Treatment algorithm
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
Although pharmacotherapy is usually indicated in patients with HbA1c >7%, 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 dietician.[2][70] 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.[71]
Nutrition therapy involves limiting caloric intake to achieve recommended weight, while offering a diversified and appealing menu of food choices. Nutrition advice needs to be tailored to the needs of each individual patient.[2][33][81] Reducing sugary beverage consumption (including soda, energy drinks, and fruit juice) is of benefit to many patients.
Moderate physical activity is recommended as tolerated to improve glycemic control, assist with weight maintenance, and reduce cardiovascular risk. It is recommended that, in general, adults should engage in 3 to 4 sessions of aerobic physical activity per week, with each session lasting on average 40 minutes and involving moderate- to vigorous-intensity physical activity.[86]
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.[33][83][84]
Alcohol use (more than 2 drinks daily for men or 1 for women) increases risk of hypoglycemia, as well as other untoward events.
Smoking cessation is imperative. Patients who smoke should be provided with smoking cessation resources and assistance.
Achieving recommended goals for weight management, nutrition, and physical activity benefits many aspects of health, including glucose, blood pressure, lipid control, and depression prevention or control, and decreases risk of major cardiovascular events and onset or progression of microvascular complications.
Treatment recommended for ALL patients in selected patient group
All patients should receive stratified glycemic management upon diagnosis.
HbA1c goals should be individualized,[88] and if HbA1c is above goal, pharmacotherapy recommended.
Metformin (along with comprehensive lifestyle modifications) should be initiated in all patients at diagnosis unless contraindicated, and often continues to be used as monotherapy in individuals with modest hyperglycemia.[2]
Choice of agents beyond metformin should be individualized, taking into account patient values and preferences, likelihood that an agent provides cardiorenal protection, adverse effect profiles, costs, and other factors.
See sections below for more information on choice of medication and dose.
Consult a specialist for guidance on treating pregnant women.
Treatment recommended for ALL patients in selected patient group
Primary options
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
or
chlorthalidone: 12.5 mg orally once daily initially, increase gradually according to response, maximum 50 mg/day
or
indapamide: 1.25 mg orally once daily initially, increase gradually according to response, maximum 5 mg/day
-- AND / OR --
lisinopril: 10 mg orally once daily initially, increase gradually according to response, maximum 40 mg/day
or
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
or
captopril: 25 mg orally twice daily initially, increase gradually according to response, maximum 200 mg/day
or
candesartan cilexetil: 4 mg orally once daily initially, increase gradually according to response, maximum 32 mg/day
or
irbesartan: 75 mg orally once daily initially, increase gradually according to response, maximum 300 mg/day
or
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
or
valsartan: 40-80 mg orally once daily initially, increase gradually according to response, maximum 320 mg/day
-- AND / OR --
amlodipine: 2.5 mg orally once daily initially, increase gradually according to response, maximum 10 mg/day
or
felodipine: 2.5 mg orally once daily initially, increase gradually according to response, maximum 10 mg/day
or
nifedipine: 30-60 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 90 mg/day
or
diltiazem: 120-180 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 480 mg/day
Adults with type 2 diabetes are twice as likely to die of stroke or myocardial infarction compared with those without diabetes, and they are more than 40 times more likely to die of macrovascular than microvascular complications of diabetes.[72][73][74] A primary goal of diabetes care is evidence-based management of cardiovascular risk factors to individualized goals.
Blood pressure guidelines differ somewhat regarding recommended blood pressure targets for those with diabetes; however, American Diabetes Association guidelines recommend a treatment goal of <140/90 mmHg or <130/80 mmHg for those with diabetes and cardiovascular disease or cardiovascular risk >15%.[2][69][139]
Combination therapy is often required to reach blood pressure goals. Antihypertensive therapy may be initiated with a thiazide (or thiazide-like) diuretic, a calcium-channel blocker, an ACE inhibitor, or an angiotensin-II receptor antagonist. Antihypertensive drugs for black people may be initiated with a thiazide diuretic or a calcium-channel blocker.[139] ACE inhibitors may reduce mortality and cardiovascular events more than angiotensin-II receptor antagonists.[77] Combining an ACE inhibitor with an angiotensin-II receptor antagonist is not recommended due to increased risk of adverse events.[140] However, most people with chronic kidney disease (CKD) should receive an ACE inhibitor or an angiotensin-II receptor antagonist as part of their regimen.[139] CKD is defined as (a) age <70 years with glomerular filtration rate (GFR) <60 mL/minute/1.73 m², or (b) people of any age with albuminuria >30 mg albumin/g of creatinine at any level of GFR.
