INTRODUCTION — The estimated overall prevalence of diabetes mellitus among adults in the United States varies with race/ethnicity and ranges from 6.8 to 15.3 percent . The large majority of patients have type 2 diabetes. More health care resources are estimated to be spent on diabetes than any other condition . Numerous factors, in addition to diabetes-associated complications, contribute to the impact of diabetes on quality of life and health care costs. Diabetes is associated with a high prevalence of depression  and adversely impacts employment, absenteeism, and work productivity [4,5].
This review will provide an overview of general medical management for nonpregnant adult patients with diabetes, with a particular emphasis on nonglycemic management (table 1). The approach is consistent with guidelines from the American Diabetes Association (ADA) for health maintenance in patients with diabetes, which are updated yearly [6-8]. Detailed discussions relating to screening, diagnosis, and initial evaluation of diabetes mellitus as well as management of hyperglycemia are discussed separately.
●(See "Screening for type 2 diabetes mellitus".)
●(See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults".)
●(See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)
●(See "Management of persistent hyperglycemia in type 2 diabetes mellitus".)
●(See "Gestational diabetes mellitus: Glucose management and maternal prognosis".)
●(See "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control".)
●(Related Pathway(s): Diabetes: Initial therapy for non-pregnant adults with type 2 DM.)
Diabetes-related complications — Patients with diabetes require ongoing evaluation for diabetes-related complications.
●We perform a history and physical examination two to four times yearly to obtain information on nutrition, physical activity, management of diabetes and cardiovascular risk factors, and diabetes-related complications (table 1).
●We check blood pressure and visually inspect the feet at every visit, and in addition, we perform a more thorough foot examination and refer patients for a dilated eye examination, usually annually. The frequency of eye examinations may vary based on the presence and severity of eye findings and other factors.
●We measure glycated hemoglobin (A1C) every three months if A1C is not in the goal range and therapy requires adjustment. We measure A1C every six months in patients with stable glycemia who are meeting A1C goals. We measure fasting lipids, basic metabolic profile, and urine albumin-to-creatinine ratio annually.
Morbidity from diabetes is a consequence of both macrovascular disease (atherosclerosis) and microvascular disease (retinopathy, nephropathy, and neuropathy). In type 2 diabetes, disease onset is often insidious, and diagnosis is therefore delayed. As a result, diabetes complications may be present at the time of diagnosis , and their frequency increases over time (figure 1). The development of complications can be delayed with management of hyperglycemia, hypertension, and dyslipidemia. Similarly, once present, the progression of these complications can be slowed with the same management strategies. In addition to management of hypertension, administration of an angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) and, if indicated, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, may specifically reduce progression of nephropathy. Laser therapy or intraocular injection of vascular endothelial growth factor (VEGF)-inhibiting agents can ameliorate advanced retinopathy and ameliorate vision loss. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Diabetic retinopathy: Prevention and treatment" and "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus" and "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus" and "Treatment of diabetic kidney disease".)
In the United States, the greatest absolute declines in people with diabetes have been reported for acute MI and stroke (between 1990 and 2010, 95.6 and 58.9 fewer cases per 10,000 persons per year for MI and stroke, respectively) . Other countries have similarly reported reductions in the rate of cardiovascular complications and lower-extremity amputation [11-13]. (See 'Reducing the risk of macrovascular disease' below.)
Routine eye examination — Patients with diabetes are at increased risk for vision loss, related both to refractive errors (correctable visual impairment), cataracts and glaucoma (which are more prevalent in persons with diabetes [14,15]), and to retinopathy.
●Visual impairment – A study using data from the National Health and Nutrition Examination Survey (NHANES) in the United States found that 20 percent of Americans with diabetes aged 40 years and older without retinopathy (or with only mild and moderate nonproliferative diabetic retinopathy [NPDR]) had visual-related functional impairment . For those with severe NPDR or proliferative diabetic retinopathy, the prevalence was 48 percent. These data indicate the need for visual acuity assessment in addition to dilated eye examinations for retinopathy to identify individuals with reduced acuity, address treatable causes, and improve quality of life.
●Diabetic retinopathy – Recommendations for the type and frequency of routine eye examinations vary based upon the type of diabetes mellitus, the presence of specific eye findings, and the level of risk factors, such as A1C levels (table 2) [7,17]. Serial examinations are indicated because of the increased incidence of retinopathy over time in patients with diabetes and the ability to intervene and reduce risk for vision loss with timely interventions (figure 2). Screening for diabetic retinopathy is reviewed in detail separately. (See "Diabetic retinopathy: Screening".)
General measures to reduce risk and progression of retinopathy include good glycemic and blood pressure control. Prevention and treatment of retinopathy is reviewed separately. (See "Diabetic retinopathy: Prevention and treatment".)
Routine foot examination — The feet should be visually inspected at each routine visit to identify problems with nail care, poorly fitting footwear resulting in barotrauma, fungal infections, and callus formation that may result in more severe foot problems. A comprehensive foot examination should be performed annually on patients with diabetes to identify risk factors predictive of ulcers and amputation [7,18]. It can be accomplished in the primary care setting and should include inspection, assessment of pedal pulses, and testing for loss of protective sensation (table 3). Systematic screening examinations for neuropathic and vascular involvement of the lower extremities and careful inspection of feet may substantially reduce morbidity from foot problems. (See "Evaluation of the diabetic foot".)
