Diabetes Mellitus

Chapter: Diabetes Mellitus
McMaster Section Editor(s): Victor M. Montori, Juan P. Brito
Section Editor(s) in Interna Szczeklika: Barbara Jarząb, Ewa Płaczkiewicz-Jankowska
McMaster Author(s): René Rodríguez-Gutiérrez, Dania L. Quintanilla-Flores, Paola Portillo-Sanchez, José Miguel Hinojosa-Amaya, Oscar L. Morey-Vargas, Victor M. Montori
Author(s) in Interna Szczeklika: Jacek Sieradzki, Ewa Płaczkiewicz-Jankowska
Additional Information

Definition, Etiology, PathogenesisTop

Diabetes mellitus (DM) is a group of metabolic disorders where various genetic and environmental factors result in the progressive loss of beta-cell mass or function (or both) that manifests clinically as hyperglycemia. Chronic hyperglycemia in the course of DM is associated with damage, dysfunction, and failure of multiple organs, particularly the eyes, kidneys, peripheral nerves, heart, and blood vessels.

1. Type DM is caused by the destruction of pancreatic beta cells due to an autoimmune process (type 1A, associated with beta-cell autoantibodies) or due to unknown mechanisms (idiopathic or type 1B) that typically results in absolute insulin deficiency. Type 1A DM (5%-10% of all patients with diabetes) develops more frequently in children, adolescents, and younger adults, but it can occur at any age. The disease occurs in genetically susceptible individuals with particular gene polymorphisms (human leukocyte antigen [HLA] associations, with linkage to DQA and DQB genes) and in many cases appears to be triggered by environmental factors (eg, perinatal events, viral infections, ingestion of cow’s milk). The autoantibodies (islet cell autoantibodies and autoantibodies to GAD65, insulin, tyrosine phosphatases IA-2 and IA-2beta, and ZnT8) may appear several years before symptoms of DM are observed. Their persistence is almost a certain predictor of clinical hyperglycemia and DM. Age at the first detection of an antibody, number of antibodies, antibody specificity, and antibody titers are the main factors that predict the rate of progression to DM. After disease onset, the process of destruction of beta cells continues for some time until their total destruction.

There are 3 staging phases of type DM that have been described:

1) Stage 1 is characterized by the presence of autoimmunity but with normal glucose levels and absence of symptoms.

2) Stage 2 is associated with glucose levels in the range of impaired fasting glucose (5.6-6.9 mmol/L [100-125 mg/dL]) and/or impaired glucose tolerance (2-hour plasma glucose of 7.8-11 mmol/L [140-199 mg/dL]) with glycated hemoglobin (HbA1c) between 5.7% and 6.4% (or an increase ≥10% in HbA1c).

3) Stage 3 is characterized by the onset of symptoms with glucose levels that meet the criteria for the diagnosis of DM.

In some cases autoimmune destruction of beta cells leads to the onset of DM in older adults (latent autoimmune diabetes in adults [LADA]; Table 5.2-1). These patients initially appear to have type 2 DM but have positive circulating beta-cell autoantibodies and progress to insulin dependence after a few months or years. LADA includes a heterogeneous group of patients, with some having high titers of beta-cell autoantibodies and progressing to insulin dependence faster. The disappearance of serum C-peptide (see Diagnostic Tests, below) indicates a total destruction of beta cells.

2. Type DM is the most common form of DM (~90% of patients). It is characterized by varying degrees of insulin resistance coexisting with progressive impairment of insulin secretion in the absence of autoimmune destruction of beta cells. Hyperglycemia occurs when insulin secretory capacity is inadequate to overcome peripheral insulin resistance. Both genetic (polygenic inheritance) and environmental factors (obesity, particularly abdominal, and low physical activity) play a strong role in the occurrence of insulin resistance. The hereditary component results in significant differences in the prevalence of type 2 DM among ethnic groups (eg, type 2 DM is common in Pima Indians and North American Indians). The pathophysiologic pathways leading to insulin resistance and deficient insulin secretion are not completely understood, but it appears that an excessive release of free fatty acids by visceral adipose tissue, lipotoxicity caused by these free fatty acids, effects of several adipokines, metabolic stress, and chronic inflammation associated with obesity all play a role in the development of DM and also contribute to the cardiovascular complications of this disease. The risk of developing DM is increased with advancing age, obesity, and lack of physical activity, as well as in patients with hypertension, dyslipidemia, women with prior gestational DM (GDM), and in certain ethnic groups.

Prediabetes is diagnosed when glucose levels and/or HbA1c does not meet the criteria for DM but is higher than what is considered normal. Its presence is associated with an increased risk of overt DM: the 5-year incidence is from 9% to 25% for HbA1c in the range of 5.5% to 6%; the incidence rises to 25% to 50% with HbA1c in the range of 6% to 6.5%. Of note, the threshold at which experts suggest diagnoses of prediabetes and DM change with time and geography (similarly to lipid levels or blood pressure thresholds).

3. Other specific types of DM may be caused by genetic defects of pancreatic beta-cell function (eg, maturity-onset diabetes of the youth [MODY]: a group of autosomal dominant monogenic defects of insulin secretion that lead to DM diagnosed at a young age and with negative beta-cell autoantibodies [Table 5.2-2]), genetic defects of insulin action, pancreatic exocrine disorders and cystic fibrosis–related diabetes, endocrinopathies (eg, Cushing syndrome; acromegaly; catecholamine-producing tumors, including pheochromocytomas, glucagonomas, somatostatinomas), drug-induced DM (eg, glucocorticoids and posttransplantation DM), viral infections (eg, congenital rubella), rare immune-mediated DM (eg, stiff man syndrome), and other genetic syndromes associated with DM (eg, Down syndrome, Klinefelter syndrome, Turner syndrome, Wolfram syndrome, and maternally inherited DM and deafness).

4. GDM (see Gestational Diabetes Mellitus) is defined by the presence of DM that is first diagnosed in the second or third trimester of pregnancy in women without preexisting DM. Women diagnosed with DM (standard diagnostic criteria) during the first trimester should be classified as having preexisting pregestational diabetes. GDM develops due to pregnancy-related elevation of hormones antagonistic to insulin, leading to insulin resistance, increased insulin requirements, and increased glucose availability for the developing fetus. These mechanisms result in increased risk of abnormal glucose metabolism in otherwise healthy women.

Clinical Features and Natural HistoryTop

1. The natural history of DM depends on the rate and extent of beta-cell dysfunction and destruction caused by the combination of genetic and environmental factors. In type 1 DM the progression seems to depend on expression of antibodies (age of detection, their number and levels). The mechanism of type 2 DM is through a state of insulin resistance and beta-cell dysfunction. Initially type 2 DM can be underdiagnosed because of the lack of typical clinical symptoms. As the disease progresses, patients typically go from a stage of mild hyperglycemia (eg, prediabetes) to overt type 2 DM. Signs and symptoms are nonspecific and variable; they are associated with the type of DM and dynamics of disease progression, which tend to be much more abrupt in type 1 than in type 2. This may result in hyperglycemic crisis such as ketoacidosis or coma. Because of difficulties in achieving complete DM control, the development of chronic complications cannot be fully prevented (see Chronic Complications of Diabetes).

2. Signs and symptoms of DM: Nonspecific and variable, including polyuria (osmotic diuresis caused by glucosuria when serum glucose rises >10 mmol/L [180 mg/dL]), nocturia (urinating during the night), polydipsia (increased thirst), polyphagia (increased hunger), blurred vision, weight loss, weakness, and signs of hypovolemia (eg, decreased skin turgor, dry skin and mucous membranes, hypotension). Hyperglycemia may become particularly evident during a concurrent illness (eg, infection, myocardial infarction).

1) Type 1 DM: The sudden loss of beta-cell reserve leads to an acute onset of the disease with marked insulinopenia and hyperglycemia; in fact, in many patients with type 1 DM the degree of insulinopenia is significant enough to cause ketoacidosis at presentation.

2) Type 2 DM: In contrast, >50% of patients with type 2 DM are asymptomatic when the diagnosis is made (disease is frequently detected incidentally or on screening glucose measurements). The majority of patients with type 2 DM are obese, most commonly showing abdominal-type obesity, and frequently have a cluster of comorbidities that includes hypertension, nonalcoholic fatty liver disease, and dyslipidemia (with low serum high-density lipoprotein cholesterol [HDL-C] and high triglyceride concentrations). Insulin resistance is a key feature in type 2 DM, although it is not a pathognomonic finding of this type of DM (eg, obese patients with type 1 DM may have varying degrees of insulin resistance).