If blood pressure remains uncontrolled on first-line therapies, discontinue or minimize interfering substances such as nonsteroidal anti-inflammatory drugs (NSAIDs), evaluate for secondary causes of hypertension (including obstructive sleep apnea), and consider the addition of a mineralocorticoid receptor agonist,[141] and/or refer to a hypertension specialist.
Beta-blockers are not contraindicated in people with diabetes but are less-preferred antihypertensive agents[139] and may mask symptoms of hypoglycemia.
Although ACE inhibitors have been reported to increase risk for hypoglycemia in conjunction with insulin or insulin secretagogue (sulfonylurea or meglitinide), the clinical relevance of these findings is uncertain, and in clinical practice these combinations are routinely used safely and effectively.[174] Concerns of hypoglycemia should not limit the use of these combinations, given the significant clinical benefits of this class of antihypertensives for individuals with type 2 diabetes.
Consult a specialist for guidance on treating pregnant women. ACE inhibitors, angiotensin-II receptor antagonists, and beta-blockers are not recommended in pregnancy and should be avoided if possible.
Treatment recommended for ALL patients in selected patient group
Primary options
atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily
OR
rosuvastatin: moderate intensity: 5-10 mg orally once daily; high intensity: 20-40 mg orally once daily
OR
simvastatin: moderate intensity: 20-40 mg orally once daily; increased risk of myopathy with 80 mg/day dose
OR
pravastatin: moderate intensity: 40-80 mg orally once daily
OR
lovastatin: moderate intensity: 40-80 mg orally (immediate-release) once daily
OR
fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily, or 80 mg orally (extended-release) once daily
OR
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
or
rosuvastatin: moderate intensity: 5-10 mg orally once daily; high intensity: 20-40 mg orally once daily
or
simvastatin: moderate intensity: 20-40 mg orally once daily; increased risk of myopathy with 80 mg/day dose
or
pravastatin: moderate intensity: 40-80 mg orally once daily
or
lovastatin: moderate intensity: 40-80 mg orally (immediate-release) once daily
or
fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily, or 80 mg orally (extended-release) once daily
or
pitavastatin: moderate intensity: 1-4 mg orally once daily
-- AND --
ezetimibe: 10 mg orally once daily
Tertiary options
atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily
or
rosuvastatin: moderate intensity: 5-10 mg orally once daily; high intensity: 20-40 mg orally once daily
or
simvastatin: moderate intensity: 20-40 mg orally once daily; increased risk of myopathy with 80 mg/day dose
or
pravastatin: moderate intensity: 40-80 mg orally once daily
or
lovastatin: moderate intensity: 40-80 mg orally (immediate-release) once daily
or
fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily, or 80 mg orally (extended-release) once daily
or
pitavastatin: moderate intensity: 1-4 mg orally once daily
-- AND --
ezetimibe: 10 mg orally once daily
-- AND --
evolocumab: 140 mg subcutaneously every 2 weeks; or 420 mg subcutaneously once monthly
or
alirocumab: 75-150 mg subcutaneously every 2 weeks; or 300 mg subcutaneously once monthly
OR
atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily
or
rosuvastatin: moderate intensity: 5-10 mg orally once daily; high intensity: 20-40 mg orally once daily
or
simvastatin: moderate intensity: 20-40 mg orally once daily; increased risk of myopathy with 80 mg/day dose
or
pravastatin: moderate intensity: 40-80 mg orally once daily
or
lovastatin: moderate intensity: 40-80 mg orally (immediate-release) once daily
or
fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily, or 80 mg orally (extended-release) once daily
or
pitavastatin: moderate intensity: 1-4 mg orally once daily
-- AND --
icosapent ethyl: 2 g orally twice daily
Adults with type 2 diabetes are twice as likely to die of stroke or myocardial infarction compared with those without diabetes, and they are more than 40 times more likely to die of macrovascular than microvascular complications of diabetes.[72][73][74] A primary goal of care is treatment of cardiovascular risk factors to individualized targets.[75]
High-intensity statin therapy is recommended as tolerated in diabetes patients with atherosclerotic cardiovascular disease, 10-year cardiovascular risk >20%, or low-density lipoprotein (LDL)-cholesterol ≥190 mg/dL. Otherwise, in those ages 40 to 75 years, moderate-intensity statin therapy should be considered.[68] The guidelines recommend an individualized approach for people aged >75 years. A moderate-intensity statin has been defined by the American College of Cardiology/American Heart Association as one that generally lowers LDL-cholesterol level by 30% to 50%, while a high-intensity statin has been defined as one that lowers LDL-cholesterol level by ≥50%.[68]
Combination therapy using statins and other lipid-lowering agents may be considered, especially in patients with very high CVD risk.[175][176] The risks of complications such as impaired liver or renal function, myositis, or rhabdomyolysis may increase when using statins in combination with other agents.[2] Statin therapy may have some beneficial (e.g., anti-inflammatory) effects independent of lipid lowering.
Ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (e.g., alirocumab, evolocumab) added to statin therapy may confer cardiovascular benefits to patients with diabetes and coronary heart disease who have LDL >70 mg/dL despite maximally-tolerated statin therapy.[2][144][146]
In individuals with established cardiovascular disease, or high cardiovascular risk on a statin with controlled LDL cholesterol but elevated triglycerides, the addition of icosapent ethyl has been shown to modestly reduce cardiovascular events.[2][147]
Consult a specialist for guidance on treating pregnant women. Statins are contraindicated in pregnancy. There is a lack of data on the use of ezetimibe and PCSK9 inhibitors in pregnancy.
Treatment recommended for SOME patients in selected patient group
Primary options
aspirin: 75-162 mg orally once daily
Secondary options
clopidogrel: 75 mg orally once daily
OR
aspirin: 75-162 mg orally once daily
-- AND --
clopidogrel: 75 mg orally once daily
or
ticagrelor: 90mg orally twice daily
or
prasugrel: body weight <60 kg: 5 mg orally once daily; body weight ≥60 kg: 10mg orally once daily
OR
aspirin: 75-162 mg orally once daily
and
rivaroxaban: 2.5 mg orally twice daily
Adults with cardiovascular disease should receive aspirin for secondary prevention.
Aspirin therapy may be considered for primary prevention in adults with type 2 diabetes ages 50 to 70 years who are at increased cardiovascular risk and do not have a contraindication to aspirin therapy. However, this should only be after a discussion and shared decision making regarding the benefits versus the comparable risks of complications of therapy from bleeding.[2] Aspirin use is not recommended for individuals at low cardiovascular risk.
For patients aged over 70 years, the risk of bleeding increases and aspirin is generally not recommended for primary prevention in this population.[150]
Clopidogrel is an alternative for patients with aspirin allergy or intolerance.
Dual antiplatelet therapy with low-dose aspirin and a P2Y12 inhibitor (e.g., clopidogrel, ticagrelor, prasugrel) is often recommended for up to 1 year after an acute coronary syndrome.
Clopidogrel or ticagrelor can be used if no percutaneous intervention was performed, and clopidogrel or ticagrelor or prasugrel may be used if PCI was performed.[2] The main adverse effect is an increased risk of gastrointestinal bleeding.[2][149]
In people with low bleeding risk, the ADA recommends combination treatment with aspirin and low-dose rivaroxaban for secondary prevention.[2]
The Food and Drug Administration released a statement in 2014 citing inadequate evidence to support widespread use of aspirin for primary prevention of cardiovascular events.[177]
Consult a specialist for guidance on treating pregnant women.
Primary options
insulin NPH: injected subcutaneously twice daily
and
insulin regular: injected subcutaneously two to three times daily
OR
insulin glargine: injected subcutaneously once daily
or
insulin detemir: injected subcutaneously twice daily
or
insulin degludec: injected subcutaneously once daily
-- AND --
insulin lispro: injected subcutaneously premeals
or
insulin aspart: injected subcutaneously premeals
or
insulin glulisine: injected subcutaneously premeals
OR
insulin NPH/insulin regular: (50/50, 70/30) injected subcutaneously twice daily
OR
insulin aspart protamine/insulin aspart: (70/30) injected subcutaneously twice daily
OR
insulin lispro protamine/insulin lispro: (50/50, 75/25) injected subcutaneously twice daily
OR
insulin degludec/insulin aspart: (70/30) injected subcutaneously once or twice daily with any main meal; administer a rapid- or short-acting insulin at other meals if needed
Immediate insulin therapy should be considered for marked hyperglycemia.
For individuals with severe hyperglycemia (HbA1c 11% or greater; or fasting or postprandial glucose >350 mg/dL), or individuals with metabolic compromise related to hyperglycemia (polyuria, polydipsia, ongoing weight loss) but without ketonuria or dehydration, both basal (background) and bolus (mealtime/prandial) insulin are typically recommended to reverse symptoms rapidly.[78] 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 mealtime/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 hypoglycemia, 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 sugar levels are within target range. Addition of mealtime/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 drop in glucose overnight, or individuals not reaching glycemic goals despite controlled fasting morning glucose values (uncontrolled postprandial glucose).[2]
If premeal sugars 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 sugar excursion and add injections for other meals as needed. Consult specialist as needed for guidance on dose.
Choice of insulin regimen should be individualized. For patients with type 2 diabetes, human insulins can be as effective as analog insulins in terms of glucose control, serious hypoglycemia risk, and mortality and cardiovascular events.[137]
[ 
]
Human insulins are 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, human insulin (NPH and regular) may be the appropriate choice of therapy.[2]
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.
