyses have shown superiority of GLP-1 receptor agonists in comparison with other antidiabetic medicines such as SGLT2 inhibitors and DPP-4 inhibitors in terms of peripheral arterial disease (PAD).[290] However, data from CV outcome trials regarding the impact of GLP-1 receptor agonists on PAD are scarce and further prospective studies are needed.

  • The most common adverse effects of GLP-1 receptor agonists are gastrointestinal, particularly nausea, vomiting, and diarrhoea; these are frequent but tend to reduce over time.[291]

  • Patients should be counselled about potential for ileus.[30]

  • An association with pancreatitis and pancreatic cancer has been reported in clinical trials, but causality has not been established; after a review of available data, the FDA and the EMA agreed that there was insufficient evidence to confirm an increased risk of pancreatic cancer with use of GLP-1-based therapies.[292] Nonetheless, GLP-1 receptor agonists should be used with caution in patients with a history of pancreatitis.[30][291]

  • GLP-1 receptor agonists have been associated with increased risk of gall bladder and biliary diseases including cholelithiasis and cholecystitis.[291]

  • Hypoglycaemia risk is increased with concomitant sulfonylureas and insulin use. Treatment de-intensification of these agents or of diuretics, particularly in older and frail individuals, is recommended to avoid hypoglycaemia and hypovolaemia.[291]

  • DKA has been reported in patients on a combination of a GLP-1 receptor agonists and insulin, when concomitant insulin was either rapidly reduced or discontinued; insulin reductions should therefore be undertaken in a cautious stepwise manner, with capillary blood glucose monitoring.[291]

  • In rodent studies, GLP-1 receptor agonists were associated with medullary thyroid cancer, resulting in a black box warning for these agents in patients with a personal or family history of multiple endocrine neoplasia type 2 or medullary thyroid cancer; however, there is conflicting evidence as to whether this risk applies in humans.[291][293][294][295][296]

  • The EMA is reviewing data on the risk of suicidal thoughts and thoughts of self-harm with GLP-1 receptor agonists, following reports of such occurrences in people using liraglutide and semaglutide.[297]

  • There is some concern that GLP1-receptor agonists, through their rapid glucose-lowering effects, may increase the risk of transient worsening of pre-existing diabetic retinopathy.[298][299][300] Further studies are required to elucidate this relationship.

One Swedish nationwide study found that the proportion of patients with type 2 diabetes who were eligible for treatment with an SGLT2 inhibitor or a GLP-1 receptor agonist was approximately 80% according to the 2019 ESC guidelines and around 50% according to the 2019 ADA/EASD consensus report. Uptake of these recommendations in routine clinical practice was limited; however, indicating that many eligible patients are missing out on the therapeutic benefits of these medicines.[301]

Glycaemic control during acute critical illness (CVD events or interventions)

Trials of tight glycaemic control in critically ill patients have yielded mixed results.[302][303]

In one study of patients with acute coronary syndrome who presented with hyperglycaemia, intensive glucose control was associated with harm and did not reduce infarct size.[304]

One large RCT raised questions about intensive blood glucose targets for inpatient glycaemic control and found a lower mortality for intensive care unit (ICU) patients with a blood glucose target of ≥10 mmol/L (≥180 mg/dL) than for those with a blood glucose target of 4.5 to 6.0 mmol/L (81 to 108 mg/dL).[305] A concern has been whether there is any additional benefit to lowering blood glucose levels below about 7.8 to 10 mmol/L (140-180 mg/dL) in the ICU setting.[306]

The ADA recommends that in critically ill patients, insulin therapy should be started for persistent hyperglycaemia ≥10 mmol/L (≥180 mg/dL) (tested on two occasions).[30] Once insulin therapy is started, a target glucose range of 7.8 to 10 mmol/L (140 to 180 mg/dL) is recommended for most patients.[30] More stringent goals, such as 6.1 to 7.8 mmol/L (110 to 140 mg/dL), may be appropriate for selected patients (e.g., critically ill post-surgical patients or patients with cardiac surgery), as long as they can be achieved without significant hypoglycaemia.[30] Critically ill patients require an intravenous insulin protocol that has demonstrated efficacy and safety for achieving targets without increasing risk for severe hypoglycaemia.[30]