Foot problems due to vascular and neurologic disease are a common and important source of morbidity. Patients who may have neuropathy (based on abnormal results from a microfilament or other test [eg, Ipswich touch test]) (see "Evaluation of the diabetic foot", section on 'Assessment for loss of protective sensation') or who have calluses or other foot deformities should be referred to clinicians with expertise in diabetic foot care (podiatrist, nurse, diabetes foot clinic, or other, depending on available local resources).
Monitoring for increased urinary albumin excretion — Measurement of the urine albumin-to-creatinine ratio in an untimed urinary sample is the preferred screening strategy in all patients with diabetes to detect elevation. It should be repeated yearly. Increased urinary protein excretion is the earliest clinical finding of diabetic nephropathy.
Measurement of urinary albumin excretion can be deferred for five years after the onset of disease in patients with type 1 diabetes because diabetic nephropathy is uncommon before this time. Monitoring should begin at diagnosis in patients with type 2 diabetes because many have had diabetes for several years before diagnosis . Abnormal results should be repeated at least two or three times for confirmation over a three- to six-month period because of the large number of false positives that can occur . Fever, exercise, heart failure, and acute poor glycemic control are among the factors that can cause transient elevation in urinary albumin-to-creatinine ratio .
The urine albumin-to-creatinine ratio test (mg/g) gives a quantitative result that correlates with the 24-hour urine values (mg/day) over a wide range of protein excretion. The normal rate of albumin excretion is less than 30 mg/day (20 mcg/min) (calculator 1).
●Persistent urine albumin-to-creatinine ratio values between 30 and 300 mg/gram creatinine suggest that albumin excretion is between 30 and 300 mg/day. This is now called moderately increased albuminuria (historically called microalbuminuria) and is usually indicative of diabetic nephropathy (unless there is some other coexistent renal disease).
●Persistent urine albumin-to-creatinine ratio values above 300 mg/gram creatinine (or 300 mg/day if a 24-hour urine is collected) are considered to represent severely increased albuminuria (the new terminology for what was formerly called macroalbuminuria) and is also called proteinuria, clinical renal disease, or dipstick-positive proteinuria.
The availability of effective therapy to prevent progression of kidney disease with ACE inhibitors, ARBs, and SGLT2 inhibitors is the rationale for yearly screening of all patients with either type 1 or type 2 diabetes for increased albumin excretion. We typically continue yearly monitoring to assess response to therapy and/or to detect kidney disease progression .
The treatment of increased urinary albumin excretion and diabetic nephropathy is reviewed in detail elsewhere. (See "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus", section on 'Effect of interventions on albuminuria' and "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus", section on 'Treatment' and "Treatment of diabetic kidney disease".)
Screening for coronary heart disease — We perform an annual assessment of risk criteria (blood pressure, fasting lipid profile, smoking history) to identify patients who might benefit from more intensive cardiovascular risk factor management. (See 'Blood pressure control' below and 'Dyslipidemia' below.)
We do not routinely perform exercise stress testing in asymptomatic patients with diabetes, including patients with type 2 diabetes who are at higher risk for atherosclerotic cardiovascular disease (ASCVD) than people without diabetes. Routine screening does not improve outcomes beyond medical management of cardiac risk factors . For sedentary adults (age >50 years) with diabetes who are beginning an exercise program, counsel initiation of a gentle exercise program with gradual progression as tolerated. We evaluate if typical or atypical signs or symptoms of ASCVD develop with exercise or are evident on examination.
The increased risk for asymptomatic coronary artery disease in those with diabetes and other risk factors suggests that the decision to perform cardiac evaluation should be individualized, with consideration given to those at very high risk, such as patients with diabetes who also have atypical cardiac symptoms (eg, unexplained dyspnea), peripheral or carotid artery disease, or electrocardiogram abnormalities (eg, Q waves) . Despite the relatively high frequency of silent ischemia in patients with diabetes, identifying asymptomatic disease or providing early intervention beyond guideline-recommended ASCVD risk factor management has not been shown to improve outcomes in this population . (See "Screening for coronary heart disease in patients with diabetes mellitus".)
The evaluation and treatment of patients with diabetes and known ASCVD is reviewed in detail elsewhere. (See "Acute myocardial infarction: Patients with diabetes mellitus" and "Coronary artery revascularization in stable patients with diabetes mellitus".)
Comorbid conditions — In addition to the microvascular and neuropathic complications of diabetes and coincident hypertension, obesity, dyslipidemia, and ASCVD, adults with type 2 diabetes are at risk for other comorbidities. These disorders, which may be present at diagnosis or may develop over time, include the following :
●Hearing impairment. (See "Etiology of hearing loss in adults" and "Evaluation of hearing loss in adults".)
●Sleep apnea. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)
●Fatty liver disease. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults".)
●Periodontal disease – Annual examination by a dentist is recommended for all patients with diabetes, even those without teeth . (See "Overview of gingivitis and periodontitis in adults".)