General nutrition and healthy lifestyle knowledge (including an individualized nutrition and exercise plan) can improve glycemic control and quality of life.[33][70]
Cardiovascular risk reduction (blood pressure and lipid control, nonsmoking, and consideration of antiplatelet therapy) should be instituted.
Metformin therapy is typically started or continued at the time of initiation of insulin in type 2 diabetes, unless contraindicated. While consideration should be given to discontinuing sulfonylurea therapy in individuals initiating insulin therapy because of additive hypoglycemia risk, other noninsulin therapies can often be continued if an individual is benefiting.[138] In particular, individuals on SGLT2 or GLP-1 therapy because of unique indications (atherosclerotic cardiovascular disease, heart failure, chronic kidney disease) can be continued on those therapies when initiating insulin.
Treatment recommended for SOME patients in selected patient group
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)
Metformin is typically given adjunctively, in the absence of nausea/vomiting or volume depletion.
Metformin reduces hyperglycemia by decreasing hepatic gluconeogenesis and glycogenolysis. At maximal effective doses, metformin may reduce HbA1c by 1% to 2%. It confers a cardiovascular benefit, rarely is associated with weight gain, is inexpensive, and has a beneficial effect on low-density lipoprotein cholesterol.
The most common side effects are diarrhea, gas, and nausea, 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 to 2 weeks until full dose of 1000 mg twice a day is reached.
Metformin is contraindicated if estimated glomerular filtration rate (eGFR) is <30 mL/minute/1.73 m². It should not be initiated if the eGFR is <45 mL/minute/1.73 m², and for patients taking metformin whose eGFR falls to within the 30-45 mL/minute/1.73 m² range, continued use can be considered with close monitoring of renal function and consideration of a 50% dose reduction.[78]
Metformin should be discontinued at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; or in patients who will be administered intra-arterial iodinated contrast. Restart metformin if renal function is stable 48 hours after the imaging procedure.[178]
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]
The extended-release formulation may improve tolerance in individuals experiencing gastrointestinal side effects with the immediate-release formulation.
HbA1c above goal at diagnosis
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)
Pharmacotherapy is recommended to reduce risk of microvascular (nephropathy, retinopathy, neuropathy) and macrovascular (myocardial infarction, stroke, peripheral vascular disease) complications, and is guided by HbA1c goals or a unique indication (presence of atherosclerotic cardiovascular disease, heart failure, chronic kidney disease).[2][78][79][80][90][91]
The American Diabetes Association recommends that in the absence of contraindications metformin be started concurrently with nonpharmacologic therapy when diabetes is diagnosed, because of the difficulty in achieving and maintaining lifestyle change.[2] People unable to take metformin should initiate individualized therapy with an alternative agent.
Metformin may reduce cardiovascular mortality in type 2 diabetes.[90][92]
Metformin reduces hyperglycemia by decreasing hepatic gluconeogenesis and glycogenolysis. At maximal effective doses, metformin may reduce HbA1c by 1% to 2%. It rarely causes hypoglycemia when used as monotherapy, rarely is associated with weight gain, is inexpensive, and has a beneficial effect on low-density lipoprotein cholesterol.
The most common side effects are diarrhea, gas, and nausea, 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 to 2 weeks until full dose of 1000 mg orally twice per day is reached.
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]
Metformin is contraindicated if estimated glomerular filtration rate (eGFR) is <30 mL/minute/1.73 m². It should not be initiated if the eGFR is <45 mL/minute/1.73 m², and for patients taking metformin whose eGFR falls to within the 30-45 mL/minute/1.73 m² range, continued use can be considered with close monitoring of renal function and a dose reduction.[78]
Metformin should be discontinued at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; or in patients who will be administered intra-arterial iodinated contrast. Restart metformin if renal function is stable 48 hours after the imaging procedure.[178]
The extended-release formulation of metformin may improve tolerance in individuals experiencing gastrointestinal side effects with the immediate-release formulation.
Those unable to take metformin due to contraindication or intolerance can either use an alternative noninsulin agent or insulin therapy.
General nutrition and healthy lifestyle knowledge (including an individualized nutrition and exercise plan) can improve glycemic control and quality of life.[33][70]
Cardiovascular risk reduction (blood pressure and lipid control, nonsmoking, and consideration of antiplatelet therapy) should be instituted.
HbA1c above goal on metformin
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)
-- AND --
empagliflozin: 10 mg orally once daily, increase according to response, maximum 25 mg/day
or
canagliflozin: 100 mg orally once daily initially, increase according to response, maximum 300 mg/day
or
dapagliflozin: 5 mg orally once daily initially, increase according to response, maximum 10 mg/day
or
ertugliflozin: 5 mg orally once daily initially, increase according to response, maximum 15 mg/day
Choice of agents should be individualized. The cardiovascular benefits and safety of some agents are much more strongly established than those of other agents, and such data should be strongly considered when selecting treatments.