Intravenous infusion of insulin allows for more rapid titration (and more reliable absorption) in critically ill patients than does subcutaneous injection. In the perioperative period for coronary artery bypass grafting (CABG), good glucose control may reduce infectious complications, such as sternal wound infections and mediastinitis, cardiac mortality caused by pump failure, and the risk of supraventricular tachycardia.[307][308][309]

BP control

It is well accepted that BP control reduces CV risk in patients with diabetes; however, certain pivotal studies investigating the benefits of intensive versus standard BP control yielded discordant results:

  • The UK Prospective Diabetes Study (UKPDS) found that tight BP control (<150 mmHg) led to a greater reduction in CV events than less tight BP control (<180 mmHg).[59]

  • The Systolic Blood Pressure Intervention Trial (SPRINT) had similar findings, with intensive BP control (<120 mmHg) significantly reducing risk of CV events compared with standard control (<140 mmHg), although patients with diabetes were excluded from enrolment.[58]

  • Conversely, the ACCORD-BP trial demonstrated that intensive BP control to a goal of <120 mmHg compared with a standard BP goal of <140 mmHg did not change CV outcomes in patients with diabetes.[57]

  • The 2021 STEP trial found that, in older adults aged 60-80 years with hypertension, intensive BP control (target 110 to <130 mmHg) was associated with a 26% reduction in CV events compared with less intensive BP control (target 130 to <150 mmHg).[60]

The reason for the difference in findings between SPRINT and ACCORD-BP remains under debate. However, a post-hoc analysis of ACCORD-BP found that although dual intensive therapy for BP and glycaemic control was detrimental, intensive BP control conferred modest CV benefits for patients on standard glycaemic control.[310]

There is a lack of high-quality evidence regarding optimal treatment of hypertension in people with diabetes.[61] However, guidelines recommend a BP treatment goal of <130/80 mmHg, providing this can be safely attained.[7][30]​​[61][62] The departure in the guidelines from the previous BP target of <140/90 mmHg was in response to studies like the meta-analysis of data from the ACCORD-BP and SPRINT trials, which showed a reduction in a composite of unstable angina, MI, acute heart failure, stroke, and CV death with intensive systolic BP targets of <120 mmHg compared with the traditional target of <140 mmHg.[311] Notably, the ADA recommends an individualised approach to BP targets, and recommends that patients and clinicians should engage in a shared decision-making process to determine individual BP targets, acknowledging that the benefits and risks of intensive BP targets are uncertain.[30]

People with diabetes plus hypertension should monitor their BP at home in addition to having it checked at regular intervals in the clinic setting, both to ensure accuracy of readings and to encourage adherence to treatment regimens.[30]

Guidelines emphasise the importance of therapeutic lifestyle interventions in the management of hypertension; these include increased physical activity, weight management, a DASH-style eating pattern (including reduced sodium intake and, increased potassium intake), moderation of alcohol intake, smoking cessation, and education to support long-term behaviour change.[30][62] These lifestyle interventions should be initiated alongside pharmacological therapy when hypertension is diagnosed, and are also recommended for individuals with diabetes and mildly elevated blood pressure (systolic >120 mmHg or diastolic >80 mmHg).[30]

The ADA recommends starting one antihypertensive agent for patients with initial BP ≥130/80 mmHg and <150/90 mmHg, and starting two antihypertensive agents for those with initial BP ≥150/90 mmHg.[30] ACE inhibitors, angiotensin-II receptor antagonists, dihydropyridine calcium-channel blockers, or thiazide diuretics are all options for initial antihypertensive therapy.[30][61][62]

For patients with diabetes who have CAD or CKD and/or albuminuria (eGFR <60 mL/minute/1.73 m², urinary albumin-to-creatinine ratio ≥30 mg/g creatinine), initial antihypertensive therapy should be with an ACE inhibitor, or an angiotensin-II receptor antagonist if an ACE inhibitor is not tolerated (a dose reduction may be required in patients with renal impairment).[30][61]

