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

The cornerstone of therapy for all patients with type 2 diabetes is a personalized management program that includes pharmacotherapy and ongoing self-management education by a diabetes education nurse or dietitian.[2][102]​ It is highly important that education and management strategies (including target-setting, lifestyle and pharmacologic interventions, and monitoring) take into account factors such as age, race and ethnicity, cultural values, cognitive and physical function and other comorbidities or disabilities, as these can affect engagement with treatment, and therefore control of diabetes.[11][25][103]​ Diabetes self-management education promotes diabetes self-care and supports beneficial lifestyle changes on an ongoing basis.[2] This requires general nutrition and health lifestyle knowledge and an individualized nutrition and exercise plan based on an initial assessment and treatment goals.[2][11][25]​ Interventions that enhance self-management can significantly reduce diabetes distress (a common psychological disorder related to the burden of managing diabetes).[2][104]

In most patients with type 2 diabetes and overweight or obesity, ≥5% weight loss is recommended through diet, physical activity, and behavioral therapy.[2] Weight management should be considered as a therapeutic target in addition to glycemia, and antihyperglycemic drugs chosen that both promote weight loss and lower glucose. 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]

Choice of antihyperglycemic therapy should be individualized, taking into account patient characteristics, their values and preferences, the likelihood that an agent reduces all-cause or cardiovascular (CV) mortality, renal effects, weight loss benefits, adverse effects such as hypoglycemic risk, costs, and other factors.[2][25]

About 80% of adults with type 2 diabetes have concurrent dyslipidemias or hypertension, 70% have overweight or obesity, and around 15% are current smokers.[15] On average, adults with type 2 diabetes are up to 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.[17][18][19]​ However, data indicate that adults with type 2 diabetes who optimally manage glucose, blood pressure (BP), lipids, smoking, and weight have a risk of major CV events that is not significantly above the risk of age and sex-matched nondiabetes peers.[20][21]

Therefore, care of adults with type 2 diabetes must include management of all major CV risk factors to individualized targets.[2] In addition to glucose control, this includes smoking cessation, BP control, lipid control, antiplatelet and anticoagulant use for patients with known coronary heart disease, and ACE inhibitors or angiotensin-II receptor antagonists for nonpregnant adults with chronic kidney disease (CKD) or proteinuria.[2][77]​​[105]

Use of antihyperglycemic agents such as sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, which reduce CV or overall mortality, CV events, heart failure (HF), or CKD progression, may be especially beneficial in those with type 2 diabetes and at risk of/with established atherosclerotic cardiovascular disease (ASCVD), HF (especially HF with reduced ejection fraction), or CKD, regardless of the level of glucose management.[2][77]​​[106][107]

Detailed guidance on the management of hyperglycemia and CV risk reduction in patients with type 2 diabetes who have comorbid ASCVD or risk factors for ASCVD, CKD, or HF is beyond the scope of this topic. See Diabetic cardiovascular disease and Diabetic kidney disease.

Diet

General dietary advice

Nutrition advice needs to be tailored to the needs of each individual patient, preferably by a nutritionist.​[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 demonstrated 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 CV risk.[77] One meta-analysis reported moderate-certainty evidence that a shift from animal-based to plant-based foods is beneficially associated with cardiometabolic health and all-cause mortality.[112]​ There is conflicting evidence on the impact of red meat consumption on glycemic parameters and cardiovascular disease (CVD) risk.[113][114]​​​ Reducing sugary beverage consumption (including soda, energy drinks, and fruit juice) is of benefit to many patients.[57][115]​ One meta-analysis of three large cohort studies found that total ultra-processed food consumption was associated with a higher risk of type 2 diabetes, but further studies are needed.[116]

​Reducing overall carbohydrate intake has demonstrated some evidence for improving glycemia; 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 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]

Dietary advice for patients with overweight or obesity

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 hemoglobin A1c (HbA1c) <6.5% (<48 mmol/mol) for 3 months or more, without the need for pharmacotherapy to reduce glucose.[126]​ The Diabetes Remission Clinical Trial (DiRECT) of supported weight loss management for people diagnosed with type 2 diabetes within the previous 6 years, and a BMI of 27 kg/m² to 45 kg/m², found that almost half of participants who received a structured weight management program achieved remission to a nondiabetes state and were off diabetes drugs at 12 months.[124]​ At 2 years, more than one third of people with type 2 diabetes had sustained remission.[127]​ Over the whole 5-year study period, people in the intervention group spent on average 27% of the time in remission. This compares with 4% for the control group who didn’t receive the weight management program. The intervention group also spent more time with their body weight lower than baseline, off diabetes drugs, and with blood sugar levels in the nondiabetes range than the control group.[128] A study in England using National Diabetes Audit data found that although remission was infrequent in the routine care setting, it is a reasonable goal for a subset of people who lose a significant amount of weight shortly after diagnosis.[129]​ Because the likelihood of relapse remains high, testing for maintenance of remission should be done at least annually.[126]​ One population-based cohort study found that those who achieved remission from diabetes, even for a short time, had a much lower risk of CVD events, including myocardial infarction and stroke, as well as macrovascular and microvascular complications.[130]

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]​ A systematic umbrella review of published meta-analyses of studies comparing hypoenergetic diets for weight management in people with type 2 diabetes did not find evidence for any particular weight-loss diet over others (e.g., low-carbohydrate, high-protein, low-glycemic index, Mediterranean, high-monounsaturated fatty acid, or vegetarian diets).[131]

Intermittent fasting or time-restricted eating as strategies for weight and glucose management have gained popularity.[132]​ They have been shown to result in mild to moderate weight loss (3% to 8% loss from baseline), but no significant difference in weight loss when compared with continuous calorie restriction.[2]​ 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] People who are on insulin and/or secretagogues should be medically monitored during the fasting period.[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 and reduction of other cardiometabolic risk factors than self-administered food-based weight-loss diets.[119][124]​ Low-energy nutritionally complete formula diets with a total diet replacement induction phase appear to be the most effective dietary approach for achieving type 2 diabetes remission.[119]

​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

To improve glycemic control, assist with weight maintenance, and reduce CV risk, physical activity is recommended as tolerated. Many individuals with type 2 diabetes do not meet the recommended exercise level per week.[2][133]​​ One systematic review and meta-analysis of observational studies concluded that physical activity, even below recommended amounts, was associated with reduced incidence of diabetes-related complications.[134]

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][135]

The following should be assessed prior to starting an exercise program: age; physical condition; BP; and presence or absence of autonomic neuropathy or peripheral neuropathy, balance impairment, history of foot ulcers or Charcot foot, or untreated proliferative retinopathy.[2]

​Vigorous exercise may be contraindicated with proliferative or severe preproliferative diabetic retinopathy because of the risk of triggering vitreous hemorrhage or retinal detachment; consultation with an ophthalmologist is therefore recommended.[2]

A thorough assessment is required in patients with peripheral neuropathy to ensure that neuropathy does not alter kinesthetic or proprioceptive sensation during physical activity. Moderate-intensity walking may be a suitable form of exercise in those with peripheral neuropathy; properly fitting footwear is essential. Advise patients to examine their feet daily to facilitate early detection of lesions. Restriction to nonweight-bearing exercise is recommended in patients with a foot injury or open sore.[2]

Clinical judgment should be used in determining whether to screen asymptomatic individuals for coronary artery disease prior to recommending an exercise program.[2]

Sleep health

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

Smoking cessation

Tobacco use is a significant risk factor for CVD, is linked to the early onset of microvascular complications, and may aggravate complications of type 2 diabetes. All patients with diabetes should be advised not to smoke or to quit smoking. Smoking counseling and other forms of smoking cessation therapy should be incorporated into routine diabetes care.[2] Varenicline combined with nicotine replacement therapy may be more effective than varenicline alone.[136] The ADA does not support e-cigarettes as an alternative to smoking or to facilitate smoking cessation.[2]​ See Smoking cessation.

Antihyperglycemic pharmacotherapy: initial considerations

HbA1c goals should be individualized.[2][25][137][138]​​​​​​​​​ Individualized HbA1c goals improve quality of life compared with uniform tight control.[138] The 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 advanced microvascular or macrovascular complications or comorbid conditions).[2][25]​​​​ For older adults with very complex or poor health, glucose control decisions should be based on avoiding hypoglycemia and symptomatic hyperglycemia, and focus on quality of life, rather than relying on HbA1c.[2][25]​​​​​ Limited evidence suggests that stringent control in older adults does not affect mortality, while some data suggests it may even be associated with higher mortality in this population.[25] If using a CGM device, the ADA recommends a target of >50% time in range with <1% time below range for those with frailty or at high risk of hypoglycemia.[2]​ 

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 diagnosis unless there are contraindications.[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. For individuals without these comorbidities, pharmacologic agents should address both individualized glycemic and weight goals.[2]​

Generally, metformin is the recommended first-choice pharmacotherapy at diagnosis in the absence of contraindications, although for patients with ASCVD, HF, or CKD, there is increasing evidence that SGLT2 inhibitors and 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 CV benefit, and low cost.[2][139][140]​​​​​​​ It is contraindicated if estimated glomerular filtration rate (eGFR) is <30 mL/minute/1.73 m².[106][141]​​​​​​​

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]

Antihyperglycemic pharmacotherapy: combination regimens

In older studies such as ACCORD, ADVANCE, and the Veterans Affairs Diabetes Trial (VADT), use of multiple drugs to achieve near-normal HbA1c was either not beneficial or increased mortality in type 2 diabetes patients with CVD or high CVD risk.[142][143][144][145][146]​ However, SGLT2 inhibitors were not available and GLP-1 receptor agonists were infrequently used in those studies; intensive glycemic control was achieved predominantly through greater use of insulin. These findings suggest that caution is needed in treating diabetes to near-normal HbA1c goals in people with long-standing type 2 diabetes using drugs with a high risk for hypoglycemia.[2] Longer-term epidemiologic follow-up has been performed on these studies, as well as the UK Prospective Diabetes Study (UKPDS), and a clear pattern of CVD benefit has emerged; collectively, the results confirm that long-term intensive glycemic control in fact reduces CVD events, particularly myocardial infarctions.[2][147]

Because type 2 diabetes is a progressive disease in many individuals, maintenance of glycemic goals often requires combination therapy. Choice of a second agent should be based on individualized assessment of glycemic and weight goals, the presence of other comorbidities (e.g., ASCVD, HF, and CKD), risk of hypoglycemia, 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 treatment goals.[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] 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.

Treatment options to consider in combination with metformin include:

  • SGLT2 inhibitor (e.g., canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, or bexagliflozin)

  • GLP-1 receptor agonist (e.g., liraglutide, semaglutide, dulaglutide, or exenatide)

  • Dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist (e.g., tirzepatide)

  • DPP-4 inhibitor (e.g., sitagliptin, saxagliptin, linagliptin, or alogliptin)

  • Sulfonylurea (e.g., glimepiride or glipizide)

  • Thiazolidinedione (e.g., pioglitazone)

  • Insulin.

The following are considered to have very high efficacy for glucose lowering: dulaglutide, semaglutide, tirzepatide, insulin, combination oral therapy, and combination injectable therapy.[2]

Of note, guidelines from the American College of Physicians (ACP) now recommend that SGLT2 inhibitors or GLP-1 receptor agonists should be the add-on therapy of choice for all patients with inadequate glycemic control (regardless of CVD status).[148]​ They advise that sulfonylureas and long-acting insulins are inferior to these drugs in reducing all-cause mortality and morbidity but may still have some limited value for glycemic management. Along with metformin and human insulin, sulfonylureas are among the more affordable antihyperglycemic drugs and may be particularly useful if cost is a concern.[149] The ACP does not recommend 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 are still listed as an antihyperglycemic treatment option by the ADA, however.[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.[150]

​Because of the progressive loss of beta-cell function that characterizes the natural history of type 2 diabetes, insulin therapy is often required over time to overcome the resulting insulin deficiency. If insulin is used, combination therapy with a GLP-1 receptor agonist, including a dual GIP/GLP-1 receptor agonist, is recommended for greater glycemic efficacy, as well as beneficial effects on weight and hypoglycemia risk (as lower insulin doses can be used).[2]

Specific recommendations for patients with established ASCVD (or at high risk of ASCVD), CKD, and HF

The ADA recommends that people with type 2 diabetes with established ASCVD or indicators of high CV risk, CKD, or HF should use an SGLT2 inhibitor (or a dual SGLT1/SGLT2 inhibitor such as sotagliflozin) with demonstrated CV benefit and/or a GLP-1 receptor agonist with demonstrated CVD benefit. 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 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 with demonstrated CV benefit (liraglutide, dulaglutide, or semaglutide) or an SGLT2 inhibitor with demonstrated CV benefit (empagliflozin, canagliflozin, or dapagliflozin) 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, ACP guidelines specify that GLP-1 receptor agonists should be prioritized over SGLT2 inhibitors in patients with an increased risk for stroke.[148][151]​​​ 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]

  • ​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]​​

​If patients are already on dual therapy or multiple glucose-lowering therapies and not on an SGLT2 inhibitor or a GLP-1 receptor agonist, consider switching to one of these agents with shown CV benefit.[2]​ A reduction in the 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. For further information, see Diabetic cardiovascular disease and Diabetic kidney disease.

Choice of antihyperglycemic agents for patients with overweight or obesity

Weight management is a distinct treatment goal; it has multifaceted benefits, including improved glycemic management, reduction in hepatic steatosis, and improvement in CV risk factors. When considering glycemic control in patients who have overweight or obesity, the ADA recommends prioritizing glucose-lowering drugs with a beneficial effect on weight; this particularly includes GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists such as tirzepatide.[2] The ESC recommends GLP-1 receptor agonists or SGLT2 inhibitors as the glucose-lowering agents of choice for weight loss in type 2 diabetes in view of their demonstrated CV benefits for these patients.[77][154]​​ One meta-analysis found that when glucose-lowering therapies were associated with weight loss, the risk of mortality was reduced by 22% for each 1% reduction in HbA1c.[155]

  • Agents associated with clinically meaningful weight loss include GLP-1 receptor agonists (particularly semaglutide and dulaglutide), tirzepatide, SGLT2 inhibitors, and amylin analogs (e.g., pramlintide).[2]​ One network meta-analysis of 531 trials with 279,118 participants confirmed that tirzepatide is the most effective drug for reducing body weight (mean reduction 8.57 kg), followed by GLP-1 receptor agonists, SGLT2 inhibitors, and metformin.[156] Two phase 3 trials in adults with obesity demonstrated mean losses of 15% to 21% of body weight with the highest dose of tirzepatide, with adverse effects similar to those seen with GLP-1 receptor agonists.[157][158]​​​​ In the larger of the two trials, over 80% of participants in all tirzepatide treatment groups lost ≥5% of body weight, compared with 35% of those assigned to placebo.[157]​ With higher body weight reduction, there were greater reductions in HbA1c, triglycerides, waist circumference, and BP.[159] Tirzepatide is approved for chronic weight management in adults with obesity or those who are overweight with at least one weight-related condition (such as high BP, type 2 diabetes, or high cholesterol) for use in addition to a reduced calorie diet and increased physical activity. 

  • DPP-4 inhibitors, metformin, alpha-glucosidase inhibitors (e.g., acarbose, miglitol), bromocriptine (a centrally-acting dopamine agonist), and bile acid sequestrants (e.g., colesevelam) are considered weight neutral.[2]

  • Insulin secretagogues (sulfonylureas and meglitinides), thiazolidinediones, and insulin are often associated with weight gain.[2]

​For those with a BMI ≥27 kg/m² (≥25 kg/m² for Asian-Americans) who are motivated to lose weight, an initial 3-month trial of drug therapy should be undertaken. When weight loss is <5% after 3 months, the benefits of ongoing treatment need to be balanced in the context of the glycemic response, the availability of other potential treatment options, treatment tolerance, and overall treatment burden.[2]

In patients who have not achieved their individualized weight goals, additional weight management interventions (e.g., intensification of lifestyle modifications, structured weight management programs, pharmacologic agents for obesity, or metabolic surgery, as appropriate) are recommended.[2]

As well as considering specific drugs to treat obesity, healthcare professionals should carefully review the individual’s other drugs and, whenever possible, minimize or provide alternatives for drugs that promote weight gain. Examples of drugs associated with weight gain include antipsychotics (e.g., clozapine, olanzapine, risperidone), some antidepressants (e.g., tricyclic antidepressants, some selective serotonin-reuptake inhibitors, monoamine oxidase inhibitors), corticosteroids, injectable progestins, some anticonvulsants (e.g., gabapentin, pregabalin), beta-blockers, and possibly sedating antihistamines and anticholinergics.[2]

Clinical properties of specific noninsulin antihyperglycemic agents

Agents should be selected based on a discussion with the patient of the pros and cons of the agents. Agents that reduce all-cause or CV mortality may be preferred.[77]​​

Metformin

Metformin decreases hepatic glucose production, diminishes intestinal absorption of glucose, and enhances insulin sensitivity.[160] It is effective and safe, inexpensive and widely available, weight neutral, and does not cause hypoglycemia. It may reduce the risk of CV events and death and may have a role in preventing the development of age-related macular degeneration.[2][139][140][161]

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 eGFR ≥30 mL/minute/1.73 m².[2] It is contraindicated if eGFR is <30 mL/minute/1.73 m². 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]

The most common adverse effects are diarrhea, bloating, and abdominal discomfort, which can be attenuated by starting at a low dose and titrating slowly.[2]​ The extended-release formulation 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 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]

​SGLT2 and dual SGLT1/SGLT2 inhibitors

SGLT2 inhibitors inhibit renal glucose reabsorption. The resulting increase in glycosuria improves glycemic control, promotes weight loss, and has a diuretic effect that reduces BP.[164] They have intermediate-to-high glycemic efficacy, with lower glycemic efficacy at lower eGFR.[106]

SGLT2 inhibitors have been shown to have multiple CV and renal benefits in patients with type 2 diabetes, leading to significant expansion in their scope of use. Compared with usual care or placebo, they reduce the risk for all-cause mortality by 12%, major adverse cardiac events (MACE; nonfatal myocardial infarction, nonfatal stroke, and CV mortality) by 10%, progression of CKD by 34%, and hospitalization due to congestive HF by 36%.[148] In large landmark CV outcome studies conducted in patients with type 2 diabetes, SGLT2 inhibitors have been consistently associated with clinically important reductions in hospitalization for HF and adverse kidney outcomes. However, probably related to differences in the prior CV risk, reduction in MACE differed across the studies, with only canagliflozin and empagliflozin showing a significant benefit.[165][166][167][168][169][170][171][172][173][174]​​ Pairwise meta-analyses of SGLT2 inhibitor CV outcome trials have since verified that SGLT2 inhibitors reduce MACE, hospitalization for HF, and a composite kidney outcome in the overall population versus placebo.[175][176]​​ 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]​​ Dapagliflozin has been shown to improve renal outcomes in patients with CKD irrespective of type 2 diabetes status, suggesting that these benefits are independent of the drug’s glucose-lowering effect.[174] It has also been shown to mitigate renal function decline in patients with type 2 diabetes at high CV risk who have low baseline kidney disease risk, suggesting it may have a role in the early prevention of diabetic kidney disease.[185]

Ertugliflozin and bexagliflozin are approved for glycemic management but not for cardiorenal protection. In the VERTIS CV trial, which recruited exclusively people with established CVD and type 2 diabetes, ertugliflozin was similar to placebo with respect to the primary MACE outcome and all key secondary outcomes (including a composite kidney outcome) except for hospitalization for HF.[171][186] The CV effects of bexagliflozin are least established. Phase 2 and 3 trials assessing its safety and effectiveness have consistently demonstrated favorable reductions in HbA1c and weight, and for the most part a trend toward BP reduction. Importantly, it has achieved noninferiority for hard clinical outcomes in high-risk CVD cohorts (BEST trial), and its effectiveness appears to be preserved in patients with moderate-severity CKD.[187]

Sotagliflozin is the first dual SGLT1/SGLT2 inhibitor.[188]​ It inhibits both renal SGLT2 (promoting significant excretion of glucose in the urine, in the same way as other already available SGLT2 inhibitors) and intestinal SGLT1 (delaying glucose absorption and therefore reducing postprandial glucose).[188]​ It has been approved for people with type 2 diabetes and HF, or with high risk of or established ASCVD, to reduce the risk of hospitalization for HF and CV death.[2]​ The approval was based on two randomized, double-blind, placebo-controlled phase 3 CV outcome trials: SOLOIST-WHF (Effects of Sotagliflozin on Clinical Outcomes in Hemodynamically Stable Patients with Type 2 Diabetes Post Worsening Heart Failure) and SCORED (Effects of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes Mellitus, Cardiovascular Risk Factors, and Moderately Impaired Renal Function).[189][190]​​​ In SCORED, sotagliflozin reduced the composite end point of CV mortality, hospitalization for HF, or urgent visits for HF by 33% compared with placebo, but had no effect on the composite kidney end point.[189] SOLOIST-WHF found that, compared with placebo, sotagliflozin reduced the risk of the primary composite of CV death or total hospitalizations/urgent visits for HF by 33% in people with type 2 diabetes and worsening HF, regardless of ejection fraction.[190] It is not currently approved for glycemic management of type 2 diabetes; however, in practice, it does lower glucose effectively.[191]

SGLT2 inhibitors may also have benefits for patients with comorbid metabolic dysfunction-associated steatotic liver disease (MASLD; previously nonalcoholic fatty liver disease).[192]​​[193]

SGLT2 inhibitors can be used with eGFR as low as 20 mL/minute/1.73 m² when used for cardiorenal protection.[2] 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] Once initiated, the SGLT2 inhibitor may be continued at lower levels of eGFR. SGLT2 inhibitors have been shown to reduce the risk of serious hyperkalemia in people with type 2 diabetes with CKD without increasing the risk of hypokalemia.[194] An initial decline in eGFR is commonly observed after initiating an SGLT2 inhibitor 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.

Reported adverse effects 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 European Medicines Agency (EMA) warns of the potential increased risk of toe amputation and the need for appropriate monitoring.[201]​ However, the Food and Drug Administration (FDA) states that the risk of amputation, while increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.[202]​​[203]​​ 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.[204][205]​​ Thus, SGLT2 inhibitors should be avoided in patients with conditions that increase the risk for limb amputations, and in patients prone to urinary tract or genital infections.

GLP-1 receptor agonists

These drugs activate GLP-1 receptors, resulting in pancreatic beta-cell-mediated glucose-dependent insulin secretion. They also cause suppression of glucagon release, which slows gastric emptying and promotes satiety.[206] They are 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.[207]​ They also have beneficial effects on CV, mortality, and kidney outcomes in patients with type 2 diabetes.[148][208]​​

The GLP-1 receptor agonists with the strongest evidence for ASCVD risk reduction are semaglutide (injectable), liraglutide, and dulaglutide.​​[106][209][210]​​​​​​​​ Liraglutide significantly reduced CV mortality and all-cause mortality in those with diabetes and CVD or high CVD risk in one randomized trial.[211]​ Dulaglutide and semaglutide have both been shown to reduce MACE, but not all-cause or CV mortality.[212][213][214]​​​​​​​​​​ The addition of semaglutide to standard care has been shown to be associated with an important gain in life-years free of new/recurrent CVD events and a decrease in 10-year CVD risk.[215] It is the only GLP-1 receptor agonist to also be available in an oral formulation.​ However, unlike for injectable semaglutide, conclusive evidence for the CV benefit of oral semaglutide has not yet been established in clinical studies.[216] In contrast to other GLP-1 receptor agonists, exenatide has not been shown to reduce MACE.[217]

Semaglutide and liraglutide have been shown to offer kidney-protective effects, which appear to be more pronounced in patients with preexisting 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 HF has been inconsistent across trials. One meta-analysis found that they may prevent new-onset HF and mortality in patients with type 2 diabetes; however, they did not reduce HF hospitalizations and mortality in those patients with preexisting HF.[219]

The most common adverse effects 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. One meta-analysis of 43 randomized controlled trials (RCTs) found no clear evidence for an increased risk of pancreatitis.[221] After a review of available data, the FDA and EMA agreed that there was insufficient evidence to confirm an increased risk of pancreatic cancer with the use of GLP-1-based therapies.[222] Nonetheless, they 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 EMA and the 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][231] A US nationwide retrospective cohort study using electronic health records found no evidence of an increased risk of suicidal ideation with semaglutide compared with non-GLP-1 receptor agonist anti-obesity or antihyperglycemic drugs.[232]

Dual GIP/GLP-1 receptor agonists

Tirzepatide is the first dual GIP/GLP-1 receptor agonist to receive approval; it has been 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.

Tirzepatide 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]​​​​​ The SURPASS-3 trial demonstrated that in patients with type 2 diabetes, tirzepatide was superior to titrated insulin degludec, with greater reductions in HbA1c and body weight at week 52 and a lower risk of hypoglycemia.[236]​ SURPASS-4 demonstrated that in patients with type 2 diabetes and elevated CV risk, tirzepatide, when compared with insulin glargine, demonstrated greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycemia.[237]​ CV safety trials are under way.

The adverse effect profile 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]

DPP-4 inhibitors

​DPP-4 inhibitors increase endogenous GLP-1 and 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 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]

Saxagliptin and alogliptin have been associated with an increased risk of hospitalization for 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 CVD or high CV risk, other glucose-lowering drugs with CV benefit (e.g., SGLT2 inhibitors or GLP-1 receptor agonists) are preferred.[2] If circumstances require use of a DPP-4 inhibitor, 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]

​Sulfonylureas and meglitinides

Sulfonylureas 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 among the more affordable antihyperglycemic drugs and particularly useful if cost is a concern.[149]​ 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. [ Cochrane Clinical Answers logo ] ​ Hypoglycemia risk is exacerbated by alcohol, salicylates, sulfa drugs, gemfibrozil, or warfarin.

Glimepiride and glipizide are preferred over glyburide due to lower risk of hypoglycemia. Glyburide should be avoided. 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 CV outcomes with sulfonylureas have been reported in some studies, although systematic reviews have not found an increase in all-cause mortality compared with other active treatments.[106][244]​​​​ An RCT in adults with type 2 diabetes showed comparable CV safety of glimepiride compared with the DPP-4 inhibitor linagliptin over 6.3 years, and a Scottish real-world comparative safety study concluded that second-line sulfonylureas are unlikely to increase CV risk or all-cause mortality.[245][246]

Similar to sulfonylureas, meglitinides 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.

Thiazolidinediones

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.

They increase the risk of congestive HF, often causing weight gain and edema, and 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.[106][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.[251]

Pioglitazone is the most widely used available drug in this class. Evidence suggests that it decreases the risk of MACE 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 MASLD.[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]

Alpha-glucosidase inhibitors

These drugs inhibit upper gastrointestinal enzymes that break down complex carbohydrates into glucose. As a result, the absorption of glucose is delayed, postprandial glucose reduced, and glycemic control improved.[261] They are not commonly used in the US due to poor efficacy and GI adverse effects. 

They can be added to metformin in people with large postprandial glucose excursions, but increased flatus and GI adverse effects are common.

There is no strong evidence of a benefit on all-cause or CV mortality.

Bromocriptine and colesevelam

These oral agents are approved for glucose lowering. Bromocriptine is a sympatholytic D2-dopamine agonist that reduces hepatic gluconeogenesis.[262] Colesevelam is a bile acid sequestrant originally developed for the treatment of hypercholesterolemia. Its mechanism of action for glucose lowering is not fully understood.[263] These drugs have limited impact on blood glucose in many patients and neither is widely used for glucose control at present. [ Cochrane Clinical Answers logo ] ​ Bromocriptine may cause GI adverse effects.[262] Colesevelam requires multiple doses per day, and may bind other drugs.[263]

Insulin therapy

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]

Intensification to insulin is also an option for individuals who are not meeting their glycemic targets on other antihyperglycemic agents; it is necessary in at least 20% to 30% of those with type 2 diabetes in order to achieve recommended treatment goals. This is related to decreasing islet cell insulin secretion after a long duration of type 2 diabetes. Of note, the ADA recommends that a GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist should be considered prior to insulin if injectable therapy is needed and the patient is not already being treated with one of these drugs.[2]​ In trials comparing the addition of an injectable GLP-1 receptor agonist, tirzepatide, or insulin in people needing further glucose lowering, the glycemic efficacies of injectable GLP-1 receptor agonists and tirzepatide were similar to or greater than those of basal insulin.[237][264]​​​[265]​​​​​​[266][267]​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.[2]

If insulin is used, combination therapy with a GLP-1 receptor agonist or 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 CV events (GLP-1 receptor agonists), and slowing CKD 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]

Types of insulin

Numerous formulations of insulin are available with differing durations of action. Human insulins (NPH [neutral protamine Hagedorn], regular, and premixed combinations of NPH and regular insulin) are recombinant DNA-derived human insulin, while insulin analogs have been designed to have a different onset or duration of action.[106]

Basal insulin

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 or the once-daily administration of the long-acting analogs glargine or 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.[103][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] [ Cochrane Clinical Answers logo ] ​ 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, whereas with newer analogs, more flexibility in the timing of insulin injection is possible (i.e., any time of the day).[106]

Combination therapy: basal insulin plus a GLP-1 receptor agonist or a dual GIP/GLP-1 receptor agonist

If basal insulin has been titrated to an acceptable fasting blood glucose level (or if the dose is >0.5 units/kg/day with indications of a need for other therapy) and HbA1c remains above goal, and a patient is not already on a GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist, addition of one of these agents is recommended.[2]

Intensification with prandial insulin

​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, insulin lispro). A once-daily prandial dose 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. The dose should generally be increased twice weekly. 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 CGM. 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.

When basal-bolus insulin is used by motivated and knowledgeable patients, the dose of rapid-acting insulin that is administered before each meal can be based on anticipated carbohydrate content of the upcoming meal and sometimes adjusted for anticipated physical activity (carbohydrate-based dosing, sometimes called “carb-counting”), rather than administered as a fixed mealtime dose. Correction doses of rapid-acting insulin can also be administered based on premeal blood glucose readings (correctional algorithms). One acceptable method of determining a correction algorithm is to divide 1800 by the total daily dose of insulin to yield the expected blood glucose reduction per unit of insulin. For example, for a patient taking 60 units of insulin per day, the expected blood glucose lowering of 1 additional unit of prandial rapid-acting insulin would be 1800/60 = 30 mg/dL.

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.

Regimens should be individualized. 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.

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]

Continuation/cessation of other hyperglycemic agents

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]

Adverse effects of insulin

Exogenous insulin is a very effective way to lower serum glucose and lower HbA1c, but its use must be guided in most patients by regular blood glucose monitoring (fingerstick blood glucose testing) or CGM. Hypoglycemia (glucose <70 mg/dL [<3.9 mmol/L]) is the most serious potential complication. Patients should be educated on how to identify and manage hypoglycemia, and the importance of preventing it.[103]​ In some people with significant clinical complexity, multimorbidity, and/or treatment burden, it may become necessary to simplify or deintensify complex insulin plans to decrease risk of hypoglycemia and improve quality of life.[2]

Another significant adverse effect is weight gain. Less common adverse effects may include hunger, nausea, diaphoresis, injection site irritation, or anaphylaxis.

CV risk management

A primary goal of diabetes care is evidence-based management of CV risk factors to individualized goals. This may include BP control, lipid control, and antiplatelet therapy.

Management of hypertension

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

  • The UK Prospective Diabetes Study (UKPDS) found that tight BP control (<150/85 mmHg) led to a greater reduction in CV events than less tight BP control (<180/105 mmHg).[271]

  • The Systolic Blood Pressure Intervention Trial (SPRINT) had similar findings, with intensive BP control (<120 mmHg systolic) significantly reducing risk of CV events compared with standard control (<140 mmHg), although patients with diabetes were excluded from enrollment.[272]

  • Conversely, the ACCORD-BP trial demonstrated that intensive BP control to a goal of <120 mmHg systolic, compared with a standard BP goal of <140 mmHg, did not change CV outcomes in patients with diabetes.[273]

  • The 2021 STEP trial found that in older adults (ages 60-80 years) with hypertension, intensive BP control (target 110 to <130 mmHg) was associated with a 26% reduction in CV events compared with less intensive BP control (target 130 to <150 mmHg).[274]

The reason for the difference in findings between SPRINT and ACCORD-BP remains under debate. However, a post-hoc analysis of ACCORD-BP found that although dual intensive therapy for BP and glycemic control was detrimental, intensive BP control conferred modest CV benefits for patients on standard glycemic control.[275]​

There is a lack of high-quality evidence regarding optimal treatment of hypertension in people with diabetes.[101]​ However, guidelines concur in recommending a BP treatment goal of <130/80 mmHg, providing this can be safely attained.[2][77]​​​[101][276]​ The departure in the guidelines from the previous BP target of <140/90 mmHg was in response to studies like the meta-analysis of data from the ACCORD-BP and SPRINT trials, which showed a reduction in a composite of unstable angina, myocardial infarction, acute HF, stroke, and CV death with intensive systolic BP targets of <120 mmHg compared with the traditional target of <140 mmHg.[277]​ Notably, the ADA recommends an individualized approach to BP targets, suggesting 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]​ It notes that people with diabetes and hypertension may be more likely to benefit from intensive BP control when they have high absolute CV risk.​​​ Potential adverse effects of antihypertensive therapy (e.g., hypotension, syncope, falls, acute kidney injury, and electrolyte abnormalities) should be taken into account as part of this decision-making process; individuals with older age, CKD, and frailty have been shown to be at particular risk.[2]

People with diabetes plus hypertension should monitor their BP at home in addition to having it checked at regular intervals in the clinic setting, both to ensure accuracy of readings and to encourage adherence to treatment regimens.[2]

Guidelines emphasize the importance of therapeutic lifestyle interventions in the management of hypertension; these include increased physical activity, weight management, a DASH-style eating pattern (including reduced sodium intake and increased potassium intake), moderation of alcohol intake, smoking cessation, and education to support long-term behavior change.[2][276]​​ These lifestyle interventions should be initiated alongside pharmacologic therapy when hypertension is diagnosed, and are also recommended for individuals with diabetes and mildly elevated BP (systolic >120 mmHg or diastolic >80 mmHg).[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, or thiazide diuretics are all options for initial antihypertensive therapy.[2][101]​​​​[276]​

​For patients who have comorbid coronary artery disease, CKD, and/or albuminuria (eGFR <60 mL/minute/1.73 m², urinary albumin-to-creatinine ratio ≥30 mg/g creatinine), initial antihypertensive therapy should be with an ACE inhibitor, or an angiotensin-II receptor antagonist if an ACE inhibitor is not tolerated (a dose reduction may be required in patients with renal impairment).[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 because of an increased risk for acute kidney injury and hyperkalemia.[2][278]​​​​ ACE inhibitors have also shown increased risk for hypoglycemia in conjunction with insulin or insulin secretagogues (sulfonylureas or meglitinides).[279]

One meta-analysis found that ACE inhibitors reduced mortality and major CV events in patients with diabetes, while angiotensin-II receptor antagonists did not improve these outcomes. Neither were found to reduce the risk of stroke.[105] Another meta-analysis showed that in patients with diabetes and kidney disease, no antihypertensive regimen improved survival. However, ACE inhibitors and angiotensin-II receptor antagonists were effective in preventing end-stage renal disease.[278] Some antihyperglycemic agents have demonstrated modest BP-lowering effects in clinical trials, including SGLT2 inhibitors and GLP-1 receptor agonists.[280] Further studies are warranted to investigate the effects of these agents on BP as the primary outcome measure.[280]

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

Beta-blockers may be appropriate to improve outcomes as antihypertensive agents in patients with prior myocardial infarction, active angina, atrial fibrillation with rapid ventricular response, or HF 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] 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, add an agent from a complementary first-line drug class.[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), 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]

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]

Lipid management

Lifestyle modification focusing on: weight loss (if indicated); application of a Mediterranean or 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 lipid profile and reduce the risk of developing CVD in people with diabetes.[2]

LDL-C is the most extensively studied modifiable risk factor associated with ASCVD. There is strong evidence that LDL-C is a causal factor in the pathophysiology of CVD, with CVD risk reduction proportional to the absolute and relative LDL-C reduction achieved.[284]​ One meta-analysis that included data from over 18,000 people with diabetes from 14 randomized trials of statin therapy (mean follow-up 4.3 years) demonstrated a 9% proportional reduction in all-cause mortality and 13% reduction in vascular mortality for each 1 mmol/L (39 mg/dL) reduction in LDL-C.[285]​ The CV benefit did not depend on baseline LDL-C levels and was linearly related to the LDL-C reduction without a low threshold beyond which there was no benefit observed. Lowering of LDL-C has also been shown to have a significant positive impact on long-term outcomes for patients with diabetes and coronary heart disease undergoing percutaneous coronary intervention (PCI).[286]

Choice of agents:

  • Statins are the first-line agent for pharmacologic treatment of dyslipidemia and may have additional therapeutic effects independent of lipid-lowering action. They are contraindicated in pregnancy. There is some evidence that they may be associated with higher rates of serious adverse events in East Asian populations due to lower metabolism of the drug.[11]​ Moderate-intensity statin therapy has been defined by the American College of Cardiology (ACC)/American Heart Association (AHA) as therapy 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]

  • If target LDL-C is not achieved with a statin alone, addition of ezetimibe can be considered.[2] Ezetimibe works by reducing cholesterol absorption from the ileum.[6]​ Subgroup analysis of the IMPROVE-IT trial showed that the benefit of adding ezetimibe to statin therapy was enhanced in patients with diabetes.[287]

  • If target LDL-C is not achieved with a statin alone, addition of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (e.g., alirocumab, evolocumab) can be considered as an alternative to ezetimibe. In placebo-controlled RCTs, alirocumab and evolocumab achieved a >50% reduction in LDL-C levels compared with placebo, with a 15% lower risk of ischemic CV events over a 2- to 3-year follow-up.[288][289]

  • ​Bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, is a novel, oral LDL-C-lowering drug that works by inhibiting cholesterol synthesis.[77] The ADA advises that it may be considered for patients who cannot use, or tolerate, other evidence-based LDL-C-lowering approaches, or for whom those other therapies are inadequately effective.[2][290]​​ One meta-analysis found that bempedoic acid therapy lowered LDL-C levels by about 23% compared with placebo, while an RCT found that it was associated with a reduction in risk of major adverse CV events (death from CV causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) in statin-intolerant patients, providing some evidence for its use in this group.[291][292]​​​

  • Icosapent ethyl has been shown to modestly reduce CV events in patients on statins with controlled LDL-C but elevated triglycerides (135-499 mg/dL [1.53-5.64 mmol/L]).[2][281][293]​​​​ There have been some concerns about the use of mineral oil as the control treatment in pivotal clinical trials of icosapent ethyl; however, evaluation of whether this had an impact on trial outcomes remains inconclusive.[294][295]​​​​ The ADA recommends that 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] 

  • Fibrates are effective for lowering very high triglyceride levels (i.e., >500 mg/dL [>565 mmol/L]) to reduce risk of pancreatitis.[281] They are most often added to statin therapy, although the ADA notes that this approach is generally not recommended due to a lack of evidence of improvement in ASCVD outcomes.[2] Furthermore, caution is recommended as statin and fibrate therapy can increase the risk of myositis and rhabdomyolysis. To lower the risk, fenofibrate is recommended over gemfibrozil.[296]

  • Supplementation with omega-3 fatty acids has not been found to reduce the rate of CV events in patients with diabetes at high risk for these events.[297]

For primary prevention of CVD in adults with diabetes without established CVD, ADA guidelines recommend:[2]

  • Moderate-intensity statin therapy in all people ages 40-75 years. Consideration of statin therapy in patients ages 20-39 years with additional ASCVD risk factors (being mindful that statins are contraindicated in pregnancy).

  • High-intensity statin therapy in people ages 40-75 years at higher CV risk, including those with one or more CVD risk factors, to reduce LDL-C by ≥50% of baseline and to target an LDL-C goal of <70 mg/dL (<1.81 mmol/L).

  • Consider addition of ezetimibe or a PCSK9 inhibitor to maximum tolerated statin therapy 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). ​BMJ: PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations Opens in new window

  • For adults ages >75 years already established on statin therapy, it is reasonable to continue statin treatment. It may be reasonable to initiate moderate-intensity statin therapy in this age group following discussion of the potential benefits and risks.

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

​European guidelines recommended a more aggressive target for LDL-C of <55 mg/dL (<1.42 mmol/L) in very high-risk patients (again, aiming for at least a 50% reduction in LDL-C).[77] This includes patients with diabetes with severe target end-organ damage or a 10-year CVD risk of 20% or more using the SCORE2-Diabetes risk calculator.[77]

A lipid profile should be checked: at time of diagnosis of diabetes or prediabetes; at initiation of statins or other lipid-lowering therapy; 4-12 weeks after initiation or a change in dose; and annually thereafter.[2]

For information on secondary prevention in adults with diabetes with established CVD and CKD, see Diabetic cardiovascular disease and Diabetic kidney disease.

Antiplatelet therapy

The routine use of aspirin for primary prevention of diabetic CVD is not generally recommended. However, in patients with diabetes ages ≥50 years who have at least one additional risk factor (e.g., hypertension, hyperlipidemia, family history of coronary artery disease, current or past smoker, or CKD) 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 artery calcium (CAC) score can be used to assess CVD risk and therefore help determine an indication for aspirin therapy.[2][75][298]​​​​​ 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 and CKD (secondary prevention), see Diabetic cardiovascular disease and Diabetic kidney disease.

Bariatric surgery for treatment of diabetes in patients with obesity

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]​ RCTs have shown a benefit with regard to diabetes remission, glycemic control, need for glucose-lowering medications, quality of life, improvement in MASLD, and reduction in CV 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 was associated with substantially lower all-cause mortality rates and longer median life expectancy (9.3 years longer than those without surgery).[307]

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][311] Compared with VSG, RYGB leads to somewhat greater weight loss and other benefits, but is a more technically challenging operation with higher reoperation and readmission rates, and more of a tendency to malabsorption of vitamins and minerals postoperatively. The benefits and risks of bariatric surgery also vary substantially across type 2 diabetes patient subgroups. In observational studies, average benefits appeared to be highest in those who are younger (age 40-50 years), those with more recent onset of type 2 diabetes, and those not on insulin therapy.[312]

Health insurers in the US generally restrict payment for bariatric surgery, but the eligibility criteria have been slowly expanding over time. The ADA 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 ESC 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]

Bariatric surgery is best done in a high-volume, specialized 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. 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.

Treatment of preexisting type 2 diabetes in pregnancy

Preconception care

The ADA stresses the importance of preconception counseling, advising that it should be incorporated into routine diabetes care for all people of childbearing potential. Preconception counseling has been shown to be highly effective in reducing the risk of congenital malformations and decreasing the risk of preterm delivery and admission to neonatal intensive care units. It is also associated with reductions in perinatal mortality and small-for-gestational-age birth weight.[2] Family planning should be discussed, and effective contraception (with consideration of long-acting, reversible contraception) should be prescribed and used until an individual’s treatment plan and HbA1c are optimized for pregnancy.[2]

Counseling should include an explanation of the risks to mother and fetus related to pregnancies associated with diabetes and the ways to reduce risks, including glycemic goal setting, lifestyle and behavioral management, and medical nutrition therapy.[2] Patients should be advised that good glucose management, with HbA1c as close to normal as is safely possible (ideally HbA1c <6.5% [<48 mmol/mol]) before conception, optimizes maternal and fetal health outcomes.[2][314][315]​​​​​​​ Individuals who are planning a pregnancy should ideally begin receiving interprofessional care, which includes an endocrinology healthcare professional, a maternal-fetal medicine specialist, a registered dietitian nutritionist, and a diabetes care and education specialist, when available.[2]

Potentially teratogenic drugs (e.g., ACE inhibitors, angiotensin-II receptor antagonists, statins) should be discontinued. Women should be assessed prenatally for diabetes complications and comorbidities, which may worsen during or complicate pregnancy.[315]​ Diabetic retinopathy, in particular, has the potential to worsen during pregnancy, particularly if there is a rapid improvement in glycemic control. An ophthalmologist with expertise in diabetic retinopathy should perform a comprehensive eye exam prior to pregnancy or during the first trimester.[2][315]​​ Ideally any necessary treatment should be undertaken before pregnancy. The ADA recommends that patients be monitored for worsening retinopathy every trimester and for 1 year postpartum.[2] It is also recommended, where no recent results are available, to perform an assessment of renal function and BP and an ECG and lipid profile in patients with preexisting diabetes who are planning a pregnancy.[315] Evidence of microvascular or macrovascular complications should be carefully considered, and where appropriate monitored and managed by a specialist.[315]

Prenatal care

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 CGM systems among pregnancies complicated by type 2 diabetes, CGM technology has been shown to be safe and to 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]

​ADA guidelines recommend the following blood glucose targets in pregnant women with preexisting type 2 diabetes (the same as for gestational diabetes):[2]

  • 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.

It should be noted that the lower limits do not apply to individuals treated with nutrition alone.[2]

Due to increased red blood cell turnover, HbA1c is slightly lower during pregnancy. HbA1c goals are stricter in pregnancy than in nonpregnant individuals; ideally, the target should be <6% (<42 mmol/mol) if this can be achieved without significant hypoglycemia, but this may be relaxed to <7% (<53 mmol/mol) if 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 insulin or insulin glargine) may be combined with short- or rapid-acting insulin (regular insulin or the rapid-acting insulin analogs insulin lispro or insulin aspart) before meals.[315] The American College of Obstetricians and Gynecologists advises that insulin lispro and insulin aspart should 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, DPP-4 inhibitors, GLP-1 receptor agonists, and 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 CV events.[320]​ 

It should be noted that preexisting type 2 diabetes, and some of its sequelae, may heighten the risk of pregnancy complications and unfavorable outcomes, and therefore patients will usually require more frequent and detailed monitoring throughout pregnancy.​[315][321]​

​Due to the higher risk of fetal neural tube defects in pregnancies complicated by diabetes, patients should be strongly advised to start taking folic acid once they are planning a pregnancy.[315] Patients are also 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 ADA recommends starting this 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.

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]

Intrapartum and postpartum care

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 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]

Care delivery models

Diabetes care in the US has, on average, dramatically improved in the past 20 years, illustrated by a decline in the incidence of CVD or CV death among patients with type 2 diabetes.[322]​ Many factors have contributed to diabetes care improvement and better clinical outcomes for patients.[323] The principal model used to frame these strategies is the Chronic Care Model.[324] The model includes 6 core elements: delivery system design, self-management support, decision support, clinical information systems, community resources and policies, and health systems. 

Evidence is generally supportive of the following care improvement strategies:

  • A multidisciplinary team approach to patient care, including the involvement of trained diabetes self-management educators, pharmacists, and case managers[325][326]

  • Advanced and integrated electronic medical record clinical decision support beyond simple reminder systems and alerts[327][328]

  • Simulated case-based learning interventions for clinicians.[329][330][331]

Other redesigns to the care delivery system such as alternative reimbursement methods, public policy changes to support healthier lifestyles, the patient-centered medical home, and mobile health (mHealth) technology may provide additional opportunities to improve care and are currently being evaluated.[332][333] Diabetes management decisions should be timely, rely on evidence-based guidelines, and be made collaboratively with the patient.

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