The SGLT2 inhibitors canagliflozin and empagliflozin have been shown to reduce cardiovascular risk in people with cardiovascular disease (CVD) and type 2 diabetes, and have renal benefits.[103][104][105][94][108] One study of patients with type 2 diabetes and established CVD treated with empagliflozin for a median of 2.6 years resulted in lower rates of cardiovascular mortality, all-cause mortality, and hospitalization for congestive heart failure, compared with placebo.[107] Canagliflozin also reduces cardiovascular mortality,[109] but may have more adverse effects than empagliflozin. In one trial, treatment with dapaglifozin did not result in a lower rate of major adverse cardiovascular events, but did result in a lower rate of hospitalization for heart failure.[110]
Dapagliflozin also improves renal outcomes in patients with, and without, diabetes.[111] One published trial on the CVD benefits of ertugliflozin supports its use in patients with diabetes and heart failure.[112][113][114]
The Food and Drug Administration (FDA) has issued a warning that the SGLT2 inhibitor class of drugs (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin) may lead to ketoacidosis. Patients who are on a SGLT2 inhibitor should seek immediate medical attention for signs of ketoacidosis (difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness), and these agents should be stopped temporarily before scheduled surgery.[115] The FDA and the European Medicines Agency (EMA) warn of the potential increased risk of toe amputation with approved SGLT2 inhibitors and the need for appropriate monitoring.[119][120] The 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 of SGLT2 inhibitors.[122][123]
General nutrition and healthy lifestyle knowledge (including an individualized nutrition and exercise plan) can improve glycemic control and quality of life.[33][70]
Cardiovascular risk reduction (blood pressure and lipid control, nonsmoking, and consideration of antiplatelet therapy) should continue.
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)
-- 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
or
dulaglutide: 0.75 mg subcutaneously once weekly initially, may increase to 1.5 mg once weekly if response is inadequate
or
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 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
Moreor
exenatide: 5 micrograms subcutaneously twice daily initially, increase to 10 micrograms twice daily in one month; 2 mg subcutaneously (extended-release) once weekly
or
lixisenatide: 10 micrograms subcutaneously once daily for 14 days, then increase to 20 micrograms once daily thereafter
As a class of drugs, GLP-1 agonist treatment has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes.[95] Choice of agents should be individualized. The cardiovascular benefits and safety of some agents are much more strongly established than those of other agents, and such data should be strongly considered when selecting treatments.
Liraglutide has been shown to reduce major cardiovascular events, cardiovascular mortality, and all-cause mortality in diabetes patients with coronary heart disease.[125] Dulaglutide and semaglutide have both been shown to reduce major cardiovascular events, but not all-cause or cardiovascular mortality.[126][127][129] Exenatide and lixisenatide have both been shown not to reduce major cardiovascular events.[130] Semaglutide is the only GLP-1 agonist that is available in both oral and injectable formulations; the other GLP-1 agonists are only available in injectable formulations.
GLP-1 agonists stimulate glucose-dependent release of insulin, suppress glucagon levels, and may slow gastric emptying and increase satiety. GLP-1 agonists may be associated with modest initial weight loss on the order of 2 to 7 kg in some patients. GLP-1 agents may lower HbA1c up to 0.9% and may lower postprandial glucose.
Response to the drug is quite variable and some patients will lose ground on glycemic control due to reduction in doses of other glycemic medications when used as part of multidrug regimens. Patients should be cautioned about this as well as potential risk of hypoglycemia, and advised to check blood sugars frequently when initiating therapy. Patients should report any new problems with high or low readings.
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.[131]
General nutrition and healthy lifestyle knowledge (including an individualized nutrition and exercise plan) can improve glycemic control and quality of life.[33][70]
Cardiovascular risk reduction (blood pressure and lipid control, nonsmoking, and consideration of antiplatelet therapy) should continue.
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)
-- AND --
sitagliptin: 100 mg orally once daily
or
linagliptin: 5 mg orally once daily
or
alogliptin: 25 mg orally once daily
or
saxagliptin: 2.5 to 5 mg orally once daily
Choice of agents should be individualized. The safety of some agents is more strongly established than the safety of other agents, and such data should be strongly considered when selecting treatments.
DPP-4 inhibitors do not confer cardiovascular benefit, and do not lower glucose as much as metformin, sulfonylureas, or thiazolidinediones.