For those whose BP is >150/90 mmHg, a calcium-channel blocker or thiazide diuretic should be considered in addition at treatment initiation.[30] Combining ACE inhibitors and angiotensin-II receptor antagonists is not recommended because of an increased risk for acute kidney injury and hyperkalaemia.[30][312] ACE inhibitors have also shown increased risk for hypoglycaemia in conjunction with insulin or insulin secretagogues (sulfonylurea or meglitinide).[313]

One meta-analysis found that ACE inhibitors reduced mortality and major CV events in patients with diabetes, while angiotensin-II receptor antagonists did not improve these outcomes. Neither ACE inhibitors or angiotensin-II receptor antagonists were found to reduce the risk of stroke.[314] Another meta-analysis showed that in patients with diabetes and kidney disease, no antihypertensive regimen improved survival. However, ACE inhibitors and angiotensin-II receptor antagonists were effective in preventing end-stage renal disease.[312] Some antihyperglycaemic agents have demonstrated modest BP-lowering effects in clinical trials, including SGLT2 inhibitors and GLP-1 receptor agonists.[315] Further studies are warranted to investigate the effects of these agents on BP as the primary outcome measure.[315]

Based on the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial, the FDA recommends that combination of the renin inhibitor aliskiren with ACE inhibitors or angiotensin-II receptor antagonists is contraindicated in patients with diabetes due to the risk of renal impairment, hypotension, and hyperkalaemia. FDA: new warning and contraindication for blood pressure medicines containing aliskiren (Tekturna) Opens in new window

Beta-blockers may be appropriate to improve outcomes as antihypertensive agents in patients with prior MI, active angina, atrial fibrillation with rapid ventricular response, or heart failure with reduced ejection fraction.[30] These patients are typically started on beta-blockers alone, with other antihypertensive therapies added as needed. If a beta-blocker is indicated, an agent should be selected that has concomitant vasodilatory effects to reduce potential for adverse metabolic impact.[115] Beta-blockers may mask symptoms of hypoglycaemia and also have the potential to exacerbate hypoglycaemic episodes, particularly when used concurrently with sulfonylureas.[30][316][317]

Multiple drug therapy is often required in order to achieve antihypertensive targets.[30] If BP remains uncontrolled on monotherapy, add an agent from a different first-line class.[30] If BP remains uncontrolled despite combination therapy with first-line agents (i.e., three classes of antihypertensive medicine [including a diuretic] plus lifestyle modifications), discontinue or minimise interfering substances such as non-steroidal anti-inflammatory drugs, evaluate for secondary causes of hypertension (including obstructive sleep apnoea), and consider the addition of an aldosterone antagonist (e.g., spironolactone, eplerenone).[30][115] Referral to a hypertension specialist may also be necessary.[30][115]

Serum creatinine/eGFR and potassium should be checked within 7-14 days of initiation of treatment with an ACE inhibitor, angiotensin-II receptor antagonist, aldosterone antagonist, or diuretic, as well as following uptitration of dose and then at least annually.[30]

European and US guidelines also recommend considering use of an ACE inhibitor (or an angiotensin-II receptor antagonist) in patients with chronic coronary disease and diabetes mellitus to reduce risk of cardiovascular events, regardless of hypertension, and particularly in patients with heart failure or CKD.[7][318][319]

Dyslipidaemia therapy

Lifestyle modification focusing on weight loss (if indicated); application of a Mediterranean or DASH eating pattern; reduction of saturated fat and trans fat; increase of dietary omega-3 fatty acids, viscous fibre, and plant stanol/sterol intake; and increased physical activity should be recommended to improve the lipid profile and reduce the risk of developing CVD in people with diabetes.[30]

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.[113] One meta-analysis which included data from over 18,000 people with diabetes from 14 randomised trials of statin therapy (mean follow-up 4.3 years) demonstrated a 9% proportional reduction in all-cause mortality and 13% reduction in vascular mortality for each 1 mmol/L (39 mg/dL) reduction in LDL-C.[125] The CV benefit did not depend on baseline LDL-C levels and was linearly related to the LDL-C reduction without a low threshold beyond which there was no benefit observed. Lowering of LDL-C has also been shown to have a significant positive impact on long-term outcomes for patients with diabetes and coronary heart disease undergoing percutaneous coronary intervention (PCI).[320]