DiagnosisTop

Diagnostic Tests

Laboratory tests:

1) Blood glucose: Fasting plasma glucose (FPG) in venous blood (reference range, 3.9-5.5 mmol/L [70-99 mg/dL]) is used as a diagnostic test for DM and for monitoring glycemic control, whereas glucose levels in capillary full blood (measured using a glucometer) are used only for monitoring DM treatment.

2) HbA1c reflects mean glycemia over the 3 months preceding the test. It is used both for the diagnosis of DM and for evaluation of metabolic control of the disease. The advantage of this test is that it can be measured at any time during the day and it is not affected by acute blood glucose level changes. When interpreting the results, consider other conditions that may affect its accuracy; if a condition results in a shorter life-span and greater proportion of younger erythrocytes (eg, hemolytic anemias), falsely low HbA1c values are likely. Red blood cell transfusion can also decrease HbA1c levels in patients with DM. In contrast, a longer erythrocyte life-span is associated with longer exposure to elevated blood glucose, hence falsely increasing HbA1c levels (eg, iron or vitamin B12 deficiency anemias). To avoid misdiagnosis of DM, HbA1c should be measured using a method certified by the NGSP and standardized to the Diabetes Control and Complications Trial (DCCT) assay.

3) A 75-g oral glucose tolerance test (OGTT) can be used for the screening or diagnosis of DM. In this test a patient without acute illness is instructed to eat a diet with normal carbohydrate content in the days before the test. The OGTT is performed in the morning after 8 to 12 hours of fasting and includes measurement of FPG. Plasma glucose measurement is obtained 2 hours after the ingestion of 75 g of glucose in the form of a solution. Normal plasma glucose levels at 2 hours are <7.8 mmol/L (140 mg/dL). A modified version of this test is used to diagnose GDM.

4) Urine glucose: Glucosuria is typically seen in patients with DM when the blood glucose level rises >10 mmol/L (180 mg/dL). In patients without DM, this can result from defects in renal tubular function (eg, proximal renal tubular acidosis). Measurement of urine glucose is not useful for the screening, diagnosis, or treatment monitoring of DM. However, finding glucosuria is an indication for blood glucose tests.

5) Fructosamine: This rarely used test demonstrates mean glycemia over the preceding 2 weeks (the half-life of albumin). Fructosamine levels are mainly measured in patients in whom HbA1c is unreliable or in whom it is necessary to evaluate short-term blood glucose control (eg, pregnant women).

6) Islet cell antibodies can be used to confirm the autoimmune etiology of DM. At least 1 antibody is present in >90% of patients with type 1 DM, and the presence of antibodies defines patients with LADA. These antibodies may be detectable before the clinical onset of DM:

a) Antibodies to glutamate decarboxylase 65 (anti-GAD65).

b) Antibodies against tyrosine phosphatase–related proteins (IA-2, IA-2 beta).

c) Insulin autoantibodies (IAAs).

d) Beta-cell-specific zinc transporter antibody (ZnT-8).

7) Serum C-peptide level reflects endogenous insulin levels. It is decreased or undetectable in type 1 DM, elevated in early type 2 DM (when insulin resistance is a dominant mechanism and insulin secretion increases), and decreased in type 2 DM after the deterioration of beta-cell secretory capacity. Measurements of C-peptide levels are not required in most cases of DM.

Screening

Screening for type DM is not recommended, because this condition is rare and there are no interventions to prevent the progression of subclinical disease. In contrast, type 2 DM is common, develops slowly, can be asymptomatic for a relatively long time, and can be treated at an early stage to prevent or delay its complications.

As an example, in the case of asymptomatic individuals the American Diabetes Association (ADA) recommends to screen for type DM in adults of any age who have a body mass index (BMI) ≥25 kg/m2 (or Asian Americans with a BMI ≥23 kg/m2) and have ≥1 additional risk factors for DM:

1) Physical inactivity.

2) A first-degree relative with DM.

3) A high-risk race/ethnicity (eg, African American, Latino, Native American, Asian American, Pacific Islander).

4) Delivery of a baby weighing >4.08 kg or confirmed diagnosis of GDM.

5) Hypertension (≥140/90 mm Hg or being treated for hypertension).

6) An HDL-C level <0.90 mmol/L (35 mg/dL) and/or triglyceride level >2.82 mmol/L (250 mg/dL).

7) Polycystic ovary syndrome (PCOS).

8) HbA1c ≥5.7% (39 mmol/mol), impaired glucose tolerance (IGT), or impaired fasting glucose (IFG) on previous testing.

9) Other clinical conditions associated with insulin resistance (eg, severe obesity, acanthosis nigricans).

10) A history of cardiovascular disease (CVD).

In the absence of the above criteria, testing for DM should begin at the age of 45 years. FPG, HbA1c, and a 75-g OGTT are appropriate tests for screening. If results are negative, the ADA recommends repeating testing at least at 3-year intervals, with consideration of more frequent testing depending on the initial results and presence of risk factors. Other organizations issued similar suggestions, noting that the quality of evidence supporting the type of screening and its overall benefit is at most moderate.

DM screening tests in pregnant women: see Gestational Diabetes Mellitus.

Diagnostic Criteria

Diagnostic workup in patients with hyperglycemia should not be performed during acute phases of other diseases (eg, infection or acute coronary syndrome), immediately following trauma or surgery, or during treatment with drugs that may cause elevated blood glucose levels (eg, glucocorticoids, thiazide diuretics, certain beta-blockers).

According to the ADA, the diagnosis of DM is established when either of these criteria is met:

1) There are typical signs and symptoms of hyperglycemia (eg, increased thirst, polyuria, weight loss, blurry vision, weakness) or hyperglycemic crisis and a random plasma glucose level ≥11.1 mmol/L (200 mg/dL).

2) HbA1c ≥6.5% (48 mmol/mol) (using a certified method), FPG ≥7.0 mmol/L (126 mg/dL) (fasting is defined as no caloric intake for ≥8 hours), or 2-hour plasma glucose ≥11.1 mmol/L (200 mg/dL) during a 75-g OGTT. In the absence of unequivocal signs and symptoms of hyperglycemia, one abnormal test result should be confirmed by repeating the same test on a subsequent day. If 2 different tests are available (eg, FPG and HbA1c) and both are consistent with DM, additional testing is not needed. If results of different tests are discordant, the test that is diagnostic for DM should be repeated.

According to the ADA, the category of increased risk for DM (prediabetes) is defined by the presence of any of the following:

1) HbA1c between 5.7% and 6.4% (39-46 mmol/mol).

2) IFG (FPG between 5.6-6.9 mmol/L [100-125 mg/dL]).

3) IGT (2-hour plasma glucose after a 75-g OGTT between 7.8-11.0 mmol/L [140-199 mg/dL]).

Differential Diagnosis

1. Other causes of clinical signs and symptoms, such as polyuria (diabetes insipidus).

2. Other causes of hyperglycemia: Stress-induced hyperglycemia, which refers to transient hyperglycemia and may occur during acute illness or significant stress in patients without DM (eg, sepsis, acute coronary syndrome, immediately following trauma or major surgery).

TreatmentTop

General Considerations

The management of DM includes:

1) Patient education, which is indispensable for treatment success.

2) Nonpharmacologic management: Nutrition, weight loss, and exercise.

3) Glucose-lowering treatment: Oral and injectable antidiabetic agents, insulin.

4) Management of other cardiovascular risk factors, particularly hypertension (see Essential Hypertension) and dyslipidemia (see Hypercholesterolemia).

5) Prevention and management of chronic diabetic complications.

1. In type DM lifestyle modification and weight loss are the fundamental aspects of care. An intensive behavioral lifestyle intervention program should be suggested to all patients with type 2 DM, including those with prediabetes, in order to induce and maintain a loss of ~7% of initial body weight and to increase moderate-intensity physical activity to at least 150 min/wk. In patients with prediabetes this program has been shown to reduce the incidence of type 2 DM by 58% over 3 years. Of note, patients’ willingness and ability to conform to recommendations concerning lifestyle modifications vary widely and cannot be assumed or even expected.

2. Insulin therapy:

1) In type 1 DM insulin therapy is mandatory once the diagnosis of DM is established.