Advantages include few identified side effects, less hypoglycemia than sulfonylureas, less risk of weight gain or congestive heart failure than thiazolidinediones, and easy dosing. DPP-4 inhibitors do not appear to confer major risk of hypoglycemia when studied as monotherapy.
Studies of DPP-4 inhibitors showed that saxagliptin did not alter the rate of ischemic events over about 2 years, although hospital admissions for heart failure increased.[179] In people with a recent acute coronary syndrome, alogliptin was not associated with increased risk of major adverse cardiovascular events over 40 months.[180]
General nutrition and healthy lifestyle knowledge (including an individualized nutrition and exercise plan) can improve glycemic control and quality of life.[33][70]
Cardiovascular risk reduction (blood pressure and lipid control, nonsmoking, and consideration of antiplatelet therapy) should continue.
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)
-- 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
or
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
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)
-- 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
or
nateglinide: 60-120 mg orally three times daily initially
Choice of agents should be individualized.
Sulfonylureas (e.g., glimepiride, glipizide) enhance the release of insulin by pancreatic islet cells by altering potassium and sodium influx.
Sulfonylureas may reduce HbA1c by 1% to 2%. 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 coumadin. 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 in older individuals, due to its dual hepatic/renal clearance and potentially lower risk of hypoglycemia.
Sulfonylureas can also be given as first-line oral agents when metformin is not tolerated or is contraindicated.
Meglitinides (e.g., repaglinide, nateglinide) are an alternative to sulfonylureas, and can also be used as a first-choice secretagogue in people with sulfa allergies. Meglitinides have a modest effect on HbA1c, with an average reduction of only 0.5%, but may help with postprandial hyperglycemia. May cause hypoglycemia; if a meal is skipped, the dose of meglitinide should be held to avoid hypoglycemia.
General nutrition and healthy lifestyle knowledge (including an individualized nutrition and exercise plan) can improve glycemic control and quality of life.[33][70]
Cardiovascular risk reduction (blood pressure and lipid control, nonsmoking, and consideration of antiplatelet therapy) should continue.
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)
-- AND --
insulin NPH: injected subcutaneously, usually at bedtime
or
insulin glargine: injected subcutaneously, usually at bedtime
or
insulin detemir: injected subcutaneously, usually at bedtime
or
insulin degludec: injected subcutaneously once daily
Choice of agents should be individualized. Basal insulin is generally added to metformin, usually at bedtime.
Insulin is 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 long duration of type 2 diabetes.
Patients should perform periodic home glucose monitoring and be instructed to watch for signs of hypoglycemia (shaking, sweating, intensive hunger, irritability, weakness, confusion) and promptly treat with 15 to 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 to 3 units every several days until morning fasting blood glucose averages 90 to 130 mg/dL (for those with a HbA1c goal of <7%). 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 obese patients, who typically are insulin-resistant, 5% to 10% increases in insulin dose every 3 to 5 days are often needed until glucose control is achieved, while taking care to avoid hypoglycemia. As insulin dose increases, sulfonylureas should be tapered, but metformin may be continued. Home glucose readings should be used to guide therapy decisions.
General nutrition and healthy lifestyle knowledge (including an individualized nutrition and exercise plan) can improve glycemic control and quality of life.[33][70]
Cardiovascular risk reduction (blood pressure and lipid control, nonsmoking, and consideration of antiplatelet therapy) should continue.
While consideration should be given to discontinuing sulfonylurea therapy in individuals initiating insulin therapy because of additive hypoglycemia risk, other noninsulin therapies can often be continued if an individual is benefiting.[138] In particular, individuals on SGLT2 or GLP-1 therapy because of unique indications (atherosclerotic cardiovascular disease, heart failure, chronic kidney disease) can be continued on those therapies when initiating insulin.
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)
-- AND --
acarbose: 25 mg orally once daily initially, increase to 25 mg twice daily in 1-2 weeks, then increase to 25 mg three times daily in 1-2 weeks, continue to increase according to response, maximum 50 mg three times daily
or
miglitol: 25 mg orally once daily initially, increase to 25 mg twice daily in 1-2 weeks, then increase to 25 mg three times daily in 1-2 weeks, continue to increase according to response, maximum 50 mg three times daily
Choice of agents should be individualized. Alpha-glucosidase inhibitors impede the enzyme needed to split disaccharides into monosaccharides prior to absorption from the gut.
May be combined with most other classes of glucose-lowering medication. May be useful in older adult patients with marked postprandial glucose excursions.
Rather modest impact on HbA1c, must be taken multiple times a day, and costly. Adverse effects can be minimized by low initial doses and by very slow titration of doses.
Any episodes of hypoglycemia must be treated with glucose tablets, because this class of medication blocks gut absorption of carbohydrates such as sucrose or fructose.