For patients with diabetes and established CVD, both European and US guidelines recommend an LDL-C goal of <1.42 mmol/L (<55 mg/dL) and at least a 50% reduction from baseline.[7][30][114]

Statins

Statins are the first-line medicine for LDL-C lowering and cardioprotection.[30] Moderate-intensity statin therapy has been defined by the American College of Cardiology (ACC)/AHA as therapy that generally lowers LDL-C level by 30% to 50%, while high-intensity statin therapy lowers it by ≥50%.[114] Guidelines recommend high-intensity statin therapy in adults of all aged with diabetes and atherosclerotic CVD, to target an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <1.42 mmol/L (<55 mg/dL).[30][114]​ 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.[30]

Ezetimibe

If target LDL-C is not achieved with a statin alone, addition of ezetimibe can be considered.[30] Ezetimibe works by reducing cholesterol absorption from the ileum.[7] One large RCT of 18,144 individuals compared the addition of ezetimibe to simvastatin therapy versus simvastatin alone in people aged ≥50 years who had experienced a recent acute coronary syndrome.[321] Overall, over an average treatment period of 6 years, addition of ezetimibe led to a 6.4% relative benefit and a 2% absolute reduction in major adverse atherosclerotic CV events, with the degree of benefit being directly proportional to the change in LDL-C. Subgroup analysis showed that the benefit of adding ezetimibe to statin therapy was enhanced in patients with diabetes.[321] Another RCT showed that among patients with diabetes and atherosclerotic CVD, moderate-intensity statin with ezetimibe combined therapy was non-inferior to high-intensity statin monotherapy with respect to the primary endpoint of CV death, major CV events, or non-fatal stroke.[322] Notably, the patients treated with moderate-intensity statin and ezetimibe had lower rates of drug discontinuation or dose reduction than patients receiving high-intensity statin. This study supports moderate-intensity statin with ezetimibe combination therapy as a suitable alternative to high-intensity statins if the latter cannot be tolerated, or further reduction in LDL-C is required among patients with diabetes and CVD.[322]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors

If target LDL-C is not achieved with a statin alone, addition of a PCSK9 inhibitor (e.g., alirocumab, evolocumab) can be considered as an alternative to ezetimibe (or in addition to ezetimibe if LDL-C is not at goal). PCSK9 inhibitors can also be used as monotherapy in patients who are statin-intolerant.[30] In placebo-controlled RCTs, alirocumab and evolocumab achieved a >50% reduction in LDL-C levels compared with placebo, with a 15% lower risk of ischaemic CV events over a 2- to 3-year follow-up.[323][324]

Bempedoic acid

Bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, is a novel, oral LDL-C-lowering drug that works by inhibiting cholesterol synthesis.[7] It is approved in the US as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with established atherosclerotic CVD who require additional lowering of LDL-C. The ADA advises that it may be considered for patients who cannot use, or tolerate, other evidence-based LDL-C-lowering approaches, or for whom those other therapies are inadequately effective.[30] Bempedoic acid is also approved for this indication in Europe.[325] One meta-analysis found that bempedoic acid therapy lowered LDL-C levels by about 23% compared with placebo, while a randomised controlled trial found that it was associated with a reduction in risk of major adverse CV events (death from CV causes, non-fatal MI, non-fatal stroke, or coronary revascularisation) in statin-intolerant patients, providing some evidence for its use in this group.[326][327]

Inclisiran

Inclisiran, a small interfering ribonucleic acid (siRNA) that inhibits hepatic synthesis of PCSK9, is now recommended by the ADA as an alternative lipid-lowering treatment for people who are intolerant of statins (off-label use).[30] In the ORION-10 and ORION-11 phase 3 trials, individuals with established CVD or at high risk of CVD were randomised to receive inclisiran or placebo.[328] Inclisiran allows less frequent administration compared with monoclonal antibodies and was administered on day 1, day 90, and every 6 months thereafter over a period of 540 days. Reductions in LDL-C levels of approximately 50% were obtained with inclisiran.[328] Adverse events were generally similar in the inclisiran and placebo groups, although injection-site adverse events were more frequent with inclisiran (2.6% vs. 0.9% in ORION-10 and 4.7% vs. 0.5% in ORION-11); such reactions were generally mild.[328] A CV outcome trial using inclisiran in people with established CVD is currently ongoing.[329]

Summary of ADA recommendations for lipid-lowering pharmacotherapy in patients with diabetes with established CVD:[30]

  • High-intensity statin therapy for adults of all aged, to target an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <1.42 mmol/L (<55 mg/dL). For people who do not tolerate the intended statin intensity, the maximum tolerated statin dose should be used.

  • Addition of ezetimibe or a PCSK9 inhibitor if this goal is not achieved on maximum tolerated statin therapy.

  • For people intolerant of statin therapy, a PCSK9 inhibitor, bempedoic acid, or inclisiran should be considered as alternative cholesterol-lowering therapies.

For certain patients at intermediate or borderline risk, coronary artery calcium (CAC) measurement may be useful to support shared decision-making for statin therapy.[77] A CAC score ≥100 Agatston units or in the ≥75th age/sex/race percentile can reclassify CV risk as being increased.[77]

A lipid profile should be checked: at time of diagnosis of diabetes or pre-diabetes; at initiation of statins or other lipid-lowering therapy; 4-12 weeks after initiation or a change in dose; and annually thereafter.​[30]

Role of other lipid-lowering pharmacotherapies

  • Icosapent ethyl can be considered in patients with atherosclerotic CVD or other CV risk factors who are on a statin and have controlled LDL-C but elevated triglycerides (1.53 to 5.64 mmol/L [135 to 499 mg/dL]).[30] It has been shown to modestly reduce CV events.[115][116] There have been some concerns about the use of mineral oil as the control treatment in pivotal clinical trials of icosapent ethyl; however, evaluation of whether this had an impact on trial outcomes remains inconclusive.[330][331]

  • Fibrates are effective for lowering very high triglyceride levels (i.e., >5.65 mmol/L [>500 mg/dL]) to reduce the risk of pancreatitis.[115] 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 CVD outcomes.[30] 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.[48]

  • 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.[117]

Antiplatelet therapy

  • Aspirin is recommended for secondary prevention in those with a history of atherosclerotic CVD.[30]

  • Clopidogrel (a P2Y12 inhibitor) should be used in patients who have an aspirin allergy or intolerance.[30]

  • In people with stable coronary and/or peripheral artery disease and low bleeding risk, the ADA and ESC recommend combination treatment with aspirin and low-dose rivaroxaban (a direct oral anticoagulant) for secondary prevention.[30][332] Rivaroxaban has similar antiplatelet effects to aspirin, and may also improve endothelial function.[333]

  • Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist (clopidogrel, ticagrelor, or prasugrel) is indicated after acute coronary syndrome (ACS).[334] Evidence supports use of either ticagrelor or clopidogrel if no PCI was performed and clopidogrel, ticagrelor, or prasugrel if PCI was performed.[30][335] Generally, prasugrel and ticagrelor have better efficacy in patients with diabetes and are preferred to clopidogrel for patients who undergo PCI.[332][335]

  • UK National Institute for Health and Care Excellence (NICE) guidelines recommend that prasugrel is used as the first-line P2Y12 inhibitor for ST-elevation MI; in contrast, European and US guidelines offer no preference for either prasugrel or ticagrelor.[335][336][337] For non-ST elevation MI, NICE recommends either prasugrel or ticagrelor.[336]

  • Short-term dual antiplatelet therapy is also recommended after high-risk transient ischaemic attack (TIA) and minor stroke.[338]