●Cognitive impairment. (See "Risk factors for cognitive decline and dementia".)
●Depression and anxiety – Concurrent depression is highly prevalent among adults with diabetes , underscoring the importance of screening at the time of diagnosis and routinely thereafter. (See "Screening for depression in adults", section on 'Screening options'.)
●Diabetes distress – Diabetes distress refers to stress, frustration, and being overwhelmed by the self-care responsibilities required for glycemic management. Clinicians should consider screening individuals for diabetes distress with validated surveys such as the Problem Areas in Diabetes Scale or the Diabetes Distress Scale.
●Eating disorders. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis".)
●Fractures. (See "Bone disease in diabetes mellitus".)
●Cancer – Some studies suggest an increased risk of certain cancers (liver, pancreas, endometrium, colon/rectum, breast, bladder) in patients with type 2 diabetes, possibly related to the coincident obesity [23-29]. Adults with type 2 diabetes also have an increased risk of cancer mortality. In a systematic review of individual patient data from 97 prospective studies (820,900 patients), adults with diabetes compared with those without had an increased risk of death from cancer (hazard ratio [HR] 1.25, 95% CI 1.19-1.31) . The increased risk of death was associated specifically with cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. In addition, the relative risk was substantially reduced when adjusting for A1C levels in multivariate analyses, consistent with a mediating effect of hyperglycemia on cancer risk. (See "Colorectal cancer: Epidemiology, risk factors, and protective factors" and "Epidemiology and risk factors for hepatocellular carcinoma" and "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder" and "Epidemiology and nonfamilial risk factors for exocrine pancreatic cancer" and "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Diabetes mellitus'.)
For patients with signs or symptoms of any of these conditions, additional assessment is warranted. Patients with diabetes should undergo recommended age- and sex-specific cancer screening . (See "Overview of preventive care in adults", section on 'Cancer screening'.)
Blood glucose monitoring and target A1C — All patients with diabetes mellitus who use insulin and some patients who take other glucose-lowering medications that can cause hypoglycemia should (at least periodically) self-monitor their glucose concentrations to help maintain safe, target-driven glucose levels. Self-monitoring is generally unnecessary in patients who are treated with diet alone or who take oral or injectable agents that do not cause hypoglycemia. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'Who should self-monitor?'.)
A1C goals in patients with diabetes should be tailored to the individual, balancing the demonstrated benefits with regard to prevention and delay of microvascular complications (intensive glycemic management) with the risk of hypoglycemia.
●A reasonable goal of therapy is an A1C value of ≤7.0 percent (53 mmol/mol) (calculator 2) for most patients (using a Diabetes Control and Complications Trial [DCCT]/United Kingdom Prospective Diabetes Study [UKPDS]-aligned assay in which the upper limit of normal is 6.0 percent) . (See "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target' and "Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Glycated hemoglobin (A1C)'.)
In order to achieve this A1C goal, a fasting glucose of 80 to 130 mg/dL (4.4 to 7.2 mmol/L) and a postprandial glucose (90 to 120 minutes after a meal) less than 180 mg/dL (10 mmol/L) are generally given as targets, but higher achieved levels may suffice (table 4) .
●The A1C goal should be set somewhat higher (eg, <8 percent [<64 mmol/mol]) for older patients and those with comorbidities, a history of severe hypoglycemia or other significant adverse medication effects or polypharmacy, or a limited life expectancy and little likelihood of benefit from intensive therapy. (See "Treatment of type 2 diabetes mellitus in the older patient", section on 'Controlling hyperglycemia'.)
●A more stringent goal (A1C <6 percent [<42 mmol/mol]) is indicated during pregnancy. (See "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control", section on 'Target A1C level'.)
●Obtain an A1C at least twice yearly in patients who are meeting treatment goals and who have stable glycemic management and quarterly in patients whose therapy has changed or requires adjustment, or who are not meeting glycemic goals.
●If interpretation of the A1C result is problematic (ie, owing to hemoglobinopathies or in the setting of altered red cell turnover [eg, hemolytic anemia], resulting in discrepancies between A1C and true mean glycemia [detected by more intensive or targeted blood glucose monitoring or use of continuous glucose monitoring]), other glycemic measurements (eg, time in range) should be used to assess degree of glycemic control. (See "Measurements of glycemia in diabetes mellitus", section on 'Unexpected or discordant values'.)
Lifestyle intervention — There are three major components to nonpharmacologic therapy of blood glucose and overall health in type 2 diabetes (see "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Intensive lifestyle modification'):
In addition to improving glycemia, lifestyle change and modest weight loss also reduce the development of obstructive sleep apnea, improve mobility and quality of life, and reduce the need for glucose-lowering and blood pressure medications [33-35]. Diet and exercise are important components of therapy in patients with type 1 diabetes. (See "Nutritional considerations in type 1 diabetes mellitus" and "Nutritional considerations in type 2 diabetes mellitus" and "Exercise guidance in adults with diabetes mellitus", section on 'Exercise guidance'.)
Bariatric surgical treatment of patients with diabetes and obesity results in a large degree of sustained weight loss and, in parallel, large improvements in blood glucose management, including remissions of type 2 diabetes (see "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Bariatric surgery'). Pharmacotherapy for weight loss may also be used for patients with type 2 diabetes. (See "Obesity in adults: Drug therapy".)