General nutrition and healthy lifestyle knowledge (including an individualized nutrition and exercise plan) can improve glycemic control and quality of life.[33][70]
Cardiovascular risk reduction (blood pressure and lipid control, nonsmoking, and consideration of antiplatelet therapy) should continue.
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)
-- AND --
pioglitazone: 15 mg orally once daily initially, increase every 6-8 weeks, maximum 45 mg once daily
or
rosiglitazone: 2-4 mg/day orally initially given as a single dose or in 2 divided doses, increase according to response, maximum 8 mg/day
Choice of agents should be individualized. The benefits and safety of some agents are much more strongly established than those of other agents, and such data should be strongly considered when selecting treatments.
Neither pioglitazone nor rosiglitazone confers a mortality benefit. Thiazolidinediones may cause fluid retention and exacerbate heart failure. Pioglitazone may be linked to an increased risk of bladder cancer.[136]
Thiazolidinediones enhance the action of endogenous or exogenous insulin by acting at PPAR-gamma receptors. The complete mechanism of action is not fully understood. May on average reduce HbA1c 1% to 1.5%: less than insulin, metformin, or sulfonylureas.
Hypoglycemia is rare unless combined with sulfonylurea or insulin.
Rosiglitazone has been removed from the European market due to persistent safety concerns.[134] In 2013, the Food and Drug Administration lifted previous restrictions applied to rosiglitazone in the US.
General nutrition and healthy lifestyle knowledge (including an individualized nutrition and exercise plan) can improve glycemic control and quality of life.[33][70]
Cardiovascular risk reduction (blood pressure and lipid control, nonsmoking, and consideration of antiplatelet therapy) should continue.
HbA1c above goal on metformin + either basal insulin or second noninsulin agent
Choice of agents should be tailored to account for patient values and preferences, advantages, and adverse effects. The safety of some agents is much more strongly established than the safety of other agents, and such data should be strongly considered when selecting treatments.
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: sulfonylureas/meglitinides, DPP-4 inhibitors, GLP-1 agonists, alpha-glucosidase inhibitors, thiazolidinediones, basal insulin, or SGLT2 inhibitors.[78] However, evidence and guidelines do not support combining a DPP-4 inhibitor and a GLP-1 agonist in the same regimen, and they are not approved for this purpose.
The American Diabetes Association recommends: basal insulin plus GLP-1 agonist, basal insulin plus rapid-acting insulin, or fixed-dose insulin as alternative combination injectable regimens.[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 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.
Liraglutide, empagliflozin, or canagliflozin can be considered for those with established cardiovascular disease as these agents have been shown to reduce cardiovascular mortality and all-cause mortality.[2][107][108][109][125][128] Semaglutide has shown a reduction in major cardiovascular events, but not in all-cause or cardiovascular mortality.[127]
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.[131]
General nutrition and healthy lifestyle knowledge (including an individualized nutrition and exercise plan) can improve glycemic control and quality of life.[33][70]
Cardiovascular risk reduction (blood pressure and lipid control, nonsmoking, and consideration of antiplatelet therapy) should continue.
Primary options
insulin NPH: injected subcutaneously twice daily
and
insulin regular: injected subcutaneously two to three times daily
OR
insulin glargine: injected subcutaneously once daily
or
insulin detemir: injected subcutaneously twice daily
or
insulin degludec: injected subcutaneously once daily
-- AND --
insulin lispro: injected subcutaneously premeals
or
insulin aspart: injected subcutaneously premeals
or
insulin glulisine: injected subcutaneously premeals
OR
insulin NPH/insulin regular: (50/50, 70/30) injected subcutaneously twice daily
OR
insulin aspart protamine/insulin aspart: (70/30) injected subcutaneously twice daily
OR
insulin lispro protamine/insulin lispro: (50/50, 75/25) injected subcutaneously twice daily
OR
insulin degludec/insulin aspart: (70/30) injected subcutaneously once or twice daily with any main meal; administer a rapid- or short-acting insulin at other meals if needed
Basal-bolus insulin is often used when basal insulin or noninsulin multidrug regimens fail to control blood sugar. For patients already on basal insulin, consider starting 3 to 5 units of bolus (short- or rapid-acting) insulin at 1 or more meals. Titrate doses up 2 to 3 units at each meal every few days until desired levels of premeal (90-130 mg/dL) and bedtime (100-140 mg/dL) glucoses are achieved, unless hypoglycemia supervenes.
Premeal insulin is tailored to anticipated meals as well as to premeal glucose testing.
Insulin dose varies; consult specialist for guidance on dose.
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.
Choice of insulin regimen should be individualized. Premixed insulin may start with a total of about 0.3 units/kg/day dose of insulin, with two-thirds dose in the morning and one third in the evening, and titrated up until goals are achieved or hypoglycemia prevents further titration.