  • Dual antiplatelet therapy may have benefit beyond 1 year in reducing long-term risk of recurrent atherosclerotic events.[332] However, recommendations regarding length of treatment are rapidly evolving and should be determined by an interprofessional team approach that includes a cardiologist following ACS or a neurologist following TIA/stroke.[30] The benefits versus risk of bleeding and thrombosis should be evaluated based on the coronary anatomy and extent of CAD, PCI complexity, bleeding risk, age, and patient’s medical comorbidities such as anaemia or renal failure.[339]

  • To reduce risk of gastrointestinal bleeding, a proton-pump inhibitor is recommended for all patients on a combination of antiplatelet or anticoagulant therapy, and the ESC recommends that it should be considered for those on a single agent depending on their individual bleeding risk.[7]

ST-elevation myocardial infarction (STEMI)

For people with STEMI and ischaemic symptoms for <12 hours, primary PCI is recommended to improve survival.[335] Primary PCI is superior to fibrinolytic therapy, and fibrinolytic therapy is therefore only recommended if PCI is not immediately available (i.e., within 120 minutes).[335] An analysis of data from 11 clinical trials compared PCI with fibrinolytic therapy in 2725 patients with STEMI, including 367 patients with diabetes.[340] Among the patients with diabetes, 30-day mortality or non-fatal reinfarction rate was 19.3% for those treated with fibrinolytics and 9.2% for those who underwent primary PCI. If onset of ischaemic symptoms is ≥12 hours and the patient is in cardiogenic shock or experiencing haemodynamic instability, primary PCI is indicated, or CABG if PCI is not feasible.[335] PCI may also be reasonable in patients who are stable and presenting 12 to 24 hours after symptom onset, as well as in those whose STEMI is complicated by ongoing ischaemia, acute severe heart failure, or life-threatening arrhythmia.[335]

For more comprehensive information on the acute management of this condition, see ST-elevation myocardial infarction.

Uncontrolled blood glucose levels in the perioperative or peri-procedural period are associated with adverse outcomes for patients with diabetes. Benefits of good control include reductions in length of hospital stay and likelihood of readmission, as well as improved postoperative survival rates.[30] One RCT examining the effects of peri-procedural intensive glycaemic control during early PCI on the rate of re-stenosis in hyperglycaemic (glucose 7.8 mmol/L [≥140 mg/dL]) patients with a STEMI showed that intensive control led to a 50% reduction in re-stenosis at 6 months compared with conventional glycaemic control.[341]

Non-ST-elevation acute coronary syndrome

Non-ST-elevation acute coronary syndrome (NSTE-ACS) most commonly manifests as non-STEMI (NSTEMI) but may also present as unstable angina.[342]

Immediate invasive strategy (coronary angiography with intent of revascularisation) is required in patients with NSTEMI and cardiogenic shock, refractory angina, or haemodynamic/electrical instability.[335] Early invasive strategy (usually within 24 hours) is recommended for patients at high risk for CV events: for example, those with a high Global Registry of Acute Coronary Events (GRACE) score. Patients with low- or intermediate-risk NSTEMI should undergo coronary angiography before discharge with the intent of revascularisation. Invasive strategy is important in NSTEMI as it will help determine the suitability for revascularisation and the appropriate mode (PCI vs. CABG).[335]

For more comprehensive information on the acute management of these conditions, see Non-ST-elevation myocardial infarction and Unstable angina.

Revascularisation for left main or multi-vessel disease

Recommendations on the mode of revascularisation in patients with diabetes differ slightly from those for the general population, particularly for patients with diabetes and multi-vessel disease.[337] Patients with diabetes and complex multi-vessel CAD should undergo a heart team approach to revascularisation, inclusive of an interventional cardiologist and a cardiac surgeon.[335]

CABG is generally recommended in preference to PCI to improve survival in patients with diabetes with multi-vessel CAD for which mechanical revascularisation is likely to improve survival.[335][343][344] This is particularly recommended if a left internal mammary artery to left anterior descending artery (LIMA-LAD) graft is used and the patient is a good surgical candidate. In patients with diabetes and multi-vessel CAD who are poor surgical candidates, meet the criteria for revascularisation, and have anatomy that is amenable to PCI, PCI can be beneficial to improve ischaemic outcomes.[335] The survival benefit associated with CABG compared with PCI may be greater in patients with diabetes receiving insulin therapy than in those not receiving insulin therapy.[345]

The 2021 ACC/AHA/Society for Cardiovascular Angiography and Interventions (SCAI) guidelines recommend CABG for left main disease.[335] However, they recognise that PCI might be considered in patients with low- or intermediate-complexity CAD in the rest of the coronary anatomy.[335] One trial (EXCEL; about 30% participants with diabetes) found that PCI was non-inferior to CABG for the end point of MI, stroke, or mortality at 3 years.[346] Mortality after CABG is higher in people with diabetes than in those without diabetes. Nevertheless, among people with diabetes, survival after indicated CABG surgery is superior to survival after medical therapy or PCI.[335][347]

The pivotal trials are summarised as follows:

  • In patients with diabetes with left main coronary disease and/or 3-vessel CAD, the SYNTAX trial found that PCI resulted in higher rates of repeat revascularisation and major adverse CV or cerebrovascular events compared with patients who underwent CABG.[348][349] However, there was no difference in rates of all-cause death, stroke, or MI. A long-term follow-up study of the SYNTAX cohort found the risk of mortality to be greater with PCI than with CABG at 5 years (19.6% vs. 13.3%), with the opposite observed between 5 and 10 years (20.8% vs. 24.4%).[345]

  • The FREEDOM trial evaluated patients with diabetes with multi-vessel coronary disease (defined as stenosis of >70% in at least two epicardial vessels without left main disease) and found that CABG was superior to PCI in terms of reducing death and MI, but CABG patients had an increased rate of stroke.[350] In an extended follow-up study, the all-cause mortality rate was lower in the CABG group (18.7%) compared with the PCI group (23.7%).[344]

  • In the Bypass Angioplasty Revascularization Investigation (BARI) trial, when comparing CABG versus balloon-only PCI (percutaneous transluminal coronary balloon angioplasty, PTCA) for 3-vessel disease, 7-year survival was 76.4% for patients with diabetes treated with CABG compared with 55.7% for those treated with PCI.[351] At 10 years, patients with diabetes who were assigned to the CABG group had higher survival than the PTCA-assigned group (PTCA 45.5% vs. CABG 57.8%).[352] This trial was performed prior to stents, aggressive statin therapy, and dual antiplatelet therapy.

  • Subgroup analyses of the Emory Angioplasty versus Surgery Trial (EAST) and the Coronary Angioplasty versus Bypass Revascularization (CABRI) trials showed that CABG tended to be associated with better long-term survival over balloon-only PCI for 3-vessel disease.[353]

  • The Arterial Revascularization Trial (ART) compared CABG with PCI with bare metal stents in patients with multi-vessel disease.[354] Subgroup analysis of patients with diabetes showed 1-year event-free survival of 84.4% for CABG and 63.4% for PCI.[354] Multiple studies comparing CABG versus PCI with drug-eluting stents have shown that diabetes is an independent predictor of target lesion restenosis.[353][355] Drug-eluting stents appear to be superior to bare-metal stents in people with diabetes, with regard to major adverse cardiac events such as death, MI, or need for repeat revascularisation.[356][357][358][359][360]

  • The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trials investigated the effects of an invasive approach (medical therapy plus revascularisation) versus a conservative approach (medical therapy alone) in patients with chronic coronary disease.[361] Overall, no benefit was observed for invasive versus conservative management in patients with diabetes (43% of total cohort).[361]

Medical management with or without revascularisation for single-vessel disease

In stable patients with single-vessel disease and no recent ACS or left ventricular dysfunction, the initial treatment is conservative and involves guideline-directed medical therapy for CAD. This may include antihypertensive agents, lipid-lowering agents, and antiplatelet therapy.[362] When optimised, medical therapy has demonstrated similar outcomes to revascularisation.[363][364] This approach needs patient-physician discussion to tailor therapy based on symptoms, response to therapy, available expertise, and patient’s preferences.