Pharmacologic therapy for hyperglycemia
●Type 2 diabetes – Initiating metformin early in the course of type 2 diabetes, assuming that no contraindications are present, remains the consensus recommendation. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".) (Related Pathway(s): Diabetes: Initial therapy for non-pregnant adults with type 2 DM.)
The therapeutic options for patients who fail initial therapy with lifestyle intervention and metformin are to add a second oral or injectable agent, including insulin (figure 3). (See "Management of persistent hyperglycemia in type 2 diabetes mellitus" and "Insulin therapy in type 2 diabetes mellitus".)
Regardless of the initial response to therapy, the natural history of most patients with type 2 diabetes is for blood glucose concentrations and A1C to rise over time (figure 4) [36,37]. The UKPDS suggested that worsening beta cell dysfunction with decreased insulin release was primarily responsible for disease progression . More severe insulin resistance or decreased compliance with the dietary regimen also may contribute to progression.
●Type 1 diabetes – Treatment of type 1 diabetes includes the coordination of meals/diet and activity with physiologic insulin replacement, which involves the frequent monitoring of blood glucose levels. (See "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Insulin regimens'.)
REDUCING THE RISK OF MACROVASCULAR DISEASE — Prevention of cardiovascular morbidity is a major priority for patients with diabetes, especially type 2. Individuals with diabetes are at increased risk for developing and dying from atherosclerotic cardiovascular disease (ASCVD); compared with those without diabetes, people with diabetes have decreased life expectancy (six to eight years less) [30,38-40]. At the time of diagnosis of type 2 diabetes, many patients already have one or more risk factors for macrovascular disease (obesity, hypertension, dyslipidemia, smoking) and many have evidence of overt atherosclerosis (past myocardial infarction [MI], ischemic changes on electrocardiogram [ECG], or peripheral vascular disease).
Multifactorial risk factor reduction — Management of ASCVD risk factors, including hypertension, hypercholesterolemia, and smoking, has been shown to reduce cardiovascular mortality. Smoking cessation is essential for patients who smoke. In addition, use of aspirin (75 to 162 mg/day), and use of certain glucose-lowering medications in patients with or at high risk for ASCVD can reduce recurrent ASCVD events and mortality. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Established cardiovascular or kidney disease' and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Monotherapy failure'.)
The benefits of multifactorial risk factor reduction are illustrated by the following:
●In a Swedish cohort study (median follow-up 5.7 years), among nonsmoking patients with type 2 diabetes who had A1C, low-density lipoprotein (LDL) cholesterol, urinary albumin, and blood pressure within target ranges, there was little or no excess risk of death, MI, or stroke compared with the general population .
●In the Steno-2 trial, 160 patients with type 2 diabetes and modestly elevated albuminuria were randomly assigned to either conventional therapy or an intensive therapy regimen, which included lifestyle modification, glycemic control (target A1C <6.5 percent), blood pressure control (target <140/85 mmHg for most of the study and <130/80 mmHg for the last two years), and lipid-lowering therapy, angiotensin-converting enzyme (ACE) inhibitor regardless of blood pressure, and aspirin . After a mean of 7.8 years, patients on intensive therapy had a significant reduction in the primary aggregate endpoint of cardiovascular death, nonfatal MI, coronary artery bypass grafting, percutaneous coronary intervention, stroke, amputation, or peripheral vascular surgery (18 versus 38 percent, hazard ratio [HR] 0.47, 95% CI 0.22-0.74). Significant reductions were also seen in progression of nephropathy, retinopathy, and autonomic neuropathy.
After the intervention study ended, 130 remaining patients participated in an observational follow-up study (5.5 years), during which time all participants were encouraged to follow intensive multifactorial treatment regimens, and A1C values, blood pressure, body mass index (BMI), and cholesterol levels in the two groups became similar . During the entire follow-up period (13.3 years), there were fewer deaths (30 versus 50 percent) in the intensive therapy group (HR for death 0.54, 95% CI 0.32-0.89). Intensive therapy was also associated with a lower risk of cardiovascular deaths (HR 0.43, 95% CI 0.19-0.94), which was a predefined secondary endpoint. Progression of diabetic retinopathy, nephropathy, and autonomic neuropathy occurred less frequently in the intensive group. These results suggest a sustained benefit of multifactorial risk reduction.
In spite of evidence that aggressive risk factor reduction lowers the risk of both micro- and macrovascular complications in patients with diabetes, a minority of adults with diabetes achieve all of the recommended goals for A1C, blood pressure control, and management of dyslipidemia [42,44,45]. It is notable that only one patient in the observational Steno study described above reached all five treatment goals at the end of follow-up. Thus, renewed efforts to implement multifactorial risk factor reduction strategies early in the course of type 2 diabetes are necessary. (See 'Adequacy of care' below.)
Smoking cessation — A survey in the United States (2001 to 2010) found that the adjusted prevalence of cigarette smoking was lower and quit attempts higher among adults with versus without diabetes . A meta-analysis of many of the cardiovascular risk reduction trials showed that cessation of smoking had a much greater benefit on survival than most other interventions . These findings suggest that discontinuation of smoking is one of the most important aspects of therapy in patients with diabetes who smoke. (See "Overview of smoking cessation management in adults".)