General nutrition and healthy lifestyle knowledge (including an individualized nutrition and exercise plan) can improve glycemic control and quality of life.[33][70]
Cardiovascular risk reduction (blood pressure and lipid control, nonsmoking, and consideration of antiplatelet therapy) should continue.
Metformin therapy is typically started or continued at the time of initiation of insulin in type 2 diabetes, unless contraindicated. While consideration should be given to discontinuing sulfonylurea therapy in individuals initiating insulin therapy because of additive hypoglycemia risk, other noninsulin therapies can often be continued if an individual is benefiting.[138] In particular, individuals on SGLT2 or GLP-1 therapy because of unique indications (atherosclerotic cardiovascular disease, heart failure, chronic kidney disease) can be continued on those therapies when initiating insulin.
Treatment recommended for SOME patients in selected patient group
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)
Metformin can be continued with basal-bolus insulin.
Metformin reduces hyperglycemia by decreasing hepatic gluconeogenesis and glycogenolysis. At maximal effective doses, metformin may reduce HbA1c by 1% to 2%. It rarely is associated with weight gain, is inexpensive, and has a beneficial effect on low-density lipoprotein cholesterol. The most common side effects are diarrhea, gas, and nausea, 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 to 2 weeks until full dose of 1000 mg twice per day is reached.
Metformin is contraindicated if estimated glomerular filtration rate (eGFR) is <30 mL/minute/1.73 m². It should not be initiated if the eGFR is <45 mL/minute/1.73 m², and for patients taking metformin whose eGFR falls to within the 30-45 mL/minute/1.73 m² range, continued use can be considered with close monitoring of renal function and a dose reduction.[78]
Metformin should be discontinued at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; or in patients who will be administered intra-arterial iodinated contrast. Restart metformin if renal function is stable 48 hours after the imaging procedure.[178]
The extended-release formulation of metformin may improve tolerance in individuals experiencing gastrointestinal side effects with the immediate-release formulation.
Bariatric (also known as metabolic) surgery is an option for type 2 diabetes management in some patients with obesity. Patients must be surgical candidates.
Bariatric surgery is recommended to treat type 2 diabetes in adults with body mass index (BMI) ≥40 kg/m² (≥37.5 kg/m² for Asian-Americans) and adults with BMI 35.0 to 39.9 kg/m² (32.5 to 37.4 kg/m² for Asian-Americans) who do not achieve long-lasting weight loss and improvement in co-morbidities, including hyperglycemia despite lifestyle and optimal non-surgical medical management. It may be considered for those with BMI 30.0 to 34.9 kg/m² (27.5 to 32.4 kg/m² for Asian-Americans) who do not achieve long-lasting weight loss and improvement in co-morbidities, including hyperglycemia despite lifestyle and optimal nonsurgical medical management.[2]
Surgery should be done in a high-volume, experienced center.[2]
Primary options
insulin NPH: injected subcutaneously twice daily
-- AND --
insulin regular: injected subcutaneously two to three times daily
or
insulin lispro: injected subcutaneously premeals
or
insulin aspart: injected subcutaneously premeals
Good glucose control with HbA1c as close to normal as is safely possible (ideally HbA1c <6.5% [48 mmol/mol]) before conception and during pregnancy optimizes maternal and fetal health outcomes.[2] The American Diabetes Association guidelines recommend the following blood glucose targets in pregnant women with preexisting type 2 diabetes (same as for gestational diabetes): <95 mg/dL fasting and either ≤140 mg/dL 1-hour postprandially or ≤120 mg/dL 2-hour postprandially; HbA1c target <6.0% (42-48 mmol/mol) is recommended; <6% may be optimal as pregnancy progresses if achievable without hypoglycemia.[2]
In clinical practice, insulin is usually used when nutrition therapy fails to achieve these goals. Intermediate-acting (NPH) insulin may be combined with human short-acting or analog rapid-acting insulin. Long-acting analog insulins (glargine or detemir) are not Food and Drug Administration-approved in pregnancy.
Retinal exam in those with diabetes prior to pregnancy should be performed prior to and during pregnancy. Diabetes patients who become pregnant require care supervision by a specialized center whenever possible.
Patients should monitor blood glucose from 4 to 7 times a day and have the pattern examined every few weeks early in pregnancy so that nutrition content and timing, exercise patterns, and the insulin doses can be modified to achieve optimal control. Premeal insulin is tailored to anticipated meals as well as to premeal glucose testing.
Insulin requirements generally increase early in pregnancy, then decrease from about 8 to 16 weeks before rising throughout the rest of the pregnancy.
Diabetes patients who become pregnant require individualized dietary counseling and team care.
Insulin dose varies; consult specialist for guidance on dose.
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