The usefulness of coronary revascularisation in improving survival is uncertain in patients with single-vessel disease involving the proximal left anterior descending artery with normal left ventricular function.[335] Revascularisation may be considered after patient-physician discussion as well as heart team discussion in regards to utility and timing.[335] Coronary revascularisation also has an important role in patients who are symptomatic with angina refractory to maximal medical therapy. If revascularisation is indicated, and the anatomy is amenable to PCI, PCI is preferred over CABG for single-vessel CAD.[335][343]

Considerations for patients with specific comorbidities

Heart failure (HF)

  • HF is common in patients with diabetes, and in many patients, HF can be the initial presentation of CVD.[7][141]

  • Patients with diabetes and heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) should receive HF therapy as per current HF guidelines.[30][158][258]

  • Presence of HF in patients with type 2 diabetes influences choice of antihyperglycaemic agent. SGLT2 inhibitors are recommended in all patients with HF and type 2 diabetes mellitus, as they reduce risk of HF-related hospitalisation and mortality. Thiazolidinediones (e.g., pioglitazone) and saxagliptin (a DPP-4 inhibitor) have been associated with an increased risk of HF hospitalisations and are not recommended in patients with or at risk of HF. Metformin, insulin, and sitagliptin and linagliptin (DPP-4 inhibitors) are considered neutral in terms of their effect on HF outcomes.[7] In patients with obesity and HFpEF, semaglutide (a GLP-1 receptor agonist) has been shown to reduce HF-related symptoms, improve exercise function, and result in greater weight loss compared with placebo.[365] A GLP-1 receptor agonist may be preferred over other antihyperglycaemic agents in those with HFpEF and obesity.

  • Screening for HF in patients with diabetes is important for starting therapy early and optimising prognosis. The ADA recommends annual screening of asymptomatic adults with diabetes for HF.[30]

  • See Heart failure with reduced ejection fraction and Heart failure with preserved ejection fraction.

CKD

  • CKD is a risk factor for CVD and worsening kidney function (lower glomerular filtration rate [GFR], increased albuminuria) is associated with progressively increased risk of coronary disease.[81] CVD (in addition to diabetes) is a risk factor for CKD progression and subsequent kidney failure with replacement therapy (dialysis or kidney transplant).[366] Patients with diabetes should be screened for CKD at least annually.[7][30]

  • Reducing the risk of both CV and kidney adverse events is key in these patients. Standard lifestyle and risk factor modifications (e.g., BP control, lipid control, glycaemic control, weight control) are important. Additionally, specific pharmacological interventions are recommended:[7][30]

    • SGLT2 inhibitors, in addition to reducing hyperglycaemia, have renal benefits through independent effects on renal tubular glucose reabsorption, weight, BP, intraglomerular pressures, albuminuria, and slowed GFR loss, and are recommended in patients with type 2 diabetes, established atherosclerotic CVD, and CKD to reduce the risk of both CV and kidney adverse events.

    • An ACE inhibitor or angiotensin-II receptor antagonist is recommended in patients with type 2 diabetes, established atherosclerotic CVD, and CKD, even if they are normotensive, to reduce the risk of cardiovascular events.[7][30][318]

    • Finerenone, a non-steroidal mineralocorticoid receptor antagonist, has been shown in randomised trials to lower risks of CV events and CKD progression in patients with type 2 diabetes, CKD, and albuminuria.[367][368] For people with type 2 diabetes and CKD with albuminuria treated with maximum tolerated doses of ACE inhibitors or angiotensin-II receptor antagonists, who are at an increased risk of cardiovascular events or CKD progression, the ADA and ESC recommend addition of finerenone.[7][30]

    • If additional glycaemic control is needed, a GLP-1 receptor agonist is recommended, as they improve renal outcomes independent of glucose lowering effect, and have benefits in CV risk reduction and weight control.

    • Low-dose aspirin is recommended in patients with diabetes, CKD, and atherosclerotic CVD.

    • In patients with diabetes, CKD, and stable moderate or severe CAD, either an intensive medical strategy or an initial invasive strategy may be considered.[7]

  • Referral to a specialist should be considered.

  • See Diabetic kidney disease.

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