Candidates — For the secondary prevention of ASCVD in patients with diabetes, we recommend aspirin (75 to 162 mg daily). For the primary prevention of ASCVD in patients with diabetes at increased cardiovascular risk (10-year risk >10 percent), we suggest aspirin (75 to 162 mg daily), although the evidence supporting this approach is weak and needs to be balanced with the increased risk of gastrointestinal bleeding. We do not routinely use aspirin for the prevention of ASCVD in adults with diabetes at low risk (10-year ASCVD risk <10 percent). (See 'Guidelines' below.)
The decision to use aspirin for the prevention of cardiovascular events in patients with diabetes should be made using shared decision-making on an individual basis, taking into account potential benefits and risks (see 'Bleeding' below). It is likely that there is some level of risk of ASCVD events that would result in a positive benefit-to-risk ratio. Large trials investigating the role of aspirin for the primary prevention of cardiovascular events in patients with diabetes have been completed or are underway [48-51].
Prevention of cardiovascular events
●Secondary prevention – The merits of daily aspirin therapy in patients with existing ASCVD are widely accepted. A meta-analysis from the Antithrombotic Trialists' Collaboration of randomized trials of antiplatelet therapy for the secondary prevention of ASCVD in high-risk patients showed that aspirin produced statistically significant and clinically important reductions in the risk of subsequent MI, stroke, and vascular death among a wide range of high-risk patients (acute MI or ischemic stroke, unstable angina, prior MI or stroke, peripheral artery disease, and other high-risk groups) . (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)
In the subset of patients with diabetes, there was a nonsignificant, 7 percent decrease in serious cardiovascular events .
The use of dual antiplatelet therapy and the use of combination therapy with aspirin plus anticoagulant therapy are reviewed in detail separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Adjunctive therapies'.)
●Primary prevention – The benefits of daily aspirin for the primary prevention of ASCVD in patients with diabetes and ASCVD risk factors (but without known ASCVD) is uncertain . In a meta-analysis of 10 trials evaluating aspirin for the primary prevention of ASCVD in patients with diabetes, aspirin modestly but significantly reduced the risk of major cardiovascular events compared with placebo or no treatment (relative risk [RR] 0.90, 95% CI 0.81-0.99) . Aspirin did not significantly reduce the risk of any of the individual endpoints (MI, coronary heart disease, stroke, ASCVD, or all-cause mortality). There were differences in effect according to underlying ASCVD risk, sex, and compliance.
In a subsequent trial, 15,480 patients with diabetes (94 percent with type 2 diabetes) but no evidence of ASCVD were randomly assigned to aspirin (100 mg daily) or placebo . (Participants were also randomly assigned to receive 1 gram n-3 fatty acid or placebo once daily.) The majority of patients were taking statins and antihypertensive medication. After a mean follow-up of 7.4 years, serious vascular events (a composite of MI, stroke [excluding intracranial hemorrhage], transient ischemic attack, or death from any vascular cause [except intracranial hemorrhage]) occurred in a smaller proportion of patients in the aspirin group (8.5 versus 9.6 percent, rate ratio 0.88, 95% CI 0.79-0.97). Aspirin did not significantly reduce the risk of any of the individual endpoints. The benefits of aspirin in reducing serious vascular events were offset by an approximate 1 percent absolute increased risk of bleeding, largely gastrointestinal and extracranial. (See 'Bleeding' below.)
In exploratory analyses, the effects of aspirin on serious vascular events and on safety events did not clearly vary according to baseline patient characteristics, including group assignment to n-3 fatty acids and baseline ASCVD risk.
Bleeding — The main adverse effect of aspirin is bleeding. In the trial described above, major bleeding events (the first occurrence of a composite of intracranial hemorrhage, sight-threatening bleeding in the eye, gastrointestinal bleeding, or bleeding that resulted in hospitalization, transfusion, or fatality) occurred in a higher proportion of patients in the aspirin group (4.1 versus 3.2 percent, rate ratio 1.29, 95% CI 1.09-1.52) . Aspirin did not significantly increase the risk of any of the individual endpoints. In a Japanese trial, however, there was an increase in nonfatal intracranial hemorrhage (23 versus 10 events) and subarachnoid hemorrhage (8 versus 4 events) in patients taking aspirin . Extracranial hemorrhage requiring transfusion or hospitalization was also more common in the aspirin group (62 versus 34 events, HR 1.85, 95% CI 1.22-2.81).
Aspirin does not appear to increase retinal hemorrhagic complications in patients with diabetic retinopathy, even if advanced. In the Early Treatment Diabetic Retinopathy Study, patients with mild to severe nonproliferative or early proliferative diabetic retinopathy had one eye treated with scatter retinal photocoagulation. The 3711 participants were also randomly assigned to receive either aspirin (650 mg/day) or placebo. During the study, periodic fundus photography of the eyes not receiving photocoagulation detected vitreous or pre-retinal hemorrhages in 32 versus 30 percent of patients treated with aspirin or placebo, respectively . Approximately 40 percent of these hemorrhages produced a loss of visual acuity to less than 20/40. However, the severity and rate of resolution of these hemorrhages were not different between the aspirin- and placebo-treated groups. Similarly, in the large trial described above (15,480 patients with diabetes), the risk of sight-threatening bleeding did not differ between the aspirin and placebo groups (0.7 and 0.8 percent, respectively, rate ratio 0.89, 95% CI 0.62-1.27) . These studies, as well as a meta-analysis of other randomized clinical trials, concluded that there were no ocular contraindications to the use of aspirin (650 mg/day) in persons with diabetes who require this medicine for treatment of ASCVD or for other medical indications [56,57].
Guidelines — Based upon these data, the American Diabetes Association (ADA) recommends the following approach :
●Aspirin (75 to 162 mg/day) is recommended for secondary prevention in patients with diabetes and a history of MI, vascular bypass, stroke or transient ischemic attack, peripheral vascular disease, claudication, or angina.
•Dual antiplatelet therapy (low-dose aspirin plus a P2Y12 inhibitor) is reasonable for a year after an acute coronary syndrome. Longer-term treatment should be considered for patients with prior coronary intervention, high ischemic risk, and low bleeding risk to prevent major adverse cardiovascular events.
•Combination therapy with aspirin plus low-dose rivaroxaban should be considered for patients with stable coronary and/or peripheral artery disease and low bleeding risk to prevent major adverse limb and cardiovascular events.
●Aspirin (75 to 162 mg/day) should be considered for primary prevention in any patient with diabetes at increased cardiovascular risk (10-year risk >10 percent) after a discussion of the benefits (reduction in major adverse cardiovascular events) versus increased risk of bleeding (primarily gastrointestinal). Increased cardiovascular risk may include most individuals >50 years who have at least one additional cardiovascular risk factor (eg, cigarette smoking, hypertension, obesity, albuminuria, dyslipidemia, or a family history of coronary heart disease). The ADA recognizes that the evidence to support this recommendation is weak.
●Aspirin is not recommended for ASCVD prevention for adults with diabetes at low risk (10-year risk <5 percent), such as those with diabetes aged <50 years with no major additional risk factors. In this population, the potential adverse effects from bleeding likely offset the potential benefits.
●For adults <50 years with diabetes who have multiple other cardiovascular risk factors (10-year risk between 5 and 10 percent), clinical judgement and shared decision-making is required.
●Clopidogrel (75 mg/day) is recommended for patients with ASCVD and documented aspirin allergy. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Antiplatelet therapy'.)
●Dual antiplatelet therapy is reasonable for up to one year after an acute coronary syndrome.
Blood pressure control — Hypertension is a common problem in type 1 and especially in type 2 diabetes. Early and effective treatment of high blood pressure is important, both to prevent cardiovascular disease (CVD) and to minimize the rate of progression of diabetic nephropathy and retinopathy.
The ADA recommends measuring blood pressure at every routine diabetes visit, with individualization of treatment goals. For most patients with hypertension, the ADA recommends treating to systolic and diastolic blood pressures of <140 and <90 mmHg, respectively . Lower treatment targets, ie, 130/80 mmHg, may be appropriate for individuals at high risk of CVD, if they can be achieved without undue treatment burden.
The 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guidelines recommend a goal blood pressure in patients with diabetes mellitus of <130/80 mmHg [58,59]. The data supporting these goals and the choice of antihypertensive drugs are discussed in detail separately. (See "Goal blood pressure in adults with hypertension", section on 'Patients with diabetes mellitus' and "Treatment of hypertension in patients with diabetes mellitus", section on 'Choice of antihypertensive drug therapy' and "Treatment of diabetic kidney disease".)
Dyslipidemia — Lipid abnormalities are common in patients with diabetes mellitus and undoubtedly contribute to the increase in risk of ASCVD. The ADA recommends screening for lipid disorders at the time of diabetes diagnosis, at an initial medical evaluation, and every five years thereafter if under age 40 and more often if indicated, as is usually the case in patients age 40 and older .
We and others recommend lifestyle intervention (diet, weight loss, increased physical activity) to improve the lipid profile in all patients with diabetes [20,60]. The initiation of statins is based upon cardiovascular risk rather than an LDL cholesterol level. In patients with clinical ASCVD, statin therapy should be added to lifestyle intervention regardless of baseline lipid levels. For patients without clinical ASCVD, we use a risk estimator, such as the ACC/AHA risk estimator (calculator 3), to guide shared decision-making for statin use and dose (see "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach", section on 'Estimate ASCVD risk using a risk calculator'). We typically administer statins to patients over age 40 years. For patients under age 40 years, statin therapy can be considered in addition to lifestyle intervention in those with multiple ASCVD risk factors.
The intensity of statin therapy can be adjusted based upon ASCVD risk, side effects, tolerability, and LDL cholesterol levels. For patients with clinical ASCVD, high-intensity statin therapy is typically added to lifestyle therapy.
Therapy of dyslipidemia is discussed in detail separately. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Hypertriglyceridemia in adults: Management", section on 'Treatment goals' and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)
Diabetes medications — Metformin does not have adverse cardiovascular effects, and it appears to decrease cardiovascular events in certain populations. In trials primarily focusing on secondary prevention of CVD in patients with type 2 diabetes, there was a reduction in CVD outcomes with many sodium-glucose co-transporter 2 (SGLT2) inhibitors and many glucagon-like peptide 1 (GLP-1) receptor agonists. Cardiovascular effects of the diabetes medications are reviewed in detail separately. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
OTHER ASPECTS OF HEALTH MAINTENANCE
Routine health maintenance — The potential exists for the clinician to overlook health maintenance not specifically targeted at diabetes, given the intensity and complexity of care required for prevention and treatment of complications of diabetes itself . (See "Overview of preventive care in adults".)
Vaccination — Patients with diabetes mellitus should receive (table 1):
●Influenza vaccination yearly, with adults 65 years of age and older administered the high-dose vaccine. In observational studies, influenza vaccine has been shown to be similarly effective in adults <65 years of age with diabetes as in older patients with or without diabetes [62,63].
●Pneumococcal vaccination, per US Center for Disease Control and Prevention (CDC) protocol, with one pneumococcal conjugate vaccine (PCV13) in adults ≥65 years and pneumococcal polysaccharide vaccine (PPSV23) once before and once after age 65.
●Hepatitis B vaccination for unvaccinated adults younger than 60 years of age without evidence of prior infection. For older adult patients with diabetes, vaccination can be administered at the discretion of the treating clinician based upon the risk of acquiring hepatitis B virus, including the need for blood glucose monitoring, and the likelihood of an adequate immune response to vaccination. The effectiveness of the hepatitis B vaccine decreases with age . This recommendation is based on outbreaks of hepatitis B in patients who were undergoing blood glucose monitoring in nursing homes or assisted-living facilities, a subsequent analysis of the risk of acquiring hepatitis B virus among all patients with diabetes in the United States, and a cost-effectiveness analysis . (See "Hepatitis B virus immunization in adults", section on 'Indications'.)
●Tetanus and diphtheria vaccinations, updated as per CDC guidelines. (See "Tetanus-diphtheria toxoid vaccination in adults".)
●Herpes zoster, recombinant vaccine, based on CDC guidelines. (See "Vaccination for the prevention of shingles (herpes zoster)", section on 'Approach to vaccination'.)
●SARS-CoV-2 vaccination, with booster vaccination dependent on vaccination history, updated as per CDC guidelines. People with type 2 diabetes are at increased risk of complications and death from coronavirus 2019 (COVID-19), and vaccine hesitancy should be assessed and addressed through evidence-based approaches. (See "COVID-19: Issues related to diabetes mellitus in adults", section on 'Risk of severe COVID-19'.)
Women of childbearing age — Women in the reproductive years should receive counseling at regular intervals regarding contraception and pregnancy planning, including the need for tight glycemic control prior to pregnancy and the risk of pregnancy to the woman and fetus.
●For women with diabetes who are contemplating pregnancy, prepregnancy counseling is important. Healthy pregnancy requires virtually normal blood glucose levels. Prior to pregnancy, glycemic management should be optimized and both angiotensin-converting enzyme (ACE) inhibitor and statin medications should be discontinued. (See "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management", section on 'Glycemic control'.)
●For women who do not wish to become pregnant, the most reliable method of contraception should be used, when not contraindicated by other health concerns, because of the risk of hyperglycemia to the developing fetus. American Diabetes Association (ADA) guidelines state that the selection of a contraceptive method for an individual patient should use the same guidelines that apply to women without diabetes . Types of hormonal and nonhormonal contraception and important factors in choosing a contraceptive method are reviewed separately. (See "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management", section on 'Contraception and timing of pregnancy' and "Contraception: Counseling and selection" and "Combined estrogen-progestin contraception: Side effects and health concerns".)
ADEQUACY OF CARE — Despite extensive data suggesting large benefits with preventive and treatment strategies and despite increasing media attention, many patients with diabetes are not receiving recommended levels of health care, including older patients [67-69]; patients with limited proficiency in English, financial hardships, or complex comorbidities; and those from countries with fewer resources to manage diabetes [70-72]. Even when recommended clinical data are obtained, rates of medication adjustment to address abnormal results are low [73-75].
There are several reasons for the large discrepancy between what should be done and what is being done, including clinical inertia and lack of an organized system for care [76-79]. Several approaches have been tried in order to improve the care of patients with diabetes. These include the following:
●"Diabetes mini-clinics" [80,81]
●Better organization and delivery of patient education [82,83]
●Structured behavioral intervention [84,85]
●Management by nurse specialists under the supervision of a diabetologist [86-88]
●Multidisciplinary disease management programs [89-91]
●Group medical visits [92,93]
●Telecare intervention via web-based systems or mobile devices [94-96]
The growing use of electronic health records with embedded guidelines and reminders at the point of care about appropriate interventions may make it easier to deliver more appropriate diabetes care in a number of settings. Processes of care (performance of retinal examination, foot examination, A1C measurements, lipid testing, nephropathy screening, flu vaccination, aspirin therapy) may be more readily improved by disease management interventions than intermediate outcomes (blood pressure control, lipid control, or A1C level) .