2) In type 2 DM insulin therapy is indicated in patients not achieving appropriate glycemic control with other medications. Insulin should also be started in patients with type 2 DM and marked hyperglycemia at the time of diagnosis (eg, HbA1c >11% [97 mmol/mol]) and in patients with hyperglycemic crisis (ie, diabetic ketoacidosis [DKA], hyperosmolar hyperglycemic state [HHS]). If insulin treatment is used early in the course of DM because of beta-cell glucotoxicity, recovery of beta-cell function after achieving adequate control of hyperglycemia may allow for de-escalation of insulin therapy and often switching to oral antidiabetic medications. As type 2 DM is a progressive disease with gradual deterioration of the secretory capacity of pancreatic beta cells, many patients with type 2 DM eventually need insulin therapy.

3. In type DM metformin is typically the first medication used. Because type 2 DM is a progressive disease, second-line and third-line agents are frequently required for appropriate glycemic control. Different glucose-lowering medications are currently available, including insulin secretagogues (eg, sulfonylureas, meglitinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, glucagon-like peptide-1 [GLP-1] receptor agonists), insulin sensitizers (eg, metformin, thiazolidinediones [TZDs]), alpha-glucosidase inhibitors (eg, acarbose), and sodium-glucose cotransporter 2 (SGLT-2) inhibitors (eg, canagliflozin or empagliflozin).

4. If the type of DM is unclear (ie, type 1 versus type 2) in a patient presenting with hyperglycemic crisis, the final diagnosis and appropriate long-term treatment can be established after control of metabolic abnormalities is achieved with insulin therapy. If autoimmune etiology of DM is excluded, patients can be sometimes successfully switched to oral glucose-lowering medications.

5. Target HbA1c levels should be achieved gradually (ie, over several months) because a rapid reduction of plasma glucose levels carries a risk of hypoglycemia (particularly in type 1 DM), and in patients with advanced microangiopathy (primarily retinopathy) it may accelerate progression of this complication; in type 2 DM it may additionally increase the cardiovascular risk. In patients who do not achieve target HbA1c levels despite maintaining target FPG, make attempts to reduce postprandial glucose levels.

6. Criteria of DM control: Glycemic goal: The intensity of glucose-lowering treatment, determined by target blood glucose and HbA1c values, should be individualized based on the patient’s cooperation and motivation, risk of hypoglycemia, disease duration, life expectancy, comorbidities, cardiovascular complications, as well as financial resources and support available. Higher glucose levels may be acceptable in patients achieving target HbA1c levels. The criteria of DM control may be less stringent in the elderly, in patients with comorbidities, and in those with frequent episodes of hypoglycemia. If target values cannot be achieved, attempts should be made to achieve results as close as practically possible. Of note, different professional societies recommend different targets, from 6.5% (American Association of Clinical Endocrinologists) through 7% (ADA) to between 7% and 8% (American College of Physicians). This may make clinicians less anxious about rigid adherence to specific values.Evidence 1High Quality of Evidence (high confidence that we know true effects of the intervention).  Abbasi J. For Patients With Type 2 Diabetes, What's the Best Target Hemoglobin A1C? JAMA. 2018 Jun 19;319(23):2367-2369. doi: 10.1001/jama.2018.5420. PubMed PMID: 29847622. The ADA suggests:

1) Target HbA1c levels <7.0% (53 mmol/mol) and preprandial capillary blood glucose levels between 3.9 and 7.2 mmol/L (70-130 mg/dL) in most nonpregnant adults with DM. To achieve this in young patients with type 1 DM, a multiple daily injection insulin therapy is usually required. ADA experts acknowledge that individual patients’ goals may be slightly lower or slightly higher. We consider the recommendation to achieve this target as strong in type 1 DMEvidence 2 Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to heterogeneity of effects in individual patients. For discussion and references, see Appendix 1 at the end of the chapter. and weak in type 2 DM.Evidence 3 Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to heterogeneity of effects in individual patients. For discussion and references, see Appendix 1 at the end of the chapter.

2) HbA1c levels <6.5% (48 mmol/mol) are suggested for selected patients with a short duration of DM, long life expectancy, and no significant CVD, as long as treatment does not induce significant hypoglycemia.

3) In contrast, the criteria of DM control may be less stringent (HbA1c <8.0% [64 mmol/mol]) in the elderly, in patients with significant comorbidities, advanced microvascular or macrovascular complications, limited life expectancy, and in patients who developed hypoglycemia unawareness or those with severe or frequent episodes of hypoglycemia.

4) Considering the lack of clear benefits on the major outcomes, risk of hypoglycemia, and potential burden and higher costs of more intensive treatment, a strong recommendation against intensive glycemic control (eg, HbA1c ≤6.5% [48 mmol/mol]) can be made for older patients with long-standing type DM and risk for CVD.Evidence 4 Strong recommendation (downsides clearly outweigh benefits; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to indirectness of evidence to that particular population. For discussion and references, see Appendix 1 at the end of the chapter.

5) The role of postprandial blood glucose targets is unclear because outcome studies relied mostly on HbA1c and preprandial glucose levels for assessing the glycemic effect of evaluated interventions. According to the ADA, postprandial testing aiming for blood glucose values <10 mmol/L (180 mg/dL) 1 to 2 hours after the beginning of a meal is a reasonable strategy in patients with high HbA1c and preprandial glucose levels within target values.

6) According to the Fifth International Workshop-Conference on Gestational Diabetes Mellitus, the following target values should be used for capillary glucose concentrations in pregnant patients: preprandial, ≤5.3 mmol/L (95 mg/dL); and 1-hour postprandial level ≤7.8 mmol/L (140 mg/dL) and/or 2-hour postprandial level ≤6.7 mmol/L (120 mg/dL). For patients with preexisting type 1 or type DM who become pregnant, the optimal recommended glycemic goals are as follows, provided they can be achieved without excessive hypoglycemia: (a) preprandial, bedtime, and overnight glucose: 3.3 to 5.4 mmol/L (60-99 mg/dL); (b) peak postprandial glucose: 5.4 to 7.1 mmol/L (100-129 mg/dL); (c) HbA1c: <6.0% (42 mmol/mol).

7. Principles of lipid control:

1) The ADA recommends to intensify lifestyle therapy and optimize glycemic control for patients with triglyceride levels ≥1.7 mmol/L (150 mg/dL) and/or HDL-C levels <1.0 mmol/L (40 mg/dL) for men or <1.3 mmol/L (50 mg/dL) for women.

2) For patients with triglyceride levels ≥5.7 mmol/L (500 mg/dL), medical therapy (eg, fibrates) should be considered to reduce the risk of pancreatitis.

3) For patients with DM of all ages and overt CVD, high-intensity statin therapy should be added to lifestyle therapy.

4) For patients aged 40 to 75 years with additional cardiovascular risk factors, consider using high-intensity statin therapy added to lifestyle therapy.

5) For patients aged <40 years or >75 years with additional cardiovascular risk factors, consider using moderate or high-intensity statin therapy added to lifestyle therapy.

6) For patients aged >40 years without additional cardiovascular risk factors, consider using moderate-intensity statin therapy added to lifestyle therapy.

8. Principles and criteria of blood pressure control:

1) General criteria: <140/90 mm Hg.

2) Less than 130/80 mm Hg (but not <120/70 mm Hg) in patients with diabetic nephropathy and in patients with recently diagnosed hypertension and no target organ damage if these targets can be achieved without undue treatment burden.

3) Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) are suggested as first-line antihypertensive agents, particularly among patients with evidence of diabetic nephropathy.Evidence 5 Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to heterogeneity of risks, benefits, and adverse effects in individual patients. For discussion and references, see Appendix 2 at the end of the chapter.

Education

1. Patient education is an important component of DM management, together with nutrition therapy, exercise, and pharmacotherapy, and it should be offered to all patients.Evidence 6 Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to uncertainty of the effects of individual components. For discussion and references, see Appendix 3 at the end of the chapter.

2. Patient education aims to improve knowledge, skills, and confidence in DM management and to promote the patient’s cooperation with a multidisciplinary therapeutic team. The reinforcement for diabetes self-management education must be addressed at diagnosis, annually, in case of appearance of new complicating factors, and when transitions in care occur.

3. Education programs typically cover aspects of the pathophysiology of DM, lifestyle modification, glucose self-monitoring, insulin dose-adjustment, management of hypoglycemia, prevention and detection of acute and chronic DM complications, and foot care. Additionally, health status and quality of life evaluation is also included.

4. Educational sessions should be patient-centered and repeated and their effects should be evaluated, including not only the patients’ knowledge but also their capability of coping with the disease and empowerment to make informed self-management decisions. The inclusion of patient-centered care must be respectful of and responsive to individual patient preferences, needs, and values. Structured education programs that promote intensive basal-bolus insulin therapy and teach the principles of dose-adjustment have been associated with improvements in glycemic control and quality of life in patients with type 1 DM. In patients with type 2 DM education should include teaching about the likely progressive nature of the disease and the necessary gradual modifications of treatment.

5. Patient education can be optimally conducted both in individual and group settings.

Self-Monitoring of Blood Glucose

All patients with DM who use insulin or take other glucose-lowering medications that can cause hypoglycemia (eg, sulfonylureas) should learn how to check their finger-stick capillary blood glucose with a glucose meter. The recommended frequency of self-monitoring of blood glucose (SMBG) depends on the type of antidiabetic therapy and long-term stability of clinical status. SMBG is a fundamental aspect of management in type 1 DM and is also important in patients with type 2 DM treated with complex insulin regimens. The ADA suggests that patients treated with multiple-dose insulin or insulin pump therapy should consider SMBG prior to meals and snacks, occasionally postprandially, at bedtime, prior to exercise, when hypoglycemia is suspected, after treating hypoglycemia, and prior to critical tasks such as driving. For some patients it may mean 6 or more measurements per day. Patients with type 2 DM treated with oral agents that can cause hypoglycemia also likely benefit from SMBG, particularly during uptitration of these medications (eg, testing once to twice per day before breakfast and before the evening meal).

In contrast, the benefit of SMBG in patients with type DM only on diet or who are treated with medications not associated with hypoglycemia is controversial. The ADA suggests that SMBG results may be helpful to guide treatment decisions in patients treated with noninsulin therapies. In this context a reasonable frequency of measurements will depend on the patient’s preference. Motivated patients with type 2 DM could take action to modify diet or exercise patterns based on SMBG readings and therefore improve their HbA1c values.

Medical Nutrition Therapy: General Considerations

The ADA recommends nutrition therapy for all patients with type 1 and type 2 DM. Nutrition therapy consists of the development of eating patterns designed to achieve and maintain an ideal body weight, improve glycemic control, lower blood pressure, improve lipid profile, reduce cardiovascular risk, and reduce the overall risk for both acute and long-term complications of DM while preserving the pleasure of eating. Nutrition therapy should aim for a beneficial effect in the overall health of patients while taking into consideration their personal and cultural preferences as well as their individual nutritional needs and their ability to sustain recommendations in the plan.

1) Adequate caloric intake should ensure maintaining an ideal body weight or gradual reduction of body weight in obese or overweight patients. A weight loss of ≥5% in patients with type DM is needed in order to produce beneficial outcomes in glycemic control, lipids, and blood pressure.

2) An optimal body weight is usually a BMI between 18.5 and 24.9 kg/m2. Healthy weight-loss diets typically aim to achieve an energy deficit of 500 to 750 kcal/d or reduce daily energy intake to 1200 to 1500 kcal in women and 1500 to 1800 kcal in men, depending on the initial weight (eg, in women >135 kg start with 1600 kcal/d, in men >135 kg start with 1800 kcal/d). Diets <1200 kcal/d for women or <1500 kcal/d in men are not generally recommended because they may be deficient in nutrients. Furthermore, very low-calorie diets have not been found to produce greater long-term weight losses than conventional low-calorie diets. The Mediterranean diet, structured low-calorie meal plan, low-fat eating plan, plant-based diet, or Dietary Approaches to Stop Hypertension (DASH) meal plan are the ones most suggested for patients with prediabetes and DM. Low-carbohydrate diets have been shown to improve hyperglycemia, reduce HbA1c, and reduce the need for antihyperglycemic medications in some patients with type 2 DM. Overall, lifestyle modifications, which include dietary changes, are strongly recommended.Evidence 7 Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to some heterogeneity among patient-important outcomes. For discussion and references, see Appendix 4 at the end of the chapter.

3) The optimal distribution of calories from carbohydrates, protein, and fat to facilitate weight loss is unknown and likely not absolute. Macronutrient distribution should be based on an individual assessment of current eating patterns, preferences, and metabolic goals.

4) Carbohydrate intake is the most important determinant of postprandial glucose levels in patients with DM. The ADA suggests choosing nutrient-dense carbohydrates containing vitamins, minerals, and fiber (eg, vegetables, whole grains, legumes, or fruit) over processed carbohydrates high in calories, sugar, sodium, and fat. Avoiding sugar-sweetened beverages and processed “low-fat” or “nonfat” food products with high amounts of refined grains and added sugars is also recommended. In patients with type 2 DM taking insulin secretagogues (eg, sulfonylureas) or insulin, meals should include carbohydrates to reduce the risk of hypoglycemia.

5) Protein intake recommendations are the same as for the general population (1-1.5 g/kg of body weight per day or 15%-20% of total calories). It can be increased to 20% to 30% of total calories to increase satiety in some patients, based on an individual approach. A reduction to 0.8 g/kg of body weight per day should be achieved in patients with diabetic kidney disease.

6) Fat quality is more important than quantity for reducing the risk for CVD. An acceptable macronutrient distribution for total fat is generally 20% to 35% of total calorie intake. The ADA suggests limiting the intake of saturated fat to 10% of calories, limiting the intake of cholesterol to <300 mg/d, and avoiding trans-fat as much as possible. These recommendations apply to the general population. It is also suggested to limit sodium intake to <2300 mg/d.

7) In patients treated with metformin, periodic testing of vitamin B12 levels should be recommended, especially in those with anemia and peripheral neuropathy. There is lack of evidence with regards to efficacy of routine supplementation with antioxidants (vitamins E and C, carotene), herbals, and micronutrients (cinnamon, curcumin, vitamin D, chromium). Therefore, their use should not be recommended, except for special populations (pregnant or lactating women, older adults, vegetarians, and people with very low-calorie or low-carbohydrate diets).

Dietary Considerations in Patients on Insulin Therapy

1. For patients with type DM (or type 1 DM) treated with fixed doses of short-acting and intermediate-acting insulin (frequently premixed), day-to-day consistency in the time of insulin administration, mealtimes, and amount of carbohydrate intake is an important consideration in order to avoid variable and unpredictable blood glucose levels and hypoglycemia. These patients should not skip meals.

2. For patients with type DM (or type 2 DM) following a multiple daily injection program treated with a long-acting insulin and fixed doses of a rapid-acting prandial insulin, it is important to eat similar amounts of carbohydrates during each meal to match the prandial insulin doses. This program gives more flexibility regarding the time when meals can be consumed. Different meal planning strategies can be used to quantify carbohydrate intake (eg, sample menus, the exchange system [list of servings in 6 categories that may be exchanged for one another, as they contain a similar amount of main nutrients], or carbohydrate counting). The ADA recommends the carbohydrate-counting approach for patients with type 1 DM on a flexible multiple daily injection program. Patients using insulin pumps also need to learn carbohydrate counting.

Physical Activity

1. The ADA and the American Heart Association (AHA) recommend performing ≥150 minutes of moderate intensity aerobic physical activity (eg, brisk walking) per week. Physical activity should be distributed over ≥3 days per week, with no more than 2 consecutive days without activity, and should be supplemented by increase in daily lifestyle activities (eg, gardening, household work). The exercise regimen should also include resistance training. At least 90 minutes of vigorous aerobic exercise per week is an alternative. For long-term maintenance of a major weight loss, the ADA and AHA recommend a larger amount of exercise (eg, 7 hours of moderate or vigorous aerobic physical activity per week). Special considerations should be addressed in patients with CVD, uncontrolled retinopathy or nephropathy, and severe neuropathy.

2. Exercise can improve glycemic control, assist with weight loss and maintenance, and affect positively different cardiovascular risk factors, including hypertension and dyslipidemia. Resistance training (eg, exercise with elastic bands or weight machines) may confer additional benefits, as it has the potential to enhance skeletal muscle mass and improve muscle strength and insulin sensitivity.

3. Patients with significant hyperglycemia (eg, blood glucose ≥13.9 mmol/L [250 mg/dL]) should avoid vigorous exercise because they may experience worsening of hyperglycemia and ketosis. Other occasional complications associated with strenuous physical activity include foot-stress fractures, retinal bleeding in patients with proliferative retinopathy (particularly during resistance training), and acute coronary events.

4. Although many individuals with DM do not need exercise stress testing before undertaking exercise more intense than brisk walking, pre-exercise evaluation and exercise stress testing should be considered in those at high risk for CVD (eg, multiple cardiovascular risk factors, known coronary artery disease, cerebrovascular disease, or peripheral artery disease), advanced nephropathy with renal failure, or cardiovascular autonomic neuropathy.

5. Patients receiving insulin treatment should measure their blood glucose before, during, and after exercise to identify glycemic patterns that can be used to develop strategies to avoid hypoglycemia. Ideally, exercise should be performed at similar times and in a consistent relation to meals and insulin injections. Some strategies to prevent hypoglycemia include consuming extra carbohydrates before exercise and then at 30-minute intervals during exercise (eg, 15-30 g of quickly absorbed carbohydrates) as well as after the end of exercise if it was prolonged; this is particularly important in type 1 DM. In type 2 DM the risk of hypoglycemia is lower; obese patients do not usually need extra carbohydrates during exercise.

6. Avoid insulin injections in the body areas that are especially active during a particular activity (eg, thigh) and reduce the dose of insulin that affects the time when exercise will be performed (eg, by 30%-50%), depending on exercise intensity and glucose levels.

Pharmacotherapy: Insulin

Of note, the term human insulin denotes genetically human insulin produced by Escherichia coli (examples: Humulin; neutral protamine Hagedorn [NPH] insulin, also known as isophane insulin). For a major proportion of patients treated with insulin, the advantages of using insulin analogues (modified human insulin) over human insulin are far from clear or obvious despite the cost of modified insulins being 2 to 10 times higher.Evidence 8Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ. Association of Initiation of Basal Insulin Analogs vs Neutral Protamine Hagedorn Insulin With Hypoglycemia-Related Emergency Department Visits or Hospital Admissions and With Glycemic Control in Patients With Type 2 Diabetes. JAMA. 2018 Jul 3;320(1):53-62. doi: 10.1001/jama.2018.7993. PubMed PMID: 29936529; PubMed Central PMCID: PMC6134432.Crowley MJ, Maciejewski ML. Revisiting NPH Insulin for Type 2 Diabetes: Is a Step Back the Path Forward? JAMA. 2018 Jul 3;320(1):38-39. doi: 10.1001/jama.2018.8033. PubMed PMID: 29936528.

1. Indications for insulin therapy:

1) Type 1 DM: All patients with type 1 DM should be treated with insulin from the moment of diagnosis (LADA may be an exception). These patients should not stop their basal insulin administration, even during fasting.

2) Type 2 DM:

a) Patients presenting with an acute DM complication or with significant hyperglycemia at the time of diagnosis (eg, DKA, HHS, FPG >16.7 mmol/L [300 mg/dL], HbA1c >11% [97 mmol/mol], or signs of increased catabolism such as weight loss, polyuria, and polydipsia). The requirement for insulin may be temporal.

b) Failure of noninsulin antidiabetic treatment despite the intensification of pharmacotherapy as well as lifestyle and behavioral interventions. In these patients insulin therapy should not be delayed. Insulin regimens can be combined with other noninsulin antidiabetic medications. Combined GLP-1 and insulin can be considered if HbA1c is >10% (86 mmol/mol) and/or >2% (23 mmol/mol) above the glycemic goal.

c) Hospitalized patients, as it allows greater flexibility in the management of hyperglycemia during acute illness.

2. Types of insulin: Table 5.2-3. The selection of insulin preparations and insulin regimen should be individualized to the patient’s lifestyle, usual mealtimes, and preferences.

1) Basal insulin preparations:

a) Intermediate-acting human insulin (insulin isophane [NPH]) is administered subcutaneously once or twice daily (typically in the morning before breakfast and before the evening meal or at bedtime). It is frequently given in combination with a short-acting insulin.

b) Long-acting insulin analogues are usually administered subcutaneously once daily, in the morning or evening, at a fixed time. However, the effect of insulin detemir can last <24 hours, and therefore bid administration is frequently required with this basal insulin (in the morning and evening). In occasional situations insulin glargine also requires twice-daily dosing (eg, early morning hyperglycemia in patients taking insulin glargine before breakfast who also experience hypoglycemia while fasting during the day, patients susceptible to hypoglycemia while on very low total daily doses of insulin, or patients using very high basal insulin doses). Long-acting analogues are frequently used in combination with rapid-acting insulin analogues as part of an intensive insulin therapy regimen (Figure 5.2-1).

2) Prandial insulin preparations:

a) Rapid-acting insulin analogues are administered subcutaneously immediately (within 0-15 minutes) before a meal, although they may also be administered during and immediately after mealtime, usually 3 times a day.

b) Short-acting human insulin (regular insulin) is administered subcutaneously within 45 minutes before meals, usually 3 times a day. It is commonly administered together with an intermediate-acting insulin (Figure 5.2-2).

3) Premixed insulin preparations (insulin combinations, biphasic insulins):

a) Premixed human insulins: A short-acting human insulin combined with an intermediate-acting insulin.

b) Premixed insulin analogues: A rapid-acting insulin analogue combined with a long-acting protamine suspension of this analogue.

With premixed insulin preparations the proportion of short-acting to long-acting insulin is fixed. Depending on preparation, 50% to 80% of the insulin dose is given as an intermediate-acting or long-acting form of insulin (Table 5.2-4). Each of insulin preparations in a combination product achieves its peak activity at a different time. The peaks associated with the effect of rapid-acting insulin or short-acting insulin are higher and their duration is shorter than those associated with intermediate-acting or long-acting insulins. These premixed insulin preparations are typically administered as 2 daily doses, before breakfast and before the evening meal (Figure 5.2-3). Patients must consume a meal after each injection and should follow a diet consistent in carbohydrates from day to day with meals consumed at similar times of the day. Because of the fixed ratios of insulins, individual basal and prandial dose adjustments cannot be made. Premixed insulin preparations should ideally be used after basal insulin requirements have been first established.

3. Initial insulin doses: Most patients with type DM are sensitive to insulin. It is recommended to start with a dose of 0.5 IU/kg/d. However, patients with type 1 DM may require a total daily insulin dose that ranges from 0.4 to 1.0 IU/kg/d. In type 1 DM insulin regimens typically try to mimic the physiologic release of insulin by administering a basal form of insulin (eg, glargine or detemir) and mealtime (prandial) boluses of short-acting or rapid-acting insulin. As an initial strategy, half of the total daily insulin dose can be administered as basal (eg, 0.25 IU/kg) and half as the daily prandial dose (eg, 0.25 IU/kg divided into 3 doses given with each main meal).

In contrast, in type DM it should be considered if significant hyperglycemia requires full doses of insulin (eg, 0.3-0.6 IU/kg/d) or if appropriate glycemic control can be achieved with low doses of intermediate-acting or long-acting insulin added to other glucose-lowering medications (10 IU or 0.1-0.2 IU/kg/d of a long-acting or intermediate-acting insulin). When full doses of insulin are required (0.3-0.6 IU/kg/d), patients who are sensitive to insulin or predisposed to complications of hypoglycemia (eg, thin, elderly, those with adrenal insufficiency, advanced kidney disease, cirrhosis, unstable coronary disease, active intracranial pathology, terminal illness) require lower starting insulin doses than those who are more insulin-resistant (eg, obese, receiving supraphysiologic glucocorticoid treatment).

4. Insulin regimens: It is important to note that there is no uniformly accepted “best available” way of prescribing insulin and monitoring its effects. In general, in type DM all insulin regimens should be combined with metformin, if not contraindicated. Insulin therapy should not be unduly delayed, because persistent hyperglycemia and elevated proinsulin levels accelerate the progression of the complications of DM.

1) Single-dose insulin program: Typically used in patients with type DM when combined treatment with 2 or 3 oral antidiabetic agents (with or without a GLP-1 agonist) is ineffective and who are transitioning to insulin therapy. One injection of intermediate-acting insulin (NPH) or a long-acting insulin analogue (eg, glargine, detemir, or degludec) is given once a day at about the same time. Patients with high FPG levels are commonly advised to administer insulin at bedtime, while patients with normal FPG levels and daytime hyperglycemia are advised to administer insulin in the morning before breakfast. Preprandial glucose targets are individualized (eg, glucose levels between 4.4 and 6.7 mmol/L [80-130 mg/dL] in younger patients without major comorbidities or between 5.6 and 7.8 mmol/L [100-140 mg/dL] in elderly patients with long-standing DM). At least 4 hours should elapse between a meal and subsequent preprandial measurement. In patients with persistently elevated HbA1c levels despite a single-dose insulin program or doses > 0.5 IU/kg/d, a more complex insulin regimen is frequently needed. Once prandial insulin is added, oral insulin secretagogues should be discontinued.

Patients using a single dose of NPH insulin are instructed to monitor their capillary glucose levels before breakfast and before the evening meal. If blood glucose levels are consistently (eg, for 3 consecutive days) above the individualized target range before breakfast and before the evening meal, the insulin dose should be increased by 10% to 20%. If blood glucose levels are consistently below the individualized target range before breakfast and before the evening meal, the insulin dose should be decreased by 10% to 20%. If unexplained symptomatic hypoglycemia occurs at any time (despite consuming adequate meals), the insulin dose may be too high and therefore should be decreased by 10% to 20%. If blood glucose levels are consistently within the individualized target range at one time of the day but consistently outside the individualized target range at another, the single-dose insulin program likely needs to be changed.

2) Split-dose intermediate-acting insulin program: A split-dose intermediate-acting insulin program with NPH insulin twice a day is used by some patients with type 2 DM. Patients following this program take one NPH insulin injection 30 minutes before breakfast and one NPH insulin injection 30 minutes before the evening meal or at bedtime (depending on the patient’s sleep habits, early morning hyperglycemia between 2:00 and 8:00—the “dawn phenomenon”—may be better controlled with NPH insulin given at bedtime because to the timing of its peak effect). Capillary blood glucose measurements before breakfast and before the evening meal are required to estimate if the insulin doses are appropriate. For the morning dose adjustments, blood glucose measurements before the evening meal are evaluated. For the evening dose adjustments, blood glucose measurements before breakfast of the following day are evaluated. The insulin doses can be adjusted by 10% to 20% based on personalized preprandial glycemic targets. Patients following this program need a diet that has a consistent amount of carbohydrates and have to eat their meals at about the same time every day.

3) Split mixed-dose insulin program: A split mixed-dose insulin program with intermediate-acting insulin (NPH) plus either short-acting insulin (regular) or rapid-acting insulin (aspart, lispro, or glulisine) administered each with breakfast and the evening meal is occasionally used. Before breakfast, patients on this program take an injection of NPH insulin plus an injection of either rapid-acting insulin or short-acting insulin. Before the evening meal, they also get an injection of NPH insulin plus an injection of one of the prandial insulin preparations. Patients are instructed to check their capillary glucose levels before breakfast, before the noon meal, before the evening meal, and at bedtime. They need to follow a diet that has a consistent amount of carbohydrates and eat their main meals at about the same time every day. Glucose measurements before breakfast indicate the effectiveness of the evening-meal NPH insulin administered the previous day. Glucose measurements before the noon meal indicate the effectiveness of the breakfast rapid-acting insulin (or short-acting insulin). Glucose measurements before the evening meal indicate the effectiveness of the breakfast NPH insulin dose. Glucose measurements before bedtime indicate the effectiveness of the evening-meal prandial insulin. The insulin doses are changed by 10% to 20% during each dose adjustment.

4) Premixed split-dose insulin program: In a premixed split-dose insulin program one of the premixed insulin preparations (Table 5.2-4) is administered twice a day, before breakfast and before the evening meal. A common practice is to initially give about 60% of the total daily insulin doses in the morning and about 40% in the evening. Patients are instructed to check their capillary blood glucose levels before breakfast, before the noon meal, before the evening meal, and at bedtime. Patients need to follow a diet that has a consistent amount of carbohydrates and eat their main meals at about the same time every day. Hypoglycemia could be the consequence, for example, of skipping or delaying a meal, eating fewer carbohydrates than usual, or doing an unusual amount of physical activity. In this program glucose measurements before the noon meal and before the evening meal indicate the effectiveness of the morning premixed insulin dose. Glucose measurements before bedtime and before breakfast the next day indicate the effectiveness of the evening premixed insulin dose.

If blood glucose values before the noon meal and before the evening meal are both consistently (eg, for 3 consecutive days) above or below the individualized target range, the breakfast premixed insulin dose should be increased or decreased by 10% to 20%. If blood glucose levels are within the goal range either before the noon meal or before the evening meal but outside the goal range at the other time (before the evening meal or before the noon meal), then the premixed split-dose insulin program may need to be changed. If blood glucose values at bedtime and before breakfast the next day are both consistently above or below the individualized target range, the evening-meal premixed insulin dose should be increased or decreased by 10% to 20%. If blood glucose levels are within the goal range either at bedtime or before breakfast the next day but outside the goal range at the other time (before breakfast the next day or at bedtime), then the premixed split-dose insulin program may need to be changed.

5) Multiple daily injection insulin program: This is the principal method of treatment of type 1 DM, which is also recommended in patients with type 2 DM who require full insulin replacement and insulin injections 4 times a day. Typically the program consists of a combination of long-acting basal insulin (eg, glargine, detemir, or degludec) given once daily in the morning or evening and rapid-acting insulin (aspart, lispro, or glulisine) with meals 3 times a day. A starting dose in type 2 DM is recommended as either 4 IU or 10% of basal dose at each meal; titration depends on capillary glucose measurements and HbA1c. This basal-bolus regimen is supplemented by correction scales that add or subtract units to the rapid-acting insulin prandial doses. Patients are instructed to check their capillary blood glucose levels before breakfast, before the noon meal, before the evening meal, and at bedtime. When the dose of a long-acting insulin analogue is appropriate, overnight blood glucose levels (difference between glucose readings at bedtime and before breakfast) should remain stable (eg, not increasing or decreasing >2.2 mmol/L [40 mg/dL]). Postprandial glycemic excursions (high glucose levels that are transitory during a period of time during the day), different levels of physical activity, and effects of prandial insulin are not present overnight; therefore, this period is optimal to assess the basal insulin requirements. If blood glucose levels consistently drop overnight (eg, >2.2 mmol/L [40 mg/dL] between bedtime and breakfast), the dose of the long-acting insulin should be decreased by 10% to 20%. If blood glucose levels consistently rise overnight (eg, >2.2 mmol/L [40 mg/dL] between bedtime and breakfast), the dose of the long-acting insulin should be increased by 10% to 20%.

To adjust the prandial insulin doses, the blood glucose values before the next meal (or at bedtime) should be assessed. Glucose measurements before the noon meal indicate the effectiveness of the breakfast rapid-acting insulin. Glucose measurements before the evening meal indicate the effectiveness of the noon-meal rapid-acting insulin. Glucose measurements before bedtime indicate the effectiveness of the evening-meal rapid-acting insulin. The objective is to keep the preprandial glucose values (typically 80-130 mg/dL) and bedtime glucose values within the individualized glycemic target. Another way to adjust the prandial insulin doses is to check the postprandial glucose levels (1-2 hours after the beginning of a meal) targeting levels <180 mg/dL. However, this approach adds burden to the program by requiring more capillary glucose measurements and is not necessary in the majority of cases. The prandial insulin doses depend on how many carbohydrates are present in diet. Two strategies can be followed when planning the prandial insulin therapy: (a) fixed meal insulin doses following a diet consistent in carbohydrates on consecutive days; (b) carbohydrate counting. For the purpose of carbohydrate counting, the ratio of insulin to grams of carbohydrate (number of grams of carbohydrate covered by 1 IU of rapid-acting insulin) is calculated for each meal. Usually the ratio will be started with 1 IU of insulin for every 15 g of carbohydrate and the scale will be readjusted individually.

6) Continuous subcutaneous insulin infusion (CSII) or insulin pump therapy: Insulin pumps are devices designed to administer short-acting or rapid-acting insulin analogues in a subcutaneous infusion, providing both a continuous basal infusion (40%-60% of total daily insulin dose) and mealtime boluses. Insulin pumps allow for programming delivery for multiple basal rates. The dose of prandial boluses is based on the estimated meal carbohydrate content and capillary blood glucose level immediately before each meal. Insulin pumps also have features that allow adjustments for the “residual insulin” action from previous boluses, potentially reducing the risk of hypoglycemia from frequent administration of boluses.

The advantages of insulin pump therapy include fewer injections, possibility of giving very low doses of insulin (doses as low as 0.05 IU can be accurately delivered, a feature particularly useful in small children), possibility of delivering >1 basal rate (useful, eg, for treating the dawn phenomenon or for patients with different basal requirements during periods of intense physical activity), and lifestyle flexibility with respect to eating schedules. There is also evidence indicating that in motivated patients properly trained on pump management skills, CSII can provide better glycemic control and lower risk of severe hypoglycemia. Insulin pump therapy is not recommended for patients who are unwilling or unable to perform a minimum of 4 blood glucose tests per day. CSII requires patient training in the fundamental aspects of intensive insulin therapy, carbohydrate counting, and manipulation of insulin pump settings. Potential risks associated with insulin pump therapy include blockage or leakage of the system (leading to rapid hyperglycemia and potentially DKA in patients with type 1 DM), infections at the site of infusion, and hypoglycemia (eg, if the basal insulin dose is too high and the patient skips a meal). Another disadvantage is the high cost of the pump and supplies.

Continuous glucose monitoring (CGM) systems measure the interstitial fluid glucose level, which is generally within 15% to 20% of the capillary glucose concentration, and provide semicontinuous real-time information about glucose levels that identifies fluctuations difficult to assess with conventional capillary blood glucose self-monitoring. These systems are now commonly used in conjunction with CSII (a sensor-augmented insulin pump) to provide more detailed information about the patients’ glycemic patterns (eg, average glucose, percentage of hypoglycemic and target ranges). CGM systems can play a valuable role in the management of patients with hypoglycemia unawareness and hyperglycemic excursions and are highly recommended in children and adolescents with type 1 DM. There are also other devices that allow measuring of the glucose levels intermittently but they lack alarms and glucose measurements are only obtained on demand. Some sensor-augmented pumps can be programmed to interrupt insulin delivery for up to 2 hours at a preset sensor glucose value (the threshold-suspend feature). This feature can reduce the frequency of nocturnal hypoglycemia and severe hypoglycemia without increasing HbA1c values or causing DKA. Patients considering using a CGM device should be willing to perform frequent capillary blood glucose measurements and to calibrate the system daily.

Overall, CSII (particularly sensor-augmented insulin pumps with threshold-suspend feature) should be offered to individuals with type DM in whom there is concern about hypoglycemia unawareness or high risk for severe hypoglycemia,Evidence 9 Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered as some critical patient-important outcome measures have not been explored. For discussion and references, see Appendix 5 at the end of the chapter. to patients requiring very low doses of insulin that cannot be given by syringes or pens, or to those who wish a tighter glycemic control with more flexible eating schedules.Evidence 10 Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of intervention). Quality of Evidence lowered as some critical patient-important outcome measures have not been explored. For discussion and references, see Appendix 5 at the end of the chapter. All such patients should be willing and able to learn the complexities of CSII therapy and follow closely their glycemic patterns.

Pharmacotherapy: Oral Antidiabetic Agents

1. When choosing an antidiabetic medication for patients with type 2 DM, the glucose-lowering efficacy, safety profile, tolerability, convenience, patient preferences, comorbidities, concurrently used drugs, adverse effects, and costs of available agents should be considered. The effect on weight and the risk of causing hypoglycemia are also important to review. As demonstrated by the most recent evidence, the reduction in mortality, CVD, heart failure, and progression of kidney disease are additional factors that should be considered in the initial selection of treatment.

2. A patient-centered approach with shared decision-making is recommended. Although there are uncertainties regarding the best choice and sequence of therapy, the general consensus is that metformin should be used as the initial drug for treatment of type DM if there are no contraindications (eg, advanced renal failure).Evidence 11 Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to heterogeneity of risks, benefits, and adverse effects in individual patients. For discussion and references, see Appendix 1 at the end of the chapter. Metformin has a relatively strong glucose-lowering effect, possible cardiovascular benefits, proven long-term safety, and is widely available at a low cost.

3. In patients with type DM progression or in whom metformin alone is contraindicated or has failed to meet the individualized glycemic targets, a stepwise therapy with the addition of other oral or injectable medications (including insulin) is frequently needed. Treatment should be individualized on a case-by-case basis rather than by applying one possible algorithm rigidly. The benefits and downsides of each medication should be evaluated in the specific context of each patient. Dosage, mechanism of action, advantages, and disadvantages of available antidiabetic agents: Table 5.2-5.

4. In patients with established CVD, ≥2 cardiovascular risk factors, and/or diabetic kidney disease, the use of an SGLT-2 inhibitor or GLP-1 receptor agonist with proven cardiovascular benefits and reduction of kidney disease progression should be considered as part of the therapeutic plan. SGLT-2 inhibitors should be specifically recommended in the setting of atherosclerotic CVD and heart failure. The renal outcome benefit is most pronounced with the use of SGLT-2 inhibitors.

5. Shared decision-making tools have been developed and can be used as aids that enable conversations resulting in DM treatment regimens consistent with patients’ preferences and values.

6. Do not delay insulin therapy in patients in whom it is indicated.

7. Always adjust doses of oral antidiabetic agents to achieve glycemic targets. Dose adjustment is also recommended to avoid hyperglycemia when adding a new agent to a regimen containing insulin, sulfonylurea or glinide therapy, particularly in patients at or near glycemic goals (see Follow-Up, below).

Management of Hypoglycemia

Hypoglycemia is defined by blood glucose levels <3.9 mmol/L (70 mg/dL). Its severity is further classified as level 1 (≥3.0 mmol/L [54 mg/dL]), level 2 (<3.0 mmol/L [54 mg/dL]; sufficiently low to indicate serious, clinically important hypoglycemia), and level 3 (altered mental and/or physical status requiring assistance of a third party for recovery; see Drug-Induced Hypoglycemia). Patients with DM should learn to recognize the symptoms of hypoglycemia (eg, sweating, tremors, weakness, hunger) and learn how to treat it. The “rule of 15” can be used to treat conscious patients with level 1 or level 2 hypoglycemia:

1) Check the capillary glucose level immediately when there are symptoms of hypoglycemia.

2) If the patient is awake and able to swallow, treat with 15 g of carbohydrates (eg, 4 glucose tablets [4 g each], 100 to 125 mL of fruit juice, 1 tablespoon of sugar or syrup).

3) Wait 15 minutes and recheck the blood glucose level.

4) If the capillary blood glucose level remains low or if there are still symptoms of hypoglycemia, treat the patient again with 15 g of carbohydrates and continue to recheck the capillary glucose levels until the target glucose levels are reached and symptoms resolve.

In patients with level 3 hypoglycemia and those who are unwilling or unable to swallow, treatment with IV glucose and/or a glucagon injection should be provided immediately.

Patients with DM receiving insulin therapy with a history of level 2 hypoglycemia should have a glucagon injection available (see Drug-Induced Hypoglycemia).

Serious Intercurrent Illness and Sick-Day Guidelines

Acute illnesses frequently lead to worsening of hyperglycemia and increased insulin requirements. Patients with type 1 or type DM following a multiple daily injection insulin program likely benefit from learning management strategies that can be applied during acute sickness (“sick-day guidelines”). These strategies include monitoring blood glucose levels more frequently, keeping good hydration, avoiding exercise as it may worsen hyperglycemia, checking for urine ketones if there is severe and persistent hyperglycemia, using extra doses of rapid-acting insulin to temporarily correct hyperglycemia—“insulin supplements”—and knowledge of when to contact health-care providers.

Alternative Treatment Methods

1. Whole pancreas transplantation is most frequently used in patients with renal failure in whom pancreas transplantation is combined with kidney transplantation.

2. Pancreatic islet transplantation is associated with lower risk than whole pancreas transplantation and allows for the normalization of blood glucose levels. Its use is limited by poor graft survival.

Follow-UpTop

1. Glycemic control: The ADA recommends checking HbA1c levels based on clinical situation. For patients with well-controlled DM, testing twice per year is appropriate. For unstable or highly intensively managed patients, testing every 3 months is appropriate.

2. Screening for hypertension: The ADA advises to measure blood pressure at every routine medical visit. Elevated values should be confirmed on a separate day.

3. Screening for dyslipidemia: The ADA recommends to measure the fasting lipid profile at least annually in most adult patients with DM but suggests postponing lipid assessment for 2 years in adults with low-risk lipid values (low-density lipoprotein cholesterol [LDL-C] <2.6 mmol/L [100 mg/dL], HDL-C >2.8 mmol/L [50 mg/dL], and triglycerides <8.3 mmol/L [150 mg/dL]).

4. Screening for chronic complications of DM:

1) Nephropathy: The ADA advises performing an annual test to quantitate urine albumin excretion in patients with type 1 DM lasting ≥5 years, and in all patients with type 2 DM since the time of diagnosis. Serum creatinine with estimated glomerular filtration rate should also be measured at least annually.

2) Retinopathy: The ADA recommends that patients with type DM should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years after the onset of DM. In patients with type 2 DM this should be done shortly after the diagnosis of DM. If there is no evidence of retinopathy for ≥1 eye examination, then examinations every 2 years may be considered. If diabetic retinopathy is present, subsequent examinations should be repeated at least annually or more frequently as per ophthalmologic recommendations.

3) Diabetic foot complications: The International Working Group on Diabetic Foot Editorial Board and the ADA recommend that all patients with DM should have a thorough foot examination at least once annually, and more frequently if high-risk foot conditions (eg, diabetic peripheral neuropathy, foot deformities, or peripheral artery disease) are identified. The ADA also advises that visual inspection of the feet should be performed at every health-care visit.

PreventionTop

1. Type 1 DM: There are no effective methods of prevention.

2. Type 2 DM: Effective preventive measures include a healthy diet and increased physical activity to reduce excessive weight and maintain appropriate body weight. Metformin can reduce the risk of progression of prediabetes to DM and therefore could be considered in this situation.

Tables and FiguresTop

Table 5.2-1. Differential diagnosis and treatment of latent autoimmune diabetes in adults and type 2 diabetes mellitus

Differential features

LADA

Type 2 diabetes mellitus

Body mass index

As in general population

Obese or overweight

Hypertension

No

Yes

Family history of diabetes

No

Yes

Past or family history of autoimmune diseases

Yes

No

Anti-GAD or other islet cell antibodies

Yes

No

C-peptide (glucagon test)

Low level

Normal or initially increased

Treatment of choice

Insulin

Initial treatment with PO antidiabetic agents

GAD, glutamic acid decarboxylase; LADA, latent autoimmune diabetes in adults; PO, oral.

Table 5.2-2. Differential diagnosis and treatment of maturity-onset diabetes of youth (MODY) and type 1 diabetes mellitus

Differential features

MODY

Type 1 diabetes mellitus

Congenital malformations (most frequently affecting the kidneys and urogenital system)

Possible

No

≥3 generations of family history of diabetes mellitus

Yes

No

Past or family history of autoimmune diseases

No

Yes

Islet cell antibodies

No

Yes

C-peptide (glucagon test)

Initially normal

Low level

Treatment of choice

Initial treatment with oral antidiabetic agents

Insulin

Onset

Slow

Usually acute

Table 5.2-3. Insulin pharmacokinetics (effective duration may differ markedly)

Insulin preparations

Time of action

Onset

Peak

Effective duration

Rapid-acting insulin analogues

Aspart

5-20 min

40-75 min

3-5 h

Glulisine

5-20 min

40-75 min

3-5 h

Lispro

5-20 min

40-75 min

3-5 h

Short-acting insulins

Regular

30 min

2-4 h

5-8 h

Intermediate-acting insulins

NPH (isophane)

2 h

4-12 h

10-18 h

Long-acting insulin analogues

Detemir

2 h

3-9 h

8-24 h

Glargine

2 h

No peak

20 to >24 h

Degludec

2 h

No peak

>40 h

NPH, neutral protamine Hagedorn.

Table 5.2-4. Premixed insulins (insulin combinations, biphasic insulins)

Types of insulins in the combination

Brand names

Premixed human insulin (longer/shorter)

Humulin® 20/80; Humulin® 70/30; Novolin® ge 30/70; Novolin® ge 40/60; Novolin® ge 50/50

Aspart plus aspart protamine suspension (30% longer)

NovoMix® 30

Lispro plus lispro protamine suspension (25% longer)

Humalog® Mix 25

Table 5.2-5. Antidiabetic agents

Biguanides

Drug and dosage

Metformin: Initially 500 or 850 mg PO once daily taken with largest meal. Dose increased by 500 mg/wk up to the usual dose of 1000 mg bid or 850 mg tid (with meals). Max dose 2550 mg/d

Commentsa

Mechanism of action: ↓ liver production of glucose

Efficacyb: HbA1c ↓ 1%-2%

Contraindications: Renal failure with GFR <30 mL/min (or serum creatinine ≥132.6 micromol/L [1.5 mg/dL] in men or ≥123.8 micromol/L [1.4 mg/dL] in women according to manufacturer), severe hepatic dysfunction, decompensated or advanced HF, acidosis, hypoxia, shock, history of severe hypersensitivity to metformin

Frequent adverse effects: Diarrhea, nausea, vomiting, bloating, abdominal cramping, metallic taste

Rare adverse effects: Lactic acidosis

Risk of hypoglycemia: No if monotherapy

Effect on weight: Neutral or modest weight loss

Miscellaneous advantages: Extensive experience, low cost

Miscellaneous disadvantages: Can cause vitamin B12 deficiency. Manufacturer recommends temporarily discontinuing metformin in patients undergoing radiologic studies where intravascular iodinated contrast media are used

Other comments: GI adverse effects more frequent early in the course of treatment. Extended-release metformin may be better tolerated in patients with GI adverse effects. Elderly patients should not be titrated to max dose. Careful use in patients ≥80 years (normal renal function has to be established)

Sulfonylureas

Drug and dosage

Glipizide: 2.5-20 mg PO once daily. Doses >15 mg/d should be administered in 2 divided doses. Immediate-release tablets should be administered 30 min before meals (typically before breakfast if once daily); extended-release tablets should be given with breakfast. Titrate in 2.5-5 mg increments. Max recommended dose 20 mg/d

Glimepiride: 1-8 mg PO once daily. Administer once daily with breakfast or first main meal of the day. Titrate in 1-2 mg increments. Max recommended dose 8 mg/d

Glyburide (INN glibenclamide): 1.25-20 mg PO once daily. Patients receiving >10 mg daily may have more satisfactory response with bid dosing. Administer with meals (typically before breakfast or first main meal of the day if once daily). Titrate in 1.25-2.5 mg increments. Max recommended dose 20 mg/d

Micronized glyburide (greater bioavailability): 0.75-12 mg PO once daily. Patients receiving >6 mg daily may have more satisfactory response with bid dosing. Administer with meals (typically before breakfast or first main meal of the day if once daily). Titrate in 0.75-1.5 mg increments. Max recommended dose 12 mg/d

Gliclazide: 80-320 mg/d in 2 divided doses, 30 min before meals. Modified-release tablets 30 mg once daily (with breakfast). Increase dose (by 30 mg every 2 weeks) up to max of 120 mg/d 

Commentsa

Mechanism of action: Closes KATP channels on beta-cell plasma membranes. ↑ insulin secretion

Efficacyb: HbA1c ↓ 1%-2%

Contraindications: History of severe hypersensitivity reactions

Frequent adverse effects: Lack of energy and strength

Rare adverse effects: Diarrhea, nausea, constipation, flatulence, dizziness, headaches

Risk of hypoglycemia: Present, particularly in the elderly, with strenuous exercise, or due to interactions with other drugs (eg, sulfonamides, alcohol)

Effect on weight: Modest gain

Miscellaneous advantages: Extensive experience, low cost

Miscellaneous disadvantages: Failure rate may exceed other drugs (this is attributed to exacerbation of islet dysfunction)

Other comments: Reduces postprandial glucose excursions. Usually start with lowest dose and increase every 1-2 weeks based on blood glucose. Patients with decreased caloric intake or fasting may need doses held to avoid hypoglycemia. Long-acting sulfonylureas (eg, glyburide) may be associated with higher risk of hypoglycemia than short-acting sulfonylureas (eg, glipizide, glimepiride)

Meglitinides (glinides)

Drug and dosage

Repaglinide: 0.5-4 mg PO 1-30 min before each meal 2, 3, or 4 times/d based on meal pattern. Titrate in 1-2 mg increments weekly. Max recommended dose 16 mg/d

Nateglinide: 60-120 mg PO 1-30 min before each meal 2, 3, or 4 times/d based on meal pattern

Commentsa

Mechanism of action: Closes KATP channels on beta-cell plasma membranes. ↑ insulin secretion

Efficacyb: HbA1c ↓ 1%-2%

Contraindications: History of severe hypersensitivity reactions

Frequent adverse effects: Headaches

Rare adverse effects: Diarrhea, arthralgias

Risk of hypoglycemia: Present (possibly smaller than with sulfonylureas)

Effect on weight: Modest gain

Miscellaneous advantages: Both can be used in patients allergic to sulfonylureas. Short duration of action allows dosing flexibility

Miscellaneous disadvantages: Tid dosing, expensive

Other comments: Reduces postprandial glucose excursions. Repaglinide is more effective at lowering HbA1c than nateglinide. Repaglinide is principally metabolized by liver with <10% excreted by kidneys (dose adjustments not typically required in patients with renal insufficiency). Nateglinide has active metabolites excreted by kidneys and should be used with caution in renal insufficiency. If patient misses a meal, glinides should not be administered to avoid hypoglycemia

Alpha-glucosidase inhibitors

Drug and dosage

Acarbose: Initially 25 mg PO tid immediately before main meals (some patients benefit from starting with 25 mg once daily with gradual titration to 25 mg tid to reduce GI adverse effects). Dose may be increased every 2-4 weeks. Max dose 50 mg tid (≤60 kg) or 100 mg tid (>60 kg)

Commentsa

Mechanism of action: