Type 2 diabetes mellitus in adults

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Your Organizational Guidance

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Diabetes Mellitus Type 2Published by: Domus Medica | SSMGLast published: 2017Diabète sucré de type 2Published by: SSMG | Domus MedicaLast published: 2017

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

at initial diagnosis

1st line – lifestyle changes

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1st line –

lifestyle changes

Although pharmacotherapy is usually indicated in patients with HbA1c >7% (>53 mmol/mol), lifestyle changes are key to diabetes management.

The cornerstone of therapy for all patients with diabetes is a personalized self-management program, usually developed by a diabetes education nurse or dietitian.[2][102]Powers MA, Bardsley JK, Cypress M, et al. Diabetes self-management education and support in adults with type 2 diabetes: a consensus report of the American Diabetes Association, the Association of Diabetes Care & Education Specialists, the Academy of Nutrition and Dietetics, the American Academy of Family Physicians, the American Academy of PAs, the American Association of Nurse Practitioners, and the American Pharmacists Association. Diabetes Care. 2020 Jul;43(7):1636-49. General nutrition and healthy lifestyle information and an individualized nutrition and exercise plan based on an initial assessment and treatment goals can significantly reduce diabetes distress.[104]

Nutrition advice needs to be tailored to the needs of each individual patient.[2][11][57] The American Diabetes Association (ADA) stresses that there is no ideal dietary macronutrient (carbohydrate, protein, and fat) distribution for people with diabetes, and that food plans should be individualized taking into account preferences and metabolic goals.[2]

The Mediterranean diet, the Dietary Approaches to Stop Hypertension (DASH) diet, and vegetarian and vegan diets have all shown some efficacy for people with diabetes.[57][108][109][110][111] European guidelines recommend a Mediterranean or plant-based diet with high unsaturated fat content for lowering cardiovascular (CV) risk.[77] Reducing sugary beverage consumption (including soda, energy drinks, and fruit juice) is of benefit to many patients.[57][115]

Reducing overall carbohydrate intake has demonstrated some evidence for improving glycemia 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.[117] However, the optimal degree of carbohydrate restriction and long-term effects on cardiovascular disease (CVD) are still unclear.[2] Both World Health Organization (WHO) and European guidelines emphasize that carbohydrate quality, rather than quantity, is key.[118][119] 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 metabolized and release glucose into the body (i.e., digestibility), and the amount of dietary fiber. It is recommended that carbohydrate intake should come primarily from high-fiber foods, such as whole grains, vegetables, whole fruits, and pulses.[118][119] Diets high in naturally occurring fiber have been shown to be protective against cardiometabolic disease and premature mortality.[119] When choosing high-fiber 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.[118][119] Fiber-enriched foods and fiber supplements can be considered when sufficient intake cannot be obtained from diet alone.[119]

There is some evidence to suggest that reducing intake of high glycemic index foods, and generally reducing glycemic 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 glycemic index or glycemic load in observational studies, and little to no improvement in cardiometabolic risk factors in randomized controlled trials.[118][120]

To reduce the risk of unhealthy weight gain, WHO guidelines suggest that adults limit total fat intake to 30% of total energy intake or less.[121] Replacing saturated fats and trans-fats with unsaturated fats and carbohydrates from foods containing naturally occurring dietary fiber (such as whole grains, vegetables, fruits, and pulses) reduces low-density lipoprotein cholesterol (LDL-C) and also benefits CVD risk.[57][122][123] Saturated fat should comprise <10% of total energy intake and trans-fats <1%.[119][123] Dietary fats should mainly come from plant-based foods high in mono- and poly-unsaturated fats, such as nuts, seeds, and nonhydrogenated nontropical vegetable oils (e.g., olive oil, rapeseed/canola oil, soybean oil, sunflower oil, and linseed oil).[119]

People with diabetes who have overweight or obesity should be supported with evidence-based nutritional support to achieve and maintain weight loss.[119] Weight-loss management programs with a healthy eating and physical activity plan resulting in an energy deficit have the potential for type 2 diabetes remission.[57][124][125] Consensus criteria for defining remission of type 2 diabetes include HbA1c of <6.5% (<48 mmol/mol) for 3 months or more, without the need for pharmacotherapy to reduce glucose.[126] In most patients with type 2 diabetes and overweight or obesity, ≥5% weight loss is recommended through diet, physical activity, and behavioral therapy.[2] The benefits of weight loss are progressive, and so more intensive weight loss goals (i.e., 15%) may be beneficial to maximize benefit.[2] Long-term support programs may be required to ensure maintenance of weight loss.[2]

A variety of weight-loss diets can be used equally effectively, provided they can be followed and meet recommendations for protein, fat, micronutrient, and fiber intake. Neither extreme high-carbohydrate nor very-low-carbohydrate ketogenic diets are recommended, however.[119] 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.[2]

Evidence indicates that low-energy 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 more effective for weight loss, reduction of other cardiometabolic risk factors, and induction of diabetes remission, when compared with the results from self-administered food-based weight-loss diets.[119][124]

Moderate alcohol intake ingested with food does not have major detrimental effects on long-term blood glucose management.[2] Risks associated with alcohol consumption include hypoglycemia and/or delayed hypoglycemia (particularly for those using insulin or insulin secretagogue therapies), weight gain, and hyperglycemia (for those consuming excessive amounts).[2] People with diabetes should be educated about these risks and encouraged to monitor glucose frequently after drinking alcohol to minimize such risks. The ADA advises that people with diabetes should follow the same guidelines as those without diabetes consistent with Dietary Guidelines for Americans.[2] Dietary Guidelines for Americans Opens in new window

Physical activity is recommended as tolerated to improve glycemic control, assist with weight maintenance, and reduce CV risk. The ADA recommends ≥150 minutes per week of moderate- to vigorous-intensity aerobic exercise. This should be performed over at least 3 days per week, with a maximum of 2 consecutive days without exercise. Younger and more physically fit individuals should aim for ≥75 minutes per week of vigorous-intensity exercise or interval training.[2] Resistance exercise should be incorporated 2-3 times per week for all individuals, performed on nonconsecutive days.[2] Older adults may benefit from flexibility training and balance training 2-3 times/week (e.g., with yoga or tai chi).[2] Prolonged sitting should be interrupted every 30 minutes with short bouts of physical activity.[2]

Smoking cessation is imperative. Patients who smoke should be provided with smoking cessation resources and assistance. The ADA does not support e-cigarettes as an alternative to smoking or to facilitate smoking cessation.[2]

Screening for sleep health should be considered, including symptoms of sleep disorders, disruption to sleep due to diabetes symptoms or management needs, and worries about sleep. Obesity, diabetes, hypertension, atrial fibrillation, and male sex are risk factors for sleep apnea, and inadequate sleep may affect glycemic control.[2] People with diabetes should be advised to practice sleep-promoting routines and habits, such as maintaining a consistent sleep schedule and limiting caffeine in the afternoon.[2] Referral to a sleep medicine specialist and/or suitable behavioral health professional should be considered if there is a positive screen result.[2]

Achieving recommended goals for weight management, nutrition, physical activity, smoking cessation, and sleep benefits many aspects of health, including glucose, blood pressure, lipid control, and depression prevention or control, and decreases risk of major CV events and onset or progression of microvascular complications.

Plus – glycemic management

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Plus –

glycemic management

Treatment recommended for ALL patients in selected patient group

All patients should receive stratified glycemic management upon diagnosis. Pharmacotherapy is recommended to reduce risk of both microvascular (nephropathy, retinopathy, neuropathy) and macrovascular (myocardial infarction, stroke, peripheral vascular disease) complications, and is guided by patient-specific factors such as comorbidities and patient preferences, as well as external factors such as safety profile and cost.[2] It should be started at the time of diagnosis unless there are contraindications.[2]

HbA1c goals should be individualized.[2][25][137][138] The American Diabetes Association (ADA) recommends a general target HbA1c goal of <7% (<53 mmol/mol) for nonpregnant adult patients. If using a continuous glucose monitoring (CGM) device to assess glycemia, a parallel goal is time in range >70% with time below range <4% and time <54 mg/dL (<3 mmol/L) <1%.[2] Less stringent goals may be appropriate for people with a limited life expectancy or if the harms of strict treatment may outweigh the benefits (e.g., in some older adults, people with a history of severe hypoglycemia, and those with limited life expectancies, advanced microvascular or macrovascular complications, or comorbid conditions).[2][25]

Generally, metformin is the recommended first-choice pharmacotherapy at diagnosis in the absence of contraindications, although for patients with atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or chronic kidney disease (CKD), there is increasing evidence that sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists should be prioritized for their cardiorenal protective effects.[106] Metformin is popular due to its favorable safety profile, low risk of hypoglycemia, likely cardiovascular (CV) benefit, and low cost.[2][139][140] People who are unable to take metformin due to contraindications or intolerance can either use an alternative noninsulin agent or start insulin therapy. The ADA recommends a GLP-1 receptor agonist over insulin when possible.[2]

Because type 2 diabetes is a progressive disease in many individuals, maintenance of glycemic goals often requires combination therapy. Early combination therapy may also be considered for some patients at the start of treatment in order to achieve more rapid attainment of treatment goals.[2]

Choice of agents beyond metformin should be individualized, taking into account patient values and preferences, adverse effect profiles, costs, and other factors. If a second agent is required, the choice should be based on individualized assessment of glycemic and weight goals, the presence of other metabolic comorbidities (e.g., ASCVD, HF, and CKD), risk of hypoglycemia, costs, and patient preference.[2] The ADA emphasizes that for patients with type 2 diabetes and established/high risk of ASCVD, HF, and/or CKD, the treatment plan should include agents that reduce cardiorenal risk; if a patient is not already on one of these drugs, it should be started.[2]

If HbA1c remains above target, tailoring of the medication plan should be undertaken as appropriate; this may involve adding new agents to the existing drug(s), or weaning the current drug(s) and starting new agents.[2]

Select your patient group to see more information about choice of specific drug(s) and doses.

Plus – blood pressure management

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Plus –

blood pressure management

Treatment recommended for ALL patients in selected patient group

The 2017 American Heart Association (AHA)/American College of Cardiology (ACC) guideline for the management of hypertension recommends a blood pressure (BP) goal of <130/80 mmHg in patients with diabetes.[101] The American Diabetes Association (ADA) makes a similar recommendation, although it caveats that an individualized approach to BP targets is required; it advises 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.[2]

The ADA recommends starting one antihypertensive agent for patients with an initial BP ≥130/80 and <150/90 mmHg, and starting two antihypertensive agents for those with an initial BP ≥150/90 mmHg.[2] ACE inhibitors, angiotensin-II receptor antagonists, dihydropyridine calcium-channel blockers, and thiazide diuretics are all options for initial antihypertensive therapy.[2][101][276]

For patients who have comorbid coronary artery disease, chronic kidney disease, and/or albuminuria (estimated glomerular filtration rate [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.[2][101][141] For those whose BP is >150/90 mmHg, a calcium-channel blocker or thiazide diuretic should be considered at treatment initiation in addition.[2]

Combining ACE inhibitors and angiotensin-II receptor antagonists is contraindicated due to increased risk for acute kidney injury and hyperkalemia.[2][278] ACE inhibitors have shown increased risk for hypoglycemia in conjunction with insulin or insulin secretagogues (sulfonylureas or meglitinides).[279]

Beta-blockers may be appropriate to improve outcomes as antihypertensive agents in patients with prior myocardial infarction, active angina, atrial fibrillation with rapid ventricular response, or heart failure with reduced ejection fraction.[2] 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.[281] Suitable examples are provided here; however, a local drug formulary should be consulted for more information. Beta-blockers may mask symptoms of hypoglycemia and also have the potential to exacerbate hypoglycemic episodes, particularly when used concurrently with sulfonylureas.[2][282][283]

Multiple drug therapy is often required in order to achieve antihypertensive targets.[2] If BP remains uncontrolled with monotherapy, an agent from a complementary first-line drug class should be added.[2] If BP remains uncontrolled despite combination therapy with first-line agents (i.e., three classes of antihypertensive medication including a diuretic, plus lifestyle modifications), healthcare professionals should discontinue or minimize interfering substances such as nonsteroidal anti-inflammatory drugs, evaluate for secondary causes of hypertension (including obstructive sleep apnea), and consider the addition of an aldosterone antagonist (e.g., spironolactone, eplerenone).[2][281] Referral to a hypertension specialist may also be necessary.[2][281]

People with diabetes and hypertension should monitor their BP at home in addition to having it checked regularly (at every clinical encounter) in the clinic setting.[2] 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.[2]

Consult a specialist for guidance on treating pregnant women; some of these drugs are contraindicated or not recommended in pregnant women (e.g., ACE inhibitors, angiotensin-II receptor antagonists, beta-blockers).

Primary options

lisinopril: 10 mg orally once daily initially, increase gradually according to response, maximum 40 mg/day

enalapril: 5 mg orally once daily initially, increase gradually according to response, maximum 40 mg/day as a single dose or in 2 divided doses

captopril: 25 mg orally twice daily initially, increase gradually according to response, maximum 200 mg/day

candesartan cilexetil: 4 mg orally once daily initially, increase gradually according to response, maximum 32 mg/day

irbesartan: 75 mg orally once daily initially, increase gradually according to response, maximum 300 mg/day

losartan: 50 mg orally once daily initially, increase gradually according to response, maximum 100 mg/day as a single dose or in 2 divided doses

valsartan: 40-80 mg orally once daily initially, increase gradually according to response, maximum 320 mg/day

-- AND / OR --

hydrochlorothiazide: 12.5 to 25 mg/day orally once daily initially, increase gradually according to response, maximum 50 mg/day as a single dose or in 2 divided doses

chlorthalidone: 12.5 mg orally once daily initially, increase gradually according to response, maximum 50 mg/day

-- AND / OR --

amlodipine: 2.5 mg orally once daily initially, increase gradually according to response, maximum 10 mg/day

felodipine: 2.5 mg orally once daily initially, increase gradually according to response, maximum 10 mg/day

nifedipine: 30-60 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 90 mg/day

-- AND / OR --

metoprolol tartrate: 50 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 450 mg/day

bisoprolol: 2.5 to 5 mg orally once daily initially, increase gradually according to response, maximum 20 mg/day

labetalol: 100 mg orally twice daily initially, increase gradually according to response, usual dose 100-400 mg twice daily, maximum 2400 mg/day

carvedilol: 6.25 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 50 mg/day

-- AND / OR --

spironolactone: 25-100 mg/day orally given in 1-2 divided doses

eplerenone: 50 mg orally once or twice daily

Plus – lipid management

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Plus –

lipid management

Treatment recommended for ALL patients in selected patient group

Lifestyle modification focusing on weight loss (if indicated), application of a Mediterranean or Dietary Approaches to Stop Hypertension (DASH)-style eating pattern, reduction of saturated fat and trans-fat, increase of dietary omega-3 fatty acids, viscous fiber, and plant stanol/sterol intake, and increased physical activity should be recommended to improve the lipid profile and reduce the risk of developing cardiovascular disease (CVD) in people with diabetes.[2]

For primary prevention in adults with diabetes without established atherosclerotic cardiovascular disease (ASCVD), American Diabetes Association (ADA) guidelines recommend moderate-intensity statin therapy in all people ages 40-75 years. This can also be considered in patients ages 20-39 years with additional ASCVD risk factors.[2] High-intensity statin therapy should be started in people ages 40-75 years at higher cardiovascular (CV) risk, including those with one or more ASCVD risk factors, with the aim of reducing low-density lipoprotein cholesterol (LDL-C) by ≥50% of baseline and achieving an LDL-C goal of <70 mg/dL (<1.81 mmol/L).[2] European guidelines recommended a more aggressive target for LDL-C of <55 mg/dL (<1.42 mmol/L) in very high-risk patients. This includes patients with 10-year CVD risk ≥20% using the SCORE2-Diabetes algorithm, or severe target end-organ damage.[77] Moderate-intensity statin therapy has been defined as treatment that generally lowers LDL-C level by 30% to 50%, while high-intensity statin therapy lowers it by ≥50%.[100] Low-dose statin therapy is generally not recommended in people with diabetes, but 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.[2]

In people ages 40-75 years at higher CV risk, especially those with multiple CVD risk factors and LDL-C ≥70 mg/dL (≥1.81 mmol/L), the ADA recommends that ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (e.g., alirocumab, evolocumab) may be added to maximum tolerated statin therapy.[2]

In people intolerant of statin therapy, treatment with bempedoic acid is recommended as an alternative cholesterol-lowering therapy.[2]

For adults ages >75 years already established on statin therapy, it is reasonable to continue treatment; for those not already on a statin, it may be reasonable to initiate moderate-intensity statin therapy following discussion of the potential benefits and risks.[2]

Icosapent ethyl may be considered for people with ASCVD or other CV risk factors who are on a statin and have controlled LDL-C but elevated triglycerides (135-499 mg/dL [1.53-5.64 mmol/L]).[2][281][293]

If triglyceride levels exceed 500 mg/dL (5.65 mmol/L), addition of fibrates may be beneficial to reduce risk of pancreatitis.[281] Fibrates 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 ASCVD outcomes.[2] Furthermore, caution is recommended as statin and fibrate therapy can increase the risk of myositis and rhabdomyolysis.

Consult a specialist for guidance on treating pregnant women; some of these drugs are contraindicated or not recommended in pregnant women (e.g., statins, bempedoic acid).

For information on lipid management in adults with diabetes with established ASCVD (secondary prevention), see Diabetic cardiovascular disease.

For information on lipid management in adults with diabetes with established chronic kidney disease (secondary prevention), see Diabetic kidney disease.

Primary options

atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily

rosuvastatin: moderate intensity: 5-10 mg orally once daily; high intensity: 20-40 mg orally once daily

simvastatin: moderate intensity: 20-40 mg orally once daily; increased risk of myopathy with 80 mg/day dose

pravastatin: moderate intensity: 40-80 mg orally once daily

lovastatin: moderate intensity: 40-80 mg orally (immediate-release) once daily

fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily, or 80 mg orally (extended-release) once daily

pitavastatin: moderate intensity: 1-4 mg orally once daily

Secondary options

atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily

rosuvastatin: moderate intensity: 5-10 mg orally once daily; high intensity: 20-40 mg orally once daily

simvastatin: moderate intensity: 20-40 mg orally once daily; increased risk of myopathy with 80 mg/day dose

pravastatin: moderate intensity: 40-80 mg orally once daily

lovastatin: moderate intensity: 40-80 mg orally (immediate-release) once daily

fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily, or 80 mg orally (extended-release) once daily

pitavastatin: moderate intensity: 1-4 mg orally once daily

-- AND --

ezetimibe: 10 mg orally once daily

atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily

rosuvastatin: moderate intensity: 5-10 mg orally once daily; high intensity: 20-40 mg orally once daily

simvastatin: moderate intensity: 20-40 mg orally once daily; increased risk of myopathy with 80 mg/day dose

pravastatin: moderate intensity: 40-80 mg orally once daily

lovastatin: moderate intensity: 40-80 mg orally (immediate-release) once daily

fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily, or 80 mg orally (extended-release) once daily

pitavastatin: moderate intensity: 1-4 mg orally once daily

-- AND --

evolocumab: 140 mg subcutaneously every 2 weeks; or 420 mg subcutaneously once monthly

alirocumab: 75-150 mg subcutaneously every 2 weeks; or 300 mg subcutaneously once monthly

atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily

rosuvastatin: moderate intensity: 5-10 mg orally once daily; high intensity: 20-40 mg orally once daily

simvastatin: moderate intensity: 20-40 mg orally once daily; increased risk of myopathy with 80 mg/day dose

pravastatin: moderate intensity: 40-80 mg orally once daily

lovastatin: moderate intensity: 40-80 mg orally (immediate-release) once daily

fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily, or 80 mg orally (extended-release) once daily

pitavastatin: moderate intensity: 1-4 mg orally once daily

-- AND --

icosapent ethyl: 2 g orally twice daily

atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily

rosuvastatin: moderate intensity: 5-10 mg orally once daily; high intensity: 20-40 mg orally once daily

simvastatin: moderate intensity: 20-40 mg orally once daily, increased risk of myopathy with 80 mg/day dose

pravastatin: moderate intensity: 40-80 mg orally once daily

lovastatin: moderate intensity: 40-80 mg orally (immediate-release) once daily

fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily, or 80 mg orally (extended-release) once daily

pitavastatin: moderate intensity: 1-4 mg orally once daily

-- AND --

fenofibrate: 40-160 mg orally once daily

Tertiary options

bempedoic acid: 180 mg orally once daily

Consider – antiplatelet therapy

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Consider –

antiplatelet therapy

Treatment recommended for SOME patients in selected patient group

The routine use of aspirin for primary prevention of diabetic cardiovascular disease (CVD) is not generally recommended. However, in patients with diabetes ages ≥50 years who have at least one additional CVD risk factor (e.g., hypertension, hyperlipidemia, family history of coronary artery disease, current or past smoker, or chronic kidney disease) and who have no indicators of high bleeding risk (e.g., anemia or prior significant bleeding episodes), aspirin therapy may be considered as a primary prevention strategy following discussion on the benefits versus increased risk of bleeding.[2] Coronary calcium score can be used to assess CVD risk and therefore help determine an indication for aspirin.[2][75][298]

The main adverse effect of antiplatelet therapy is an increased risk of gastrointestinal bleeding. For patients ages >70 years, the risk of bleeding increases, and aspirin is generally not recommended for primary prevention in this population.[2][299] Of note, 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.[300]

For information on antiplatelet therapy in adults with diabetes with established CVD (secondary prevention), see Diabetic cardiovascular disease.

For information on antiplatelet therapy in adults with diabetes with established chronic kidney disease (secondary prevention), see Diabetic kidney disease.

Primary options

aspirin: 75-162 mg orally once daily

ACUTE

marked hyperglycemia nonpregnant: serum glucose ≥300 mg/dL (≥16.7 mmol/L) or HbA1c >10% (>86 mmol/mol) or symptomatic

1st line – basal-bolus insulin + cardiovascular risk reduction/lifestyle measures

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1st line –

basal-bolus insulin + cardiovascular risk reduction/lifestyle measures

Insulin therapy is required if there is evidence of ongoing catabolism (weight loss, hypertriglyceridemia and ketosis), symptoms of hyperglycemia (polyuria and polydipsia) or when HbA1c or blood glucose levels are very high (i.e., HbA1c >10% [>86 mmol/mol] and/or blood glucose ≥300 mg/dL [≥16.7 mmol/L]), regardless of background glucose-lowering therapy or disease stage.[2] The primary advantage of insulin is that it lowers glucose in a dose-dependent manner and thus can address almost any level of blood glucose.[106] As glucose toxicity resolves, simplifying the medication plan and/or changing to noninsulin agents is often possible.[2]

Individuals with uncontrolled marked hyperglycemia will typically require initiation of basal and bolus insulin therapy at higher doses (0.2 units/kg/day of basal, and 0.2 units/kg/day of bolus mealtime/prandial insulin), with the bolus/prandial insulin being divided between the three meals (e.g., if the dose is 24 units, then divide that by 3 to get 8 units per meal, with the option to redistribute these mealtime doses slightly if the size of the meal is known).

For individuals with more modest hyperglycemia, insulin therapy can be started with long-acting insulin at 0.1 to 0.2 units/kg/day in the morning or bedtime. Adjustments can be made by 2-4 units every 3 days until fasting blood glucose levels are within target range. Addition of bolus/prandial insulin should be considered for individuals reaching a background insulin dose of 0.5 units/kg/day, individuals experiencing a greater than 50 mg/dL (2.8 mmol/L) drop in glucose overnight, or individuals not reaching glycemic goals despite controlled fasting morning glucose values (uncontrolled postprandial glucose).[2] A once-daily prandial dose of 4 units or 10% of the amount of basal insulin, given with the largest meal or the meal with the greatest postprandial excursion, is a safe estimate for initiating therapy. To avoid an imbalance in the ratio of basal to prandial insulin, the same number of units of prandial insulin should be subtracted from the basal insulin dose.[2]

If premeal glucose values remain over target, rapid-acting insulin can be added at meals (approximately 4 units) and titrated by 2 units every 3 days until within the desired range. It is common to start rapid-acting insulin with the meal with the largest blood glucose excursion and add injections for other meals as needed. Consult specialist as needed for guidance on dose.

Choice of insulin regimen should be individualized. A basal-bolus regimen typically consists of a long-acting basal insulin analog (e.g., insulin glargine or insulin degludec) injection once daily and a rapid-acting insulin analog (e.g., insulin lispro, insulin aspart, insulin glulisine) injected before each meal. Intermediate NPH (neutral protamine Hagedorn) insulin and short-acting (regular) insulin can also be used. Observational studies suggest regular and NPH insulins can be as effective as analog insulins in terms of glucose management, serious hypoglycemia risk, and mortality and cardiovascular events.[268] [ ] They may be less expensive than insulin analogs, and for individuals with relaxed HbA1c goals, low rates of hypoglycemia, and prominent insulin resistance, as well as those with cost concerns, they may be the appropriate choice of therapy.[2] Of note, however, the Endocrine Society recommends that for patients at high risk of hypoglycemia, insulin analogs are preferred (for both basal and bolus insulin) over NPH and regular insulin.[103] This recommendation is based on moderate-certainty evidence demonstrating reduced mild-moderate and severe hypoglycemia with rapid-acting analogs compared with regular insulin, and reduced severe hypoglycemia with long-acting analogs compared with NPH insulin.[103] Long-acting analogs also have the added benefit of once-daily dosing (whereas NPH insulin is often injected twice daily), which may simplify treatment and be more desirable for patients.[103]

Premixed insulin is available in various ratios of rapid-acting/NPH and regular/NPH insulin combinations. When injected before (typically) breakfast and dinner meals, it can sometimes be used effectively to cover both basal and prandial insulin needs in appropriate individuals (desire for no more than 2 injections per day, less insulin-sensitive and hypoglycemia-prone, and willing to eat consistent meals on a reasonably consistent schedule). For many, however, the greater flexibility and adaptability of a basal (background) and bolus (mealtime) regimen outweighs the potential convenience of premixed insulin. Premixed insulin may start at a dose of 0.1 to 0.2 units/kg dosed twice a day before breakfast and evening meal, and titrated up until goals are achieved or hypoglycemia prevents further titration.

Insulin delivery devices (insulin pens) that can be adjusted to administer set doses of insulin are widely available, and offer increased convenience and accuracy in insulin dosing. Less frequently, insulin pumps and patch pump systems are used in individuals with type 2 diabetes who require multiple daily dose insulin.[2] While allowing improved precision in insulin administration and dosing, they require significant engagement and involvement by the user to achieve clinical benefits beyond multiple daily dose injection-based therapy.

Another route of delivery for prandial or correction insulin doses is via inhalation. Inhaled insulin has a very rapid onset.[2] It may be an option for patients who would otherwise delay initiating or intensifying insulin therapy because they are unwilling or unable to use injectable insulin.[269] Use of inhaled insulin may result in a decline in lung function (reduced forced expiratory volume in 1 second [FEV₁]). Inhaled insulin is contraindicated in individuals with chronic lung disease, such as asthma and chronic obstructive pulmonary disease, and is not recommended in individuals who smoke or who recently stopped smoking. All individuals require spirometry (FEV₁) testing to identify potential lung disease prior to and after starting inhaled insulin therapy.[2]

Cardiovascular risk reduction (blood pressure and lipid control and consideration of antiplatelet therapy) should be instituted.

Noninsulin glucose-lowering agents may be continued upon initiation of insulin therapy (unless contraindicated or not tolerated) for ongoing glycemic and metabolic benefits (i.e., weight, cardiometabolic, or kidney benefits).[2] Metformin is typically started or continued at the time of initiation of insulin, unless not tolerated or contraindicated.[2][106] While consideration should be given to discontinuing sulfonylurea therapy in individuals initiating insulin because of additive hypoglycemia risk, other noninsulin therapies can often be continued if an individual is benefiting.[2][106][270]

Primary options

insulin NPH

and

insulin regular

insulin glargine

insulin degludec

-- AND --

insulin lispro

insulin aspart

insulin glulisine

insulin NPH/insulin regular

insulin aspart protamine/insulin aspart

insulin lispro protamine/insulin lispro

insulin degludec/insulin aspart

Secondary options

insulin glargine

insulin degludec

-- AND --

insulin inhaled

Consider – metformin

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Consider –

metformin

Treatment recommended for SOME patients in selected patient group

Metformin is typically given adjunctively, in the absence of nausea/vomiting or volume depletion. Metformin has a favorable safety profile, is associated with a low risk of hypoglycemia, probably has cardiovascular benefit, and is low cost.[2][139][140]

Metformin reduces hyperglycemia by decreasing hepatic gluconeogenesis and glycogenolysis.

The most common adverse effects are diarrhea, bloating, and abdominal discomfort, which can be attenuated by initiating slowly 500 mg orally once a day with a meal, increasing as needed by 500 mg/day every 1-2 weeks until full dose of 1000 mg twice a day is reached.[2] The extended-release formulation of metformin may be recommended to prevent gastrointestinal (GI) symptoms; however, one systematic review and meta-analysis found minimal improvement in GI symptoms with the extended-release versus immediate-release formulations.[162]

Metformin is contraindicated if estimated glomerular filtration rate (eGFR) is <30 mL/minute/1.73 m². A dose reduction should be considered when eGFR is <45 mL/minute/1.73 m² in patients continuing on existing therapy. However, metformin should not be initiated in patients with an eGFR of 30-45 mL/minute/1.73 m².[106][141] Dose reduction may also be considered in some patients with eGFR 45-59 mL/minute/1.73 m² who are at high risk of lactic acidosis.[141]

Individuals treated with metformin are at increased risk for vitamin B12 deficiency, and periodic testing for vitamin B12 deficiency and B12 supplementation may be needed.[2]

Primary options

metformin: 500 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 2000 mg/day; 850 mg orally (immediate-release) once daily initially, increase gradually according to response, maximum 2000 mg/day; 500-1000 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 2000-2500 mg/day (depending on brand used)

Consider – glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist

Back

Consider –

glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist

Treatment recommended for SOME patients in selected patient group

If insulin is used, combination therapy with a GLP-1 receptor agonist or a dual GIP/GLP-1 receptor agonist is recommended for greater glycemic efficacy, as well as the beneficial effects of these drugs on reducing weight and hypoglycemia risk (as lower insulin doses can be used), reducing cardiovascular events (liraglutide, dulaglutide, and semaglutide), and slowing chronic kidney disease progression (semaglutide).[2]

Fixed-ratio combinations of GLP-1 receptor agonists and basal insulin (if available) give the option of convenience with fewer injections, increased efficacy, and reduced risk of adverse effects.[151]

Insulin dosing should be reassessed upon addition or dose escalation of the GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist, with a reduction in dose required to reduce risk of hypoglycemia.[2]

Primary options

liraglutide: 0.6 mg subcutaneously once daily initially, increase by 0.6 mg/day increments at weekly intervals according to response, maximum 1.8 mg/day

dulaglutide: 0.75 mg subcutaneously once weekly initially, may increase to 1.5 mg once weekly if response is inadequate, then increase by 1.5 mg/week increments every 4 weeks according to response, maximum 4.5 mg/week

semaglutide: 0.25 mg subcutaneously once weekly for 4 weeks initially, then increase to 0.5 mg once weekly for at least 4 weeks, then may increase to 1 mg once weekly for at least 4 weeks if response is inadequate, then may increase to 2 mg once weekly if response is inadequate; 3 mg orally once daily for 30 days initially, then increase to 7 mg once daily for at least 30 days, then may increase to 14 mg once daily if response is inadequate

exenatide: 5 micrograms subcutaneously twice daily initially, then may increase to 10 micrograms twice daily in one month; 2 mg subcutaneously (extended-release) once weekly

tirzepatide: 2.5 mg subcutaneously once weekly for 4 weeks, followed by 5 mg once weekly, then may increase by 2.5 mg/week every 4 weeks, maximum 15 mg/week

without marked hyperglycemia nonpregnant asymptomatic: serum glucose <300 mg/dL (<16.7 mmol/L) or HbA1c <10% (<86 mmol/mol)

HbA1c above goal at diagnosis

1st line – metformin + cardiovascular risk reduction/lifestyle measures

Back

1st line –

metformin + cardiovascular risk reduction/lifestyle measures

All patients should receive stratified glycemic management upon diagnosis. Pharmacotherapy is recommended to reduce risk of microvascular (nephropathy, retinopathy, neuropathy) and macrovascular (myocardial infarction, stroke, peripheral vascular disease) complications, and is guided by patient-specific factors such as comorbidities and patient preferences, as well as external factors such as safety profile and cost.[2] It should be started at the time of diagnosis unless there are contraindications.[2]

HbA1c goals should be individualized.[2] The American Diabetes Association (ADA) recommends a general target HbA1c goal of <7% (<53 mmol/mol) for nonpregnant adult patients. If using a continuous glucose monitoring (CGM) device to assess glycemia, a parallel goal is time in range >70% with time below range <4% and time <54 mg/dL (<3 mmol/L) <1%.[2] Less stringent goals may be appropriate for people with a limited life expectancy or if the harms of stringent treatment may outweigh the benefits (e.g., in some older adults, people with a history of severe hypoglycemia, and those with limited life expectancies, advanced microvascular or macrovascular complications, or comorbid conditions).[2][25]

Generally, metformin is the recommended first-choice pharmacotherapy and should be started at diagnosis in the absence of contraindications, although for patients with atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or chronic kidney disease (CKD), there is increasing evidence that sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists should be prioritized for their cardiorenal protective effects.[106] Metformin is popular due to its favorable safety profile, low risk of hypoglycemia, likely cardiovascular benefit, and low cost.[2][139][140] Metformin decreases hepatic glucose production, diminishes intestinal absorption of glucose, and enhances insulin sensitivity.[160]

The most common adverse effects are diarrhea, bloating, and abdominal discomfort, which can be attenuated by initiating slowly 500 mg orally once a day with a meal, increasing as needed by 500 mg/day every 1-2 weeks until full dose of 1000 mg orally twice per day is reached.[2] The extended-release formulation of metformin may be recommended to prevent gastrointestinal (GI) symptoms; however, one systematic review and meta-analysis found minimal improvement in GI symptoms with the extended-release versus immediate-release formulations.[162]

Metformin is cleared by renal filtration, and very high circulating levels (e.g., as a result of overdose or acute renal failure) have been associated with lactic acidosis. However, the occurrence of this complication is now known to be very rare, and metformin may be safely used in people with estimated glomerular filtration rate (eGFR) rate ≥30 mL/minute/1.73 m².[2]

Metformin is contraindicated if eGFR is <30 mL/minute/1.73 m². A dose reduction should be considered when eGFR is <45 mL/minute/1.73 m² in patients continuing on existing therapy. However, metformin should not be initiated in patients with an eGFR of 30-45 mL/minute/1.73 m².[106][141] Dose reduction may also be considered in some patients with eGFR 45-59 mL/minute/1.73 m² who are at high risk of lactic acidosis.[141]

Metformin is associated with vitamin B12 deficiency in up to 1 in 10 people, with the risk increasing with dose and duration of treatment; periodic testing of B12 levels is recommended in people treated with metformin for extended periods of time.[2][163]

Those unable to take metformin due to contraindications or intolerance can either use an alternative noninsulin agent or insulin therapy. The American Diabetes Association recommends a GLP-1 receptor agonist over insulin when possible.[2]

General nutrition and healthy lifestyle knowledge (including an individualized nutrition and exercise plan and nonsmoking) can improve glycemic control and quality of life.[57][102]Powers MA, Bardsley JK, Cypress M, et al. Diabetes self-management education and support in adults with type 2 diabetes: a consensus report of the American Diabetes Association, the Association of Diabetes Care & Education Specialists, the Academy of Nutrition and Dietetics, the American Academy of Family Physicians, the American Academy of PAs, the American Association of Nurse Practitioners, and the American Pharmacists Association. Diabetes Care. 2020 Jul;43(7):1636-49. In most patients with type 2 diabetes and overweight or obesity, ≥5% weight loss is recommended through diet, physical activity, and behavioral therapy.[2] The benefits of weight loss are progressive, and so more intensive weight loss goals (i.e., 15%) may be beneficial to maximize benefit.[2] Long-term support programs may be required to ensure maintenance of weight loss.[2]

Cardiovascular risk reduction (blood pressure and lipid management and consideration of antiplatelet therapy) should be instituted.

Primary options

Consider – sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor and/or glucagon-like peptide-1 (GLP-1) receptor agonist

Back

Consider –

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor and/or glucagon-like peptide-1 (GLP-1) receptor agonist

Treatment recommended for SOME patients in selected patient group

SGLT2 inhibitors with a demonstrated CVD benefit include empagliflozin, canagliflozin, and dapagliflozin. The only dual SGLT1/SGLT2 inhibitor currently available is sotagliflozin. GLP-1 receptor agonists with a demonstrated CVD benefit include liraglutide, semaglutide, and dulaglutide.

For patients in whom ASCVD predominates (e.g., previous myocardial infarction, unstable angina, ischemic stroke, or indicators of high CV risk present), either a GLP-1 receptor agonist or an SGLT2 inhibitor can be used.[2][106] 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, dyslipidemia, or albuminuria.[106] GLP-1 receptor agonists, particularly dulaglutide and semaglutide, have shown better results in stroke prevention than other glucose-lowering therapies; accordingly, American College of Physicians guidelines specify that GLP-1 receptor agonists should be prioritized over SGLT2 inhibitors in patients with an increased risk for stroke.[148] If HbA1c remains above target on either an SGLT2 inhibitor or a GLP-1 receptor agonist, combined therapy with an SGLT2 inhibitor plus a GLP-1 receptor agonist may be considered, because this may provide additive reduction in the risk of adverse CV and kidney events.[2][141][152]

For those patients in whom HF (with either preserved or reduced ejection fraction) predominates, an SGLT2 inhibitor or a dual SGLT1/SGLT2 inhibitor should be favored over GLP-1 receptor agonists in order to reduce the risk of worsening HF and CV death, as well as to improve symptoms, physical limitations, and quality of life.[2] It should be noted that the dual SGLT1/SGLT2 inhibitor sotagliflozin is not currently approved for glycemic management of type 2 diabetes; however, in practice, it does lower glucose effectively.[191]

In patients with CKD, an SGLT2 inhibitor should be favored to reduce CKD progression and risk of CV events (although patients may be offered a GLP-1 receptor agonist if an SGLT2 inhibitor is not tolerated or contraindicated).[2][106][153]McDonagh TA, Metra M, Adamo M, et al. 2023 focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2024 Jan;26(1):5-17.

Reported adverse effects of SGLT2 and dual SGLT1/SGLT2 inhibitors include a higher rate of genitourinary infections (reported to be typically mild and treatable), diabetic ketoacidosis (DKA), acute kidney injury, fracture, and/or amputation.[196][197][198][199][200] The Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) warn of cases of necrotizing fasciitis of the perineum (also known as Fournier gangrene) observed in post-marketing surveillance.[204][205] 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.

The most common adverse effects of GLP-1 receptor agonists are gastrointestinal, particularly nausea, vomiting, and diarrhea; these are frequent but tend to reduce over time.[220] An association with pancreatitis and pancreatic cancer has been reported in clinical trials; these drugs should be used with caution in patients with a history of pancreatitis.[2][220] GLP-1 receptor agonists have also been associated with increased risk of gallbladder and biliary diseases including cholelithiasis and cholecystitis.[220] Patients should be counseled about potential for ileus.[2] Hypoglycemia risk is increased with concomitant sulfonylureas and insulin use. Treatment deintensification of these agents or of diuretics, particularly in older and frail individuals, is recommended to avoid hypoglycemia and hypovolemia.[220] DKA has been reported in patients on a combination of a GLP-1 receptor agonist and insulin when the insulin was either rapidly reduced or discontinued; insulin reductions should therefore be undertaken in a cautious stepwise manner, with capillary blood glucose monitoring.[220][223] In rodent studies, GLP-1 receptor agonists were associated with medullary thyroid cancer, resulting in a 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.[220][224][225][226][227][228] The FDA and the European Medicines Agency are 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.[229][230]

For further information, see Diabetic cardiovascular disease and Diabetic kidney disease.

Primary options

empagliflozin: 10 mg orally once daily, increase according to response, maximum 25 mg/day

canagliflozin: 100 mg orally once daily initially, increase according to response, maximum 300 mg/day

dapagliflozin: 5 mg orally once daily initially, increase according to response, maximum 10 mg/day

sotagliflozin: 200 mg orally once daily initially, increase according to response, maximum 400 mg/day

-- AND / OR --

liraglutide: 0.6 mg subcutaneously once daily initially, increase by 0.6 mg/day increments at weekly intervals according to response, maximum 1.8 mg/day

HbA1c above goal on metformin

1st line – sodium-glucose cotransporter-2 (SGLT2) inhibitor added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

Back

1st line –

sodium-glucose cotransporter-2 (SGLT2) inhibitor added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

If patients are above target after an initial period of treatment (e.g., 3 months) on metformin, a second agent may be added based on individualized assessment of necessary clinical benefit, safety considerations, costs, and patient preference.[2] Early combination therapy may be considered for some patients at the start of treatment in order to achieve more rapid attainment of glycemic goals.[2]

American College of Physicians (ACP) guidelines now recommend that SGLT2 inhibitors (or glucagon-like peptide-1 [GLP-1] receptor agonists) should be the add-on therapy of choice for all patients with inadequate glycemic control, regardless of cardiovascular disease (CVD) status.[148]

SGLT2 inhibitors inhibit renal glucose reabsorption. The resulting increase in glycosuria improves glycemic control, promotes weight loss, and has a diuretic effect that reduces blood pressure.[164] They have intermediate-to-high glycemic efficacy, with lower glycemic efficacy at lower estimated glomerular filtration rate (eGFR).[106] As a result, when used specifically for the treatment of hyperglycemia, they are not recommended for initiation in patients with eGFR <30 mL/minute/1.73 m² (empagliflozin, canagliflozin, bexagliflozin) or <45 mL/minute/1.73 m² (dapagliflozin, ertugliflozin). An initial decline in eGFR is commonly observed after initiation but this decline is not associated with subsequent risk of CV or kidney events.[195] Thus, SGLT2 inhibitors should not be interrupted or discontinued in response to an initial eGFR decline.

Compared with usual care or placebo, SGLT2 inhibitors also reduce the risk for all-cause mortality, major adverse cardiovascular events (MACE), progression of chronic kidney disease (CKD), and hospitalization due to congestive heart failure (HF).[148] They have been shown to improve CV outcomes in patients with HF regardless of left ventricular ejection fraction, and irrespective of type 2 diabetes status.[156][173][177][178][179][180][181][182][183][184] While the glucose-lowering effects of these drugs are blunted with eGFR <45 mL/minute/1.73 m², the renal and CV benefits are still seen at eGFR levels as low as 20 mL/minute/1.73 m², even with no significant change in glucose.[2] SGLT2 inhibitors with a demonstrated CVD benefit include empagliflozin, canagliflozin, and dapagliflozin. Dapagliflozin has been shown to improve renal outcomes in patients with CKD, regardless of the presence or absence of diabetes, suggesting that these benefits are independent of the drug’s glucose-lowering effect.[174] Ertugliflozin and bexagliflozin are approved for glycemic management but not for cardiorenal protection.

Cardiovascular risk reduction (blood pressure and lipid control and consideration of antiplatelet therapy) should continue.

Primary options

-- AND --

empagliflozin: 10 mg orally once daily, increase according to response, maximum 25 mg/day

canagliflozin: 100 mg orally once daily initially, increase according to response, maximum 300 mg/day

dapagliflozin: 5 mg orally once daily initially, increase according to response, maximum 10 mg/day

ertugliflozin: 5 mg orally once daily initially, increase according to response, maximum 15 mg/day

bexagliflozin: 20 mg orally once daily

Consider – glucagon-like peptide-1 (GLP-1) receptor agonist

Back

Consider –

glucagon-like peptide-1 (GLP-1) receptor agonist

Treatment recommended for SOME patients in selected patient group

For patients at high risk of atherosclerotic cardiovascular disease (ASCVD), or with established ASCVD or chronic kidney disease, if HbA1c remains above target and the patient is already taking an SGLT2 inhibitor, combined therapy with an SGLT2 inhibitor plus a GLP-1 receptor agonist may be considered, because this may provide additive reduction in the risk of adverse cardiovascular and kidney events.[2]

The most common adverse effects of GLP-1 receptor agonists are gastrointestinal, particularly nausea, vomiting, and diarrhea; these are frequent but tend to reduce over time.[220] An association with pancreatitis and pancreatic cancer has been reported in clinical trials; these drugs should be used with caution in patients with a history of pancreatitis.[2][220] GLP-1 receptor agonists have also been associated with increased risk of gallbladder and biliary diseases including cholelithiasis and cholecystitis.[220] Patients should be counseled about potential for ileus.[2] Hypoglycemia risk is increased with concomitant sulfonylureas and insulin use. Treatment deintensification of these agents or of diuretics, particularly in older and frail individuals, is recommended to avoid hypoglycemia and hypovolemia.[220] Diabetic ketoacidosis (DKA) has been reported in patients on a combination of a GLP-1 receptor agonist and insulin when the insulin was either rapidly reduced or discontinued; insulin reductions should therefore be undertaken in a cautious stepwise manner, with capillary blood glucose monitoring.[220][223] In rodent studies, GLP-1 receptor agonists were associated with medullary thyroid cancer, resulting in a 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 conflicing evidence as to whether this risk applies in humans.[220][224][225][226][227][228] The Food and Drug Administration (FDA) and the European Medicines Agency are 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.[229][230]

Primary options

liraglutide: 0.6 mg subcutaneously once daily initially, increase by 0.6 mg/day increments at weekly intervals according to response, maximum 1.8 mg/day

1st line – glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

Back

1st line –

glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

If patients are above target after an initial period of treatment (e.g., 3 months) on metformin, a second agent may be added based on individualized assessment of necessary clinical benefit, safety considerations, costs, and patient preference.[2] Early combination therapy may also be considered for some patients at the start of treatment in order to achieve more rapid attainment of glycemic goals.[2]

GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists are highly effective antihyperglycemic drugs.[2] They augment glucose-dependent insulin secretion and glucagon suppression, decelerate gastric emptying, curb postmeal glycemic increments, and reduce appetite, energy intake, and body weight.[106] They are primarily available as injectable therapies (subcutaneous administration), with one oral GLP-1 receptor agonist now available (semaglutide).[106]

American College of Physicians (ACP) guidelines now recommend that GLP-1 receptor agonists (or sodium-glucose cotransporter-2 [SGLT2] inhibitors) should be the add-on therapy of choice for all patients with inadequate glycemic control, regardless of cardiovascular disease (CVD) status.[148]

The American Diabetes Association (ADA) recommends prioritizing GLP-1 receptor agonists or the dual GIP/GLP-1 receptor agonist tirzepatide when considering glycemic management in patients who have overweight or obesity (in light of the beneficial effects on weight loss of these drugs).[2]

Beyond improving HbA1c in adults with type 2 diabetes, specific GLP-1 receptor agonists (liraglutide, dulaglutide, and semaglutide) have also been approved for reducing risk of major cardiovascular (CV) events in adults with type 2 diabetes with established CVD or multiple CV risk factors.[106] Liraglutide has been shown to reduce major CV events, CV mortality, and all-cause mortality in diabetes patients with coronary heart disease.[211] Dulaglutide and semaglutide have both been shown to reduce major CV events, but not all-cause or CV mortality.[212][213][214] In contrast to other GLP-1 receptor agonists, exenatide has not been shown to reduce major CV events.[217]

Semaglutide and liraglutide have also been shown to offer kidney-protective effects, which appeared more pronounced in patients with preexisting chronic kidney disease (CKD).[208][218] However, renal protection from GLP-1 receptor agonists is more modest than that offered by SGLT2 inhibitors.[208]

Unlike for SGLT2 inhibitors, the evidence for GLP-1 receptor agonists in reducing heart failure has been inconsistent across trials.

Tirzepatide is the first dual GIP/GLP-1 receptor agonist to be approved; it is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It is suitable for patients with overweight or obesity without gastroparesis who desire weight loss, are willing to take injections, and can tolerate the common adverse effect of initial nausea. It has been shown to have a greater effect on glucose levels and weight control than selective GLP-1 receptor agonists, without increased risk of hypoglycemia.[233][234][235] CV safety trials are under way.

The most common adverse effects of GLP-1 receptor agonists are gastrointestinal, particularly nausea, vomiting, and diarrhea; these are frequent but tend to reduce over time.[220] 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 Food and Drug Administration (FDA) and the European Medicines Agency (EMA) agreed that there was insufficient evidence to confirm an increased risk of pancreatic cancer with use of GLP-1-based therapies.[222] Nonetheless, GLP-1 receptor agonists should be used with caution in patients with a history of pancreatitis.[2][220] GLP-1 receptor agonists have also been associated with increased risk of gallbladder and biliary diseases including cholelithiasis and cholecystitis.[220] Patients should also be counseled about potential for ileus.[2] In rodent studies, GLP-1 receptor agonists were associated with medullary thyroid cancer, resulting in a 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.[220][224][225][226][227][228] The EMA and FDA are 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.[229][230]

The adverse effect profile for tirzepatide is as per GLP-1 receptor agonists, with the most common adverse effects being gastrointestinal. Like GLP-1 receptor agonists, tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia syndrome type 2. It should also be avoided in patients with a history of gastroparesis.[2]

Hypoglycemia risk is increased with concomitant sulfonylureas and insulin use. Treatment deintensification of these agents or of diuretics, particularly in older and frail individuals, is recommended to avoid hypoglycemia and hypovolemia.[220] Diabetic ketoacidosis (DKA) has been reported in patients on a combination of a GLP-1 receptor agonist and insulin when the insulin was either rapidly reduced or discontinued; insulin reductions should therefore be undertaken in a cautious stepwise manner, with capillary blood glucose monitoring.[220][223]

CV risk reduction (blood pressure and lipid management and consideration of antiplatelet therapy) should continue.

Primary options

-- AND --

liraglutide: 0.6 mg subcutaneously once daily initially, increase by 0.6 mg/day increments at weekly intervals according to response, maximum 1.8 mg/day

exenatide: 5 micrograms subcutaneously twice daily initially, then may increase to 10 micrograms twice daily in one month; 2 mg subcutaneously (extended-release) once weekly

tirzepatide: 2.5 mg subcutaneously once weekly for 4 weeks, followed by 5 mg once weekly, then may increase by 2.5 mg/week every 4 weeks, maximum 15 mg/week

Consider – sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor

Back

Consider –

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor

Treatment recommended for SOME patients in selected patient group

For patients at high risk of atherosclerotic cardiovascular disease (ASCVD), or with established ASCVD or chronic kidney disease, if HbA1c remains above target and the patient is already taking a glucagon-like peptide-1 (GLP-1) receptor agonist or glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, combined therapy with a GLP-1 receptor agonist or GIP/GLP-1 receptor agonist plus an SGLT2 inhibitor or dual SGLT1/SGLT2 inhibitor may be considered, because this may provide additive reduction in the risk of adverse cardiovascular and kidney events.[2] SGLT2 inhibitors with a demonstrated CVD benefit include empagliflozin, canagliflozin, and dapagliflozin. The only dual SGLT1/SGLT2 inhibitor currently available is sotagliflozin.

For further information, see Diabetic cardiovascular disease and Diabetic kidney disease.

Primary options

empagliflozin: 10 mg orally once daily, increase according to response, maximum 25 mg/day

canagliflozin: 100 mg orally once daily initially, increase according to response, maximum 300 mg/day

dapagliflozin: 5 mg orally once daily initially, increase according to response, maximum 10 mg/day

sotagliflozin: 200 mg orally once daily initially, increase according to response, maximum 400 mg/day

1st line – dipeptidyl peptidase-4 (DPP-4) inhibitor added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

Back

1st line –

dipeptidyl peptidase-4 (DPP-4) inhibitor added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

If patients are above target after after an initial period of treatment (e.g., 3 months) on metformin, a second agent may be added based on individualized assessment of necessary clinical benefit, safety considerations, costs, and patient preference.[2] Early combination therapy may be considered for some patients at the start of treatment in order to achieve more rapid attainment of glycemic goals.[2]

Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are generally preferred due to their additional cardiorenal benefits. However, DPP-4 inhibitors are still listed as an antihyperglycemic treatment option by the American Diabetes Association (ADA).[2] They might be considered for older people or others for whom adverse effects are especially worrisome, when hyperglycemia is mild and mainly postprandial, and when insulin sensitivity is high. These characteristics are common in Asian populations where DPP-4 inhibitors are widely used.[150] It is noteworthy that this class of drugs has been reported to provide better glycemic control for Asian populations than for other populations.[239] It should be noted that, in contrast to the ADA, the American College of Physicians specifically recommends against DPP-4 inhibitors 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.[148]

DPP-4 inhibitors increase endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) levels, resulting in a lowering of fasting and postprandial glucose concentrations.[238] They have a modest glucose-lowering effect, are well tolerated and weight-neutral, and do not cause hypoglycemia, but confer no mortality benefit.[106] They do not lower glucose as much as metformin, sulfonylureas, thiazolidinediones, or GLP-1 receptor agonists.

Saxagliptin and alogliptin have been associated with an increased risk of hospitalization for heart failure (HF) and should be avoided in patients with known HF.[240] If a patient develops HF while taking saxagliptin or alogliptin, the drug should be discontinued.[240] In patients with existing cardiovascular disease or high cardiovascular (CV) risk, other glucose-lowering drugs with CV benefit (e.g., sodium-glucose cotransporter-2 [SGLT2] inhibitors or GLP-1 receptor agonists) are preferred.[2] If circumstances require use of DPP-4 inhibitor therapy in these patients, saxagliptin and alogliptin should be avoided and an alternative drug from this class (e.g., sitagliptin, linagliptin) selected.

While DPP-4 inhibitors are generally well tolerated, pancreatitis has been reported in clinical trials (although causality has not been established); the ADA advises discontinuation of the drug if pancreatitis is suspected.[2] An increased risk of acute liver injury and cholecystitis has also been reported.[241][242] There have been rare reports of arthralgia and bullous pemphigoid.[2]

CV risk reduction (blood pressure and lipid management and consideration of antiplatelet therapy) should continue.

Primary options

-- AND --

sitagliptin: 100 mg orally once daily

linagliptin: 5 mg orally once daily

alogliptin: 25 mg orally once daily

saxagliptin: 2.5 to 5 mg orally once daily

Consider – sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor

Back

Consider –

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor

Treatment recommended for SOME patients in selected patient group

The American Diabetes Association recommends that people with type 2 diabetes with established atherosclerotic cardiovascular disease (ASCVD) or indicators of high cardiovascular (CV) risk, established chronic kidney disease (CKD), or heart failure (HF) should use an SGLT2 inhibitor or dual SGLT1/SGLT2 inhibitor and/or a glucagon-like peptide-1 (GLP-1) receptor agonist with demonstrated cardiovascular disease (CVD) benefit as part of their comprehensive CV risk reduction regimen, independent of HbA1c or individualized HbA1c goal.[2] However, evidence and guidelines do not support combining a dipeptidyl peptidase-4 (DPP-4) inhibitor and a GLP-1 receptor agonist in the same regimen, and they are not approved for this purpose. Therefore, only an SGLT2 inhibitor should be added to a DPP-4 inhibitor for the purposes of cardiorenal protection in this population.

SGLT2 inhibitors with a demonstrated CVD benefit include empagliflozin, canagliflozin, and dapagliflozin. The only dual SGLT1/SGLT2 inhibitor currently available is sotagliflozin.

For patients in whom ASCVD predominates (e.g., previous myocardial infarction, unstable angina, ischemic stroke, or indicators of high CV risk present), an SGLT2 inhibitor with demonstrated CV benefit can be used.[2][106]

In people with established heart failure with either preserved or reduced ejection fraction, an SGLT2 inhibitor or a dual SGLT1/SGLT2 inhibitor with demonstrated benefit in this patient population is recommended to reduce the risk of worsening heart failure and CV death.[2]

In patients with CKD, an SGLT2 inhibitor should be favored to reduce CKD progression and risk of CV events.[2][106][153]McDonagh TA, Metra M, Adamo M, et al. 2023 focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2024 Jan;26(1):5-17.

These agents are being used for their cardiorenal protective benefits and their use in these patients is independent of HbA1c or individualized HbA1c goal.

For further information, see Diabetic cardiovascular disease and Diabetic kidney disease.

Primary options

empagliflozin: 10 mg orally once daily, increase according to response, maximum 25 mg/day

canagliflozin: 100 mg orally once daily initially, increase according to response, maximum 300 mg/day

dapagliflozin: 5 mg orally once daily initially, increase according to response, maximum 10 mg/day

sotagliflozin: 200 mg orally once daily initially, increase according to response, maximum 400 mg/day

1st line – sulfonylurea or meglitinide added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

Back

1st line –

sulfonylurea or meglitinide added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are generally preferred due to their additional cardiorenal benefits. However, there is still a role for sulfonylureas and meglitinides. Along with metformin and human insulin, sulfonylureas are among the more affordable antihyperglycemic drugs and are particularly useful if cost is a concern.[149]

Sulfonylureas (e.g., glimepiride, glipizide) stimulate the release of insulin from pancreatic beta-cells and have several extrapancreatic effects, including decreasing hepatic insulin clearance and reducing glucagon secretion.[243] They are the subject of long clinical experience and may reduce microvascular complications, but confer no mortality benefit and may cause weight gain and hypoglycemia.[106] Hypoglycemia is a major concern, especially in patients with irregular or unpredictable eating and exercise habits. [ ] Hypoglycemia risk is exacerbated by alcohol, salicylates, sulfa drugs, gemfibrozil, or warfarin. In general, longer-acting sulfonylureas such as glyburide are avoided because of concern about hypoglycemia. In older adult patients, treatment should start with very low doses. Glimepiride may be the preferred sulfonylurea due to its dual hepatic/renal clearance and potentially lower risk of hypoglycemia. Adverse cardiovascular (CV) outcomes have been reported with sulfonylureas in some studies, although systematic reviews have not found an increase in all-cause mortality compared with other active treatments.[106][244]

Similar to sulfonylureas, meglitinides (e.g., repaglinide, nateglinide) work by stimulating the release of insulin. They only have a modest effect on HbA1c but may help with postprandial hyperglycemia.[247] Due to their fast onset and short duration of action, they can be used flexibly around mealtimes and adjusted to fit around individual eating habits, which may be beneficial for some patients.[248] Generally, however, they are a less preferred option than sulfonylureas. They are associated with weight gain and may cause hypoglycemia (although less frequently than sulfonylureas).[249] If a meal is skipped, the dose of meglitinide should be held to avoid hypoglycemia.

CV risk reduction (blood pressure and lipid management and consideration of antiplatelet therapy) should continue.

Primary options

-- AND --

glimepiride: 1-2 mg orally once daily initially, increase by 1-2 mg/day increments every 1-2 weeks, maximum 4 mg twice daily

glipizide: 2.5 to 5 mg orally (immediate-release) once daily initially, increase by 2.5 to 5 mg/day increments every 1-2 weeks, maximum 10 mg twice daily; 5 mg orally (extended-release) once daily initially, increase to 10 mg once daily in 1-2 weeks if necessary

Secondary options

-- AND --

repaglinide: 0.5 to 1 mg orally up to four times daily initially, increase by 0.5 to 1 mg/day increments every week, maximum 4 mg four times daily

nateglinide: 60-120 mg orally three times daily initially

Consider – sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor and/or glucagon-like peptide-1 (GLP-1) receptor agonist

Back

Consider –

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor and/or glucagon-like peptide-1 (GLP-1) receptor agonist

Treatment recommended for SOME patients in selected patient group

The American Diabetes Association (ADA) recommends that people with type 2 diabetes with established atherosclerotic cardiovascular disease (ASCVD) or indicators of high cardiovascular (CV) risk, chronic kidney disease (CKD), or heart failure (HF) should use an SGLT2 inhibitor or dual SGLT1/SGLT2 inhibitor and/or a GLP-1 receptor agonist with demonstrated cardiovascular disease (CVD) benefit as part of their comprehensive CV risk reduction regimen, independent of HbA1c.[2]

For patients in whom ASCVD predominates (e.g., previous myocardial infarction, unstable angina, ischemic stroke, or indicators of high CV risk present), either a GLP-1 receptor agonist or an SGLT2 inhibitor with demonstrated CV benefit can be used.[2][106] 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, dyslipidemia, or albuminuria.[106] American College of Physicians guidelines specify that GLP-1 receptor agonists should be prioritized in patients with an increased risk for stroke.[148] If HbA1c remains above target on either an SGLT2 inhibitor or a GLP-1 receptor agonist, combined therapy with an SGLT2 inhibitor plus a GLP-1 receptor agonist may be considered, because this may provide additive reduction in the risk of adverse CV and kidney events.[2][141][152]

For those patients in whom HF (with either preserved or reduced ejection fraction) predominates, an SGLT2 inhibitor or a dual SGLT1/SGLT2 inhibitor should be favored over a GLP-1 receptor agonist in order to reduce the risk of worsening HF and CV death, as well as to improve symptoms, physical limitations, and quality of life.[2] It should be noted that sotagliflozin is not approved for glycemic control, only cardiorenal protection.

A reduction in the dose of sulfonylurea may be needed when used with a GLP-1 receptor agonist in order to reduce the risk of hypoglycemia.

For further information, see Diabetic cardiovascular disease and Diabetic kidney disease.

Primary options

empagliflozin: 10 mg orally once daily, increase according to response, maximum 25 mg/day

canagliflozin: 100 mg orally once daily initially, increase according to response, maximum 300 mg/day

dapagliflozin: 5 mg orally once daily initially, increase according to response, maximum 10 mg/day

sotagliflozin: 200 mg orally once daily initially, increase according to response, maximum 400 mg/day

-- AND / OR --

liraglutide: 0.6 mg subcutaneously once daily initially, increase by 0.6 mg/day increments at weekly intervals according to response, maximum 1.8 mg/day

2nd line – thiazolidinedione added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

Back

2nd line –

thiazolidinedione added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

If patients are above target after an initial period of treatment (e.g., 3 months) on metformin, a second agent may be added based on individualized assessment of necessary clinical benefit, safety considerations, costs, and patient preference. Early combination therapy may be considered for some patients at the start of treatment in order to achieve more rapid attainment of glycemic goals.[2]

Thiazolidinediones lower blood glucose effectively by increasing insulin sensitivity through their action at peroxisome proliferator-activated receptor (PPAR)-gamma receptors. Their complete mechanism of action is not fully understood. Hypoglycemia is rare unless combined with sulfonylurea or insulin.

Thiazolidinediones are generally considered second-line to other oral antihyperglycemic agents due to their adverse effect profile. Notably, they increase the risk of congestive heart failure (HF), often causing weight gain and edema.[106] They are not recommended in patients with New York Heart Association (NYHA) class III-IV HF and should be used with caution and frequent monitoring in patients with NYHA class I-II HF.[250] They should be discontinued in patients who develop signs and symptoms of HF. They may also increase fracture rates in both women and men.

Pioglitazone is the most widely used drug in this class. Evidence suggests that it decreases the risk of major adverse cardiac events in patients with diabetes or prediabetes.[252][253][254] It has also been shown to improve hepatic steatosis, inflammation, and liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD; previously nonalcoholic fatty liver disease).[255] However, it is associated with significantly increased risk of HF, edema, and weight gain.[253] It 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.[256][257][258][259][260]

Cardiovascular risk reduction (blood pressure and lipid management and consideration of antiplatelet therapy) should continue.

Primary options

and

pioglitazone: 15 mg orally once daily initially, increase gradually according to response, usual dose 30 mg/day, maximum 45 mg/day

Consider – sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor and/or glucagon-like peptide-1 (GLP-1) receptor agonist

Back

Consider –

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor and/or glucagon-like peptide-1 (GLP-1) receptor agonist

Treatment recommended for SOME patients in selected patient group

The American Diabetes Association (ADA) recommends that people with type 2 diabetes with indicators of high cardiovascular (CV) risk, or established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or heart failure (HF) should use an SGLT2 inhibitor or a dual SGLT1/SGLT2 inhibitor and/or a GLP-1 receptor agonist with demonstrated cardiovascular disease (CVD) benefit as part of their comprehensive CV risk reduction regimen, independent of HbA1c.[2]

For patients in whom ASCVD predominates (e.g., previous myocardial infarction, unstable angina, ischemic stroke, or indicators of high CV risk present), either a GLP-1 receptor agonist or an SGLT2 inhibitor with demonstrated CV benefit can be used.[2][106] 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, dyslipidemia, or albuminuria.[106] American College of Physicians guidelines specify that GLP-1 receptor agonists should be prioritized in patients with an increased risk for stroke.[148] If HbA1c remains above target on either an SGLT2 inhibitor or a GLP-1 receptor agonist, combined therapy with an SGLT2 inhibitor plus a GLP-1 receptor agonist may be considered, because this may provide additive reduction in the risk of adverse CV and kidney events.[2][141][152]

For those patients in whom HF (with either preserved or reduced ejection fraction) predominates, an SGLT2 inhibitor or a dual SGLT1/SGLT2 inhibitor should be favored over GLP-1 receptor agonists in order to reduce the risk of worsening HF and CV death, as well as to improve symptoms, physical limitations, and quality of life.[2] It should be noted that sotagliflozin is not approved for glycemic control, only cardiorenal protection.

For further information, see Diabetic cardiovascular disease and Diabetic kidney disease.

Primary options

empagliflozin: 10 mg orally once daily, increase according to response, maximum 25 mg/day

canagliflozin: 100 mg orally once daily initially, increase according to response, maximum 300 mg/day

dapagliflozin: 5 mg orally once daily initially, increase according to response, maximum 10 mg/day

sotagliflozin: 200 mg orally once daily initially, increase according to response, maximum 400 mg/day

-- AND / OR --

liraglutide: 0.6 mg subcutaneously once daily initially, increase by 0.6 mg/day increments at weekly intervals according to response, maximum 1.8 mg/day

2nd line – basal insulin added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

Back

2nd line –

basal insulin added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

If patients are above target after an initial period of treatment (e.g., 3 months) on metformin, intensification to basal insulin is an option; however, the American Diabetes Association recommends considering a glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist prior to insulin if injectable therapy is needed and the patient is not already being treated with one of these drugs.[2] If HbA1c remains above target despite the addition of a GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist, or if a patient is already taking one of these drugs, or if they are not appropriate or insulin is preferred, a basal insulin regimen should be initiated.

Insulin is a necessary treatment in at least 20% to 30% of those with type 2 diabetes in order to achieve recommended treatment goals, related to decreasing islet cell insulin secretion after a long duration of type 2 diabetes.

Basal insulin refers to longer-acting insulin that is designed to cover the body’s basal metabolic insulin requirement (regulating hepatic glucose production) and is the preferred initial insulin formulation in patients with type 2 diabetes.[106] Options include once- or twice-daily administration of intermediate-acting NPH (neutral protamine Hagedorn) insulin or the once-daily administration of the long-acting analogs insulin glargine or insulin degludec.[106] If affordable, basal insulin analog formulations are typically preferred to NPH insulin because of their reduced risk of hypoglycemia, particularly nocturnal hypoglycemia, when titrated to the same fasting glucose target.[106] However, observational studies suggest regular and NPH insulins can be as effective as analogs for glucose management, serious hypoglycemia risk, and mortality and CV events.[268] [ ] They are also significantly less expensive than analog insulins. For individuals with relaxed HbA1c goals, low rates of hypoglycemia, and prominent insulin resistance, as well as those with cost concerns, NPH and regular insulin may be the appropriate choice of therapy.[2] For patients at high risk of hypoglycemia, however, including those with hypoglycemia unawareness or potentiating comorbidities, insulin analogs are preferred (for both basal and bolus insulin) over NPH and regular insulin.[103] Basal insulins are typically administered before bedtime, but, with newer analogs, more flexibility in the timing of insulin injection is possible (i.e., any time of the day).[106]

Patients should perform periodic home glucose monitoring or utilize continuous glucose monitoring, and be instructed to watch for signs of hypoglycemia (shaking, sweating, intensive hunger, irritability, weakness, confusion) and promptly treat with 15-20 g glucose orally. Recurrent severe hypoglycemia requires ongoing close monitoring and adjustment of eating and medications to prevent recurrence.

Treatment with basal insulin can be started with 0.1 units/kg/dose subcutaneously at bedtime and increase by 2-3 units every several days until morning fasting blood glucose averages 90-130 mg/dL (for those with an HbA1c goal of <7% [<53 mmol/mol]). Consultation with a specialist should be considered for further guidance if the patient is having difficulty achieving blood glucose levels or experiencing symptoms of hyper- or hypoglycemia.

In patients with obesity, who typically are insulin-resistant, 5% to 10% increases in insulin dose every 3-5 days are often needed until glucose control is achieved, while taking care to avoid hypoglycemia.

Noninsulin glucose-lowering agents may be continued upon initiation of insulin (unless contraindicated or not tolerated) for ongoing glycemic and metabolic benefits (i.e., weight, cardiometabolic, or kidney benefits).[2] Metformin is typically started or continued at the time of initiation of insulin, unless not tolerated or contraindicated.[2][106] While consideration should be given to discontinuing sulfonylureas in individuals initiating insulin therapy because of additive hypoglycemia risk, other noninsulin therapies can often be continued if an individual is benefiting.[2][106][270]

Cardiovascular risk reduction (blood pressure and lipid management and consideration of antiplatelet therapy) should continue.

Primary options

-- AND --

insulin NPH

insulin glargine

insulin degludec

Plus – glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist

Back

Plus –

glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist

Treatment recommended for ALL patients in selected patient group

If insulin is used, combination therapy with a GLP-1 receptor agonist or a dual GIP/GLP-1 receptor agonist (e.g., tirzepatide) is recommended for greater glycemic efficacy, as well as the beneficial effects of these drugs on reducing weight, reducing hypoglycemia risk (as lower insulin doses can be used), reducing cardiovascular events (GLP-1 receptor agonists), and slowing chronic kidney disease progression (semaglutide).[2] Insulin dosing should be reassessed upon addition or dose escalation of the GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist, with a reduction in dose required to reduce risk of hypoglycemia.[2]

The most common adverse effects of GLP-1 receptor agonists are gastrointestinal, particularly nausea, vomiting, and diarrhea; these are frequent but tend to reduce over time.[220] An association with pancreatitis and pancreatic cancer has been reported in clinical trials; these drugs should be used with caution in patients with a history of pancreatitis.[2][220] GLP-1 receptor agonists have also been associated with increased risk of gallbladder and biliary diseases including cholelithiasis and cholecystitis.[220] Patients should be counseled about potential for ileus.[2] Hypoglycemia risk is increased with concomitant sulfonylureas and insulin use. Treatment deintensification of these agents or of diuretics, particularly in older and frail individuals, is recommended to avoid hypoglycemia and hypovolemia.[220] Diabetic ketoacidosis (DKA) has been reported in patients on a combination of a GLP-1 receptor agonist and insulin when the insulin was either rapidly reduced or discontinued; insulin reductions should therefore be undertaken in a cautious stepwise manner, with capillary blood glucose monitoring.[220][223] In rodent studies, GLP-1 receptor agonists were associated with medullary thyroid cancer, resulting in a 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.[220][224][225][226][227][228] The Food and Drug Administration (FDA) and the European Medicines Agency are 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.[229][230]

Primary options

liraglutide: 0.6 mg subcutaneously once daily initially, increase by 0.6 mg/day increments at weekly intervals according to response, maximum 1.8 mg/day

exenatide: 5 micrograms subcutaneously twice daily initially, then may increase to 10 micrograms twice daily in one month; 2 mg subcutaneously (extended-release) once weekly

tirzepatide: 2.5 mg subcutaneously once weekly for 4 weeks, followed by 5 mg once weekly, then may increase by 2.5 mg/week every 4 weeks, maximum 15 mg/week

Consider – sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor

Back

Consider –

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor

Treatment recommended for SOME patients in selected patient group

For patients at high risk of atherosclerotic cardiovascular disease (ASCVD), or with established ASCVD or chronic kidney disease, if HbA1c remains above target and the patient is already taking a glucagon-like peptide-1 (GLP-1) receptor agonist or glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, combined therapy with a GLP-1 receptor agonist or GIP/GLP-1 receptor agonist plus an SGLT2 inhibitor or dual SGLT1/SGLT2 inhibitor may be considered, because this may provide additive reduction in the risk of adverse cardiovascular and kidney events.[2] SGLT2 inhibitors with a demonstrated cardiovascular disease benefit include empagliflozin, canagliflozin, and dapagliflozin. The only dual SGLT1/SGLT2 inhibitor currently available is sotagliflozin.

For further information, see Diabetic cardiovascular disease and Diabetic kidney disease.

Primary options

empagliflozin: 10 mg orally once daily, increase according to response, maximum 25 mg/day

canagliflozin: 100 mg orally once daily initially, increase according to response, maximum 300 mg/day

dapagliflozin: 5 mg orally once daily initially, increase according to response, maximum 10 mg/day

sotagliflozin: 200 mg orally once daily initially, increase according to response, maximum 400 mg/day

HbA1c above goal on metformin + second noninsulin agent or basal insulin

1st line – individualized augmented regimen + continued cardiovascular risk reduction/lifestyle measures

Back

1st line –

individualized augmented regimen + continued cardiovascular risk reduction/lifestyle measures

Because type 2 diabetes is a progressive disease in many individuals, maintenance of glycemic goals often requires combination therapy. If HbA1c remains above target, tailoring of the medication plan should be undertaken as appropriate; this may involve adding new agents to the existing drug(s), or weaning the current drug(s) and starting new agents.[2] Selection of additional agents should be based on individualized assessment of glycemic and weight goals, the presence of other comorbidities (e.g., atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease), risk of hypoglycemia, costs, and patient preference.[2]

Metformin serves as the basis for most 3-drug combinations in the absence of contraindications. Additional agents for 3-drug regimens are selected from the same choices as for 2-drug regimens: SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, sulfonylureas, meglitinides, thiazolidinediones, and insulin.[2]

However, evidence and guidelines do not support combining a DPP-4 inhibitor and a GLP-1 receptor agonist in the same regimen, and they are not approved for this purpose.

For patients already on basal insulin, addition of a GLP-1 receptor agonist should be considered if not already in the regimen before intensification to basal-bolus insulin.[2]

To reduce the risk of hypoglycemia, a sulfonylurea should be tapered if insulin is started. A reduction in dose of sulfonylurea or insulin or both may be needed when used with a GLP-1 receptor agonist, in order to reduce the risk of hypoglycemia. A DPP-4 inhibitor (less commonly, a thiazolidinedione, considering risks versus benefit) might be considered as an add-on to a metformin/sulfonylurea combination in people at high risk for hypoglycemia.

The UK Medicines and Healthcare products Regulatory Agency warns of cases of diabetic ketoacidosis in patients with type 2 diabetes on a combination of a GLP-1 receptor agonist and insulin who had doses of concomitant insulin rapidly reduced or discontinued.[223]

Cardiovascular risk reduction (blood pressure and lipid management and consideration of antiplatelet therapy) should continue.

1st line – switch to basal-bolus insulin + continued cardiovascular risk reduction/lifestyle measures

Back

1st line –

switch to basal-bolus insulin + continued cardiovascular risk reduction/lifestyle measures

If HbA1c still remains above target, prandial (bolus) insulin may need to be added.[2] Options include regular insulin and rapid-acting insulin analogs (insulin aspart, insulin glulisine, and insulin lispro). A once-daily prandial dose of 4 units or 10% of the amount of basal insulin, given with the largest meal or the meal with the greatest postprandial excursion, is a safe estimate for initiating therapy. To avoid an imbalance in the ratio of basal to prandial insulin, the same number of units of prandial insulin should be subtracted from the basal insulin dose.[2] The prandial insulin plan can then be intensified based on individual needs. Premeal insulin is tailored to anticipated meals as well as to premeal glucose testing. The dose should generally be increased by 1-2 units or 10% to 15% twice weekly until desired levels of premeal (70-130 mg/dL [3.9-7.2 mmol/L]) and bedtime (100-140 mg/dL [5.6-7.8 mmol/L]) glucose are achieved, unless hypoglycemia supervenes. If HbA1c remains above target, additional injections of prandial insulin can be initiated in a stepwise manner until the patient is on a full basal-bolus regimen (i.e., basal insulin and prandial insulin with each meal).[2]

Titration can be based on home self-monitored blood glucose or continuous glucose monitoring. Individuals with type 2 diabetes are generally more insulin resistant than those with type 1 diabetes, require higher daily doses, and have lower rates of hypoglycemia.[2] Therapeutic inertia in intensification of insulin therapy should be avoided, and, when clinicians are not familiar with multiple daily injection therapy, referral to specialist care and/or diabetes self-management education and support is warranted.

Choice of insulin regimen should be individualized. The Endocrine Society recommends that for patients at high risk of hypoglycemia, insulin analogs are preferred (both for basal and bolus insulin) over human insulins.[103] This recommendation is based on moderate-certainty evidence that found reduced mild-moderate and severe hypoglycemia with rapid-acting insulin analogs compared with regular insulin, and reduced severe hypoglycemia with long-acting insulin analogs compared with NPH (neutral protamine Hagedorn) insulin.[103]

Insulin delivery devices (insulin pens) that can be adjusted to administer set doses of insulin are widely available, and offer increased convenience and accuracy in insulin dosing. Less frequently, insulin pumps and patch pump systems are used in individuals with type 2 diabetes requiring multiple daily dose insulin.[2] While allowing improved precision in insulin administration and dosing, insulin pump systems require significant engagement and involvement by the individuals using the systems to achieve clinical benefits beyond multiple daily dose injection-based therapy.

Premixed insulin is available in various ratios of rapid-acting/NPH and regular/NPH insulin combinations. When injected before (typically) breakfast and dinner meals, premixed insulin can sometimes be used effectively to cover both basal and prandial insulin needs in appropriate individuals (desire for no more than 2 injections per day, less insulin-sensitive and hypoglycemia-prone, and willing to eat consistent meals on a reasonably consistent schedule). For many, however, the greater flexibility and adaptability of a basal (background) and bolus (mealtime) regimen outweighs the potential convenience of premixed insulin.

Cardiovascular risk reduction (blood pressure and lipid management and consideration of antiplatelet therapy) should continue.

Insulin dose varies; consult specialist for guidance on dose.

Primary options

insulin NPH

and

insulin regular

insulin glargine

insulin degludec

-- AND --

insulin lispro

insulin aspart

insulin glulisine

insulin NPH/insulin regular

insulin aspart protamine/insulin aspart

insulin lispro protamine/insulin lispro

insulin degludec/insulin aspart

Secondary options

insulin glargine

insulin degludec

-- AND --

insulin inhaled

Plus – glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist

Back

Plus –

glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist

Treatment recommended for ALL patients in selected patient group

If insulin is used, combination therapy with a GLP-1 receptor agonist or a dual GIP/GLP-1 receptor agonist (e.g., tirzepatide) is recommended for greater glycemic efficacy, durability of treatment effect, and weight and hypoglycemia benefit (the latter due to the facilitation of lower insulin doses).[2] Insulin dosing should be reassessed upon addition or dose escalation of the GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist, with a reduction in dose required to reduce risk of hypoglycemia.[2]

The most common adverse effects of GLP-1 receptor agonists are gastrointestinal, particularly nausea, vomiting, and diarrhea; these are frequent but tend to reduce over time.[220] An association with pancreatitis and pancreatic cancer has been reported in clinical trials; these drugs should be used with caution in patients with a history of pancreatitis.[2][220] GLP-1 receptor agonists have also been associated with increased risk of gallbladder and biliary diseases including cholelithiasis and cholecystitis.[220] Patients should be counseled about potential for ileus.[2] Hypoglycemia risk is increased with concomitant sulfonylureas and insulin use. Treatment deintensification of these agents or of diuretics, particularly in older and frail individuals, is recommended to avoid hypoglycemia and hypovolemia.[220] Diabetic ketoacidosis (DKA) has been reported in patients on a combination of a GLP-1 receptor agonist and insulin when the insulin was either rapidly reduced or discontinued; insulin reductions should therefore be undertaken in a cautious stepwise manner, with capillary blood glucose monitoring.[220][223] In rodent studies, GLP-1 receptor agonists were associated with medullary thyroid cancer, resulting in a 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.[220][224][225][226][227][228] The Food and Drug Administration (FDA) and the European Medicines Agency are 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.[229][230]

The adverse effect profile for tirzepatide is similar to that of GLP-1 receptor agonists, with the most common adverse effects being gastrointestinal. Like GLP-1 receptor agonists, tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia syndrome type 2. It should also be avoided in patients with a history of gastroparesis.[2]

Primary options

liraglutide: 0.6 mg subcutaneously once daily initially, increase by 0.6 mg/day increments at weekly intervals according to response, maximum 1.8 mg/day

exenatide: 5 micrograms subcutaneously twice daily initially, then may increase to 10 micrograms twice daily in one month; 2 mg subcutaneously (extended-release) once weekly

tirzepatide: 2.5 mg subcutaneously once weekly for 4 weeks, followed by 5 mg once weekly, then may increase by 2.5 mg/week every 4 weeks, maximum 15 mg/week

Consider – continued metformin

Back

Consider –

continued metformin

Treatment recommended for SOME patients in selected patient group

Metformin can be continued with basal-bolus insulin. Metformin has a favorable safety profile, is associated with a low risk of hypoglycemia, probably has cardiovascular benefit, and is low cost.[2][139][140] Metformin reduces hyperglycemia by decreasing hepatic gluconeogenesis and glycogenolysis.

The most common adverse effects are diarrhea, bloating, and abdominal discomfort, which can be attenuated by initiating slowly 500 mg orally once per day with a meal, increasing as needed by 500 mg/day every 1-2 weeks until full dose of 1000 mg twice per day is reached.[2] The extended-release formulation of metformin may be recommended to prevent gastrointestinal (GI) symptoms; however, one systematic review and meta-analysis found minimal improvement in GI symptoms with the extended-release versus immediate-release formulations.[162]

Individuals treated with metformin are at increased risk for vitamin B12 deficiency, and periodic testing for vitamin B12 deficiency and B12 supplementation may be needed.[2]

Primary options

Consider – sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor

Back

Consider –

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor

Treatment recommended for SOME patients in selected patient group

For patients at high risk of atherosclerotic cardiovascular disease (ASCVD), or with established ASCVD or chronic kidney disease, if HbA1c remains above target and the patient is already taking a glucagon-like peptide-1 (GLP-1) receptor agonist or glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, combined therapy with a GLP-1 receptor agonist or GIP/GLP-1 receptor agonist plus an SGLT2 inhibitor or dual SGLT1/SGLT2 inhibitor may be considered, because this may provide additive reduction in the risk of adverse cardiovascular and kidney events.[2] SGLT2 inhibitors with a demonstrated cardiovascular disease benefit include empagliflozin, canagliflozin, and dapagliflozin. The only dual SGLT1/SGLT2 inhibitor currently available is sotagliflozin.

For further information, see Diabetic cardiovascular disease and Diabetic kidney disease.

Primary options

empagliflozin: 10 mg orally once daily, increase according to response, maximum 25 mg/day

canagliflozin: 100 mg orally once daily initially, increase according to response, maximum 300 mg/day

dapagliflozin: 5 mg orally once daily initially, increase according to response, maximum 10 mg/day

sotagliflozin: 200 mg orally once daily initially, increase according to response, maximum 400 mg/day

2nd line – bariatric surgery

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2nd line –

bariatric surgery

Bariatric surgery (also referred to as metabolic surgery) is the most effective long-term treatment for obesity and many of its associated health conditions.[32] It is an option for type 2 diabetes management in some patients with obesity. Patients must be surgical candidates. Randomized clinical trials have shown a benefit with regard to diabetes remission, glycemic control, need for glucose-lowering drugs, quality of life, and reduction in cardiovascular risk factor markers over the short term (e.g., 1-3 years) in people with type 2 diabetes compared with medical therapy alone, as well as for possible prevention of type 2 diabetes.[32][301][302][303][304][305][306] A study of adults with obesity with preexisting diabetes found that bariatric surgery is associated with substantially lower all-cause mortality rates and longer median life expectancy (9.3 years longer than those without surgery).[307]

Health insurers in the US generally restrict payment for bariatric surgery, but the eligibility criteria have been slowly expanding over time. The American Diabetes Association recommends bariatric 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.[2] The European Society of Cardiology recommends it 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 pharmacotherapy.[77]

Vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) are the most commonly performed procedures.[32] 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.[2] Cohort studies suggest that both RYGB and VSG lead to diabetes remission that lasts a mean of about 5 years in more than half of patients, and significantly reduce mortality, stroke, myocardial infarction, and microvascular complications in those with type 2 diabetes.[308][309][310]

Surgery should be done in a high-volume, experienced center to reduce the risk of perioperative and longer-term complications.[2] A comprehensive medical, psychological, and nutritional evaluation involving a multidisciplinary team should be completed before surgery is considered, to determine patient suitability and identify any issues that need addressing; lifelong follow-up, as well as cessation of tobacco, alcohol, and drugs, is also required.[32]

Postbariatric hypoglycemia can occur following RYGB, VSG, and other bariatric procedures.[2] Symptoms typically present >1 year after surgery, and may range in severity from sweating and tremor to loss of consciousness and seizures.[2] Management includes education, nutrition therapy with a specialist dietitian, and possibly medical treatment.[2] Continuous glucose monitoring is also advised.[2] Bariatric surgery procedures, in particular RYGB, have also been associated with subsequent alcohol-use disorder-related complications.[32][313] It is important to take this into account when selecting patients for these procedures, and to consider alcohol-related counseling.[313]

For more comprehensive information, see Obesity in adults.

pregnant

1st line – lifestyle measures + basal-bolus insulin + medication review

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1st line –

lifestyle measures + basal-bolus insulin + medication review

Women with diabetes who anticipate pregnancy or who are pregnant benefit from care by a specialized center whenever possible.[2] Patients will usually require more frequent and detailed monitoring throughout pregnancy.[315]

Self-monitoring of blood glucose (fasting, preprandial, and postprandial) is recommended when pregnant to help achieve optimal glucose levels.[2][315] Patients should monitor blood glucose from 4-7 times a day and have the pattern examined every few weeks early in pregnancy so that nutrition content and timing, exercise patterns, and insulin doses can be modified to achieve optimal control. Premeal insulin is tailored to anticipated meals as well as to premeal glucose testing. Although there is a paucity of literature on continuous glucose (CGM) systems among pregnancies complicated by type 2 diabetes, CGM technology has been shown to be safe and improve hyperglycemia and neonatal outcomes in patients with type 1 diabetes. Currently, CGM use in pregnancy should not be substituted for capillary blood glucose self-monitoring, but used in addition to optimize glycemia.[2][316]

American Diabetes Association guidelines recommend the following blood glucose targets in pregnant women with preexisting type 2 diabetes (the same as for gestational diabetes): 70-95 mg/dL (3.9-5.3 mmol/L) fasting and either 110-140 mg/dL (6.1-7.8 mmol/L) 1 hour postprandially or 100-120 mg/dL (5.6-6.7 mmol/L) 2 hours postprandially. HbA1c goal is individualized to <6% (<42 mmol/mol) or up to <7% (<53 mmol/mol) as necessary to prevent hypoglycemia.[2] Pregnant patients are more susceptible to hypoglycemia (which is exacerbated by strict glycemic targets) and should be educated on how to identify, avoid, and treat it promptly.[315]

Diet and lifestyle changes are key to managing preexisting diabetes in pregnancy.[315] Nutrition counseling should endorse a balance of macronutrients including nutrient-dense fruits, vegetables, legumes, whole grains, and healthy fats with omega-3 fatty acids that include nuts, seeds, and fish in the eating pattern.[2] Diets that severely restrict any macronutrient class should be avoided, specifically the ketogenic diet that lacks carbohydrates, the Paleo diet because of dairy restriction, and any diet characterized by excess saturated fats. Processed foods, fatty red meat, and sweetened foods and beverages should be limited.[2] Because glycemic goals in pregnancy are stricter than in nonpregnant individuals, it is important that pregnant people with diabetes eat consistent amounts of carbohydrates to match with insulin dosage and to avoid hyperglycemia or hypoglycemia. Referral to a registered dietitian nutritionist is important to establish a food plan and insulin-to-carbohydrate ratio and to determine weight gain goals. The quality of the carbohydrates should also be evaluated.[2]

In addition to lifestyle measures, most women will require insulin in order to achieve glycemic targets. Background insulin (e.g., NPH [neutral protamine Hagedorn] insulin or insulin glargine) may be combined with short- or rapid-acting insulin (regular insulin or the rapid-acting analogs insulin lispro and insulin aspart) before meals.[315] The American College of Obstetricians and Gynecologists advises that insulin lispro and insulin aspart be used preferentially over regular insulin because they have a more rapid onset of action, enabling the patient to administer their insulin right before the time of a meal rather than 10-15 minutes or longer before an anticipated meal.[315] Although their rapid onset of action improves concordance, patient satisfaction, and glycemic control, insulin lispro or insulin aspart can cause significant hypoglycemia if administered inappropriately. However, it appears that, generally, there are fewer hypoglycemic episodes with these rapid-acting analogs than with regular insulin.[315] Insulin requirements generally increase early in pregnancy, then decrease from about 8-16 weeks before rising throughout the rest of the pregnancy.[315]

Metformin has been used as an adjunct to insulin, but should be considered with caution.[316] The MiTy trial of pregnant people with type 2 diabetes found that metformin added to insulin resulted in lower gestational weight gain, lower overall insulin dose requirements, and fewer infants with macrosomia, but a significantly higher rate of small-for-gestational-age neonates, compared with insulin plus placebo.[317] Another study found no evidence of increased malformation risk with metformin versus insulin in the first trimester.[318]

A large cohort study using multinational databases found that periconceptional (from 90 days before the first day of the last menstrual period to the end of the first trimester) use of noninsulin antidiabetic drugs (sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, glucagon-like peptide-1 [GLP-1] receptor agonists, and sodium-glucose cotransporter-2 [SGLT2] inhibitors) was not associated with an increased risk of major congenital malformations compared with use of insulin in pregnant patients with type 2 diabetes who required treatment.[319] While this is promising, further research is needed to fully establish the safety of these newer drugs in pregnancy. ACE inhibitors, angiotensin-II receptor antagonists, and beta-blockers are not recommended in pregnancy and should be avoided. Statins are contraindicated in pregnancy and should be discontinued; however, practitioners need to consider the ongoing therapeutic needs of the individual patient, particularly those at very high risk for cardiovascular events.[320]

Women with preexisting type 2 diabetes should be assessed prenatally for diabetes complications and comorbidities.[315] They are at increased risk of development and/or progression of diabetic retinopathy during pregnancy, and should be counseled accordingly. A dilated eye exam should be performed prior to pregnancy or during the first trimester.[2] Assessment of renal function and blood pressure, and an ECG and lipid profile, is also recommended for those planning a pregnancy.[315] Due to the higher risk of fetal neural tube defects in pregnancies complicated by diabetes, patients with preexisting type 2 diabetes should be strongly advised to start taking folic acid once they are planning a pregnancy. This should be taken until 12 weeks of gestation.[315]

First-trimester anatomy ultrasonography is useful to identify major cardiac and central nervous system pathology early in this high-risk population.[316] Preexisting diabetes is associated with structural abnormalities of the fetal heart as well as diastolic dysfunction and performance. Therefore, comprehensive anatomy ultrasonography and consideration of a fetal echocardiogram in the second trimester are recommended. Serial biometry and prenatal fetal surveillance in the third trimester are useful to monitor fetal growth and status for delivery planning.[316]

Delivery timing should be individualized to account for clinical status, fetal well-being, glycemic control, and other comorbidities that increase the risk for perinatal complications.[316] Strict glycemic control throughout labor has been shown to improve postnatal transition and outcomes among patients with preexisting diabetes. Intravenous insulin infusion and dextrose protocols are necessary to achieve optimal predelivery glycemic control; these can be discontinued on delivery of the placenta.[316]

Patients with type 2 diabetes have significant decreases in drug requirements after delivery and interventions can be individualized to reach glycemic targets used in nonpregnant populations (70-180 mg/dL [3.9-10.0 mmol/L]).[316] Early lactation support and education for postpartum patients helps mitigate type 2 diabetes-associated delayed lactogenesis stage II and reduced milk supply.[316] There are insufficient data to determine the role of metformin as a galactagogue, but it has been used without adverse outcomes among breastfed infants. Because there are no breastmilk data for SGLT2 inhibitors and GLP-1 receptor agonists, these drugs are not encouraged for use during lactation.[316]

Insulin dose varies; consult specialist for guidance on dose.

Primary options

insulin NPH

insulin glargine

-- AND --

insulin lispro

insulin aspart

insulin regular

Plus – low-dose aspirin

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Plus –

low-dose aspirin

Treatment recommended for ALL patients in selected patient group

Patients with preexisting diabetes are at increased risk of preeclampsia, and it is recommended that they are started on prophylactic daily low-dose aspirin during pregnancy to reduce this risk: the American Diabetes Association recommends starting this treatment at 12-16 weeks gestation; similarly the American College of Obstetricians and Gynecologists advises that it be started between 12 and 28 weeks gestation, but ideally before 16 weeks.[2][315] Once started, it should be taken until delivery.[315] See Preeclampsia.

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Type 2 diabetes mellitus in adults

Treatment algorithm

Your Organizational Guidance

at initial diagnosis

lifestyle changes

glycemic management

blood pressure management

Primary options

lipid management

Primary options

Secondary options

Tertiary options

antiplatelet therapy

Primary options

marked hyperglycemia nonpregnant: serum glucose ≥300 mg/dL (≥16.7 mmol/L) or HbA1c >10% (>86 mmol/mol) or symptomatic

basal-bolus insulin + cardiovascular risk reduction/lifestyle measures

Primary options

Secondary options

metformin

Primary options

glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist

Primary options

without marked hyperglycemia nonpregnant asymptomatic: serum glucose <300 mg/dL (<16.7 mmol/L) or HbA1c <10% (<86 mmol/mol)

metformin + cardiovascular risk reduction/lifestyle measures

Primary options

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor and/or glucagon-like peptide-1 (GLP-1) receptor agonist

Primary options

sodium-glucose cotransporter-2 (SGLT2) inhibitor added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

Primary options

glucagon-like peptide-1 (GLP-1) receptor agonist

Primary options

glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

Primary options

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor

Primary options

dipeptidyl peptidase-4 (DPP-4) inhibitor added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

Primary options

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor

Primary options

sulfonylurea or meglitinide added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

Primary options

Secondary options

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor and/or glucagon-like peptide-1 (GLP-1) receptor agonist

Primary options

thiazolidinedione added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

Primary options

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor and/or glucagon-like peptide-1 (GLP-1) receptor agonist

Primary options

basal insulin added to continued metformin + continued cardiovascular risk reduction/lifestyle measures

Primary options

glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist

Primary options

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor

Primary options

individualized augmented regimen + continued cardiovascular risk reduction/lifestyle measures

switch to basal-bolus insulin + continued cardiovascular risk reduction/lifestyle measures

Primary options

Secondary options

glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist

Primary options

continued metformin

Primary options

sodium-glucose cotransporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor

Primary options

bariatric surgery

pregnant

lifestyle measures + basal-bolus insulin + medication review

Primary options

low-dose aspirin