INDICATIONS FOR REFERRAL — Intensive insulin therapy is recommended for the majority of patients with type 1 diabetes, and therefore, patients with type 1 diabetes should be referred to an endocrinologist for management of diabetes .
The majority of patients with type 2 diabetes (greater than 90 percent) receive their routine care from primary care providers. A major unresolved controversy is the place of the generalist and the specialist in the treatment of patients with type 2 diabetes. Studies comparing care by specialists and generalists have generated conflicting findings [98-102]. For most patients with type 2 diabetes, care can be delivered by primary care providers and their health care teams in coordination with other specialists where appropriate. Patients in need of insulin therapy should be managed by or in consultation with an endocrinologist, if at all possible.
The decision to refer to an endocrinologist with expertise in diabetes management usually hinges on the complexity of the patient, the ability of the primary care team to achieve established goals of care in an individual, the need to manage complications, and other factors such as the capacity of the primary care practitioner to teach self-management skills such as monitoring and insulin injections. The ideal balance between primary and subspecialty care for the ever-increasing population of patients with type 2 diabetes will vary based on the resources and expertise available in different communities.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults" and "Society guideline links: Assessment of cardiovascular risk".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: The ABCs of diabetes (The Basics)" and "Patient education: Type 1 diabetes (The Basics)" and "Patient education: Type 2 diabetes (The Basics)" and "Patient education: Treatment for type 2 diabetes (The Basics)" and "Patient education: Diabetic retinopathy (The Basics)" and "Patient education: Coping with high drug prices (The Basics)")
●Beyond the Basics topics (see "Patient education: Type 1 diabetes: Overview (Beyond the Basics)" and "Patient education: Type 2 diabetes: Overview (Beyond the Basics)" and "Patient education: Type 2 diabetes: Treatment (Beyond the Basics)" and "Patient education: Coping with high prescription drug prices in the United States (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Initial and ongoing evaluation – Morbidity from diabetes involves both macrovascular (atherosclerosis) and microvascular (retinopathy, nephropathy, and neuropathy) disease. Interventions can limit end-organ damage, and therefore, patients with diabetes require initial and ongoing evaluation for diabetes-related complications.
We perform a history and physical examination two to four times yearly to address current glycemic management as well as management of nutrition, physical activity, cardiovascular risk factors, and diabetes-related complications and comorbidities (table 1). (See 'Diabetes-related complications' above and 'Comorbid conditions' above.)
●Glycemic management and prevention of micro- and macrovascular complications – Achieving glycemic goals can minimize risks for retinopathy, nephropathy, and neuropathy in both type 1 and type 2 diabetes and has been shown to decrease the risk for cardiovascular disease (CVD) for type 1 diabetes. (See 'Glycemic management' above and "Glycemic control and vascular complications in type 2 diabetes mellitus" and "Glycemic control and vascular complications in type 1 diabetes mellitus".)
●A1C goals – Glycated hemoglobin (A1C) goals in patients with diabetes should be tailored to the individual, balancing the improvement in microvascular complications with the risk of hypoglycemia. A reasonable goal of therapy is an A1C value of ≤7.0 percent for most patients (using an assay in which the upper limit of normal is 6.0 percent). Glycemic targets are generally set somewhat higher (eg, <8 percent) for older adult patients and those with comorbidities or a limited life expectancy and little likelihood of benefit from intensive therapy. More stringent management (A1C <6 percent) may be indicated during pregnancy. (See 'Blood glucose monitoring and target A1C' above and "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target' and "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control", section on 'Target blood glucose values' and "Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Glycemic targets'.)
●Prevention of cardiovascular morbidity – Prevention of cardiovascular morbidity is a major priority for patients with diabetes, especially type 2. Smoking cessation is essential for patients who smoke. Cardiovascular morbidity can also be significantly reduced with aggressive management of hypertension, cholesterol, use of aspirin (75 to 162 mg/day), and use of certain glucose-lowering medications in patients with or at high risk for cardiovascular disease (CVD). (See 'Reducing the risk of macrovascular disease' above and "Treatment of hypertension in patients with diabetes mellitus", section on 'Approach to lowering blood pressure' and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Monotherapy failure'.)
●Delivery of care
•Many patients with diabetes are not receiving recommended levels of health care, and development of systems of care involving disease management principles may be important in delivering improved care. (See 'Adequacy of care' above.)
•Intensive insulin therapy targeting physiologic insulin replacement is recommended for the majority of patients with type 1 diabetes, and therefore, patients with type 1 diabetes should be referred to an endocrinologist for management of diabetes.
For most patients with type 2 diabetes, care can be delivered by primary care providers and their health care teams in coordination with other specialists where appropriate. Patients in need of multiple daily injections of insulin therapy should be managed by or in consultation with an endocrinologist, if at all possible. The decision to refer to an endocrinologist with expertise in diabetes management usually hinges on the complexity of the patient, the ability of the primary care team to achieve established goals of care in an individual, the need to manage complications, and other factors such as the capacity of the primary care practitioner to teach self-management skills such as monitoring and insulin injections. (See 'Indications for referral' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to earlier versions of this topic review.
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63 : Clinical effectiveness of first and repeat influenza vaccination in adult and elderly diabetic patients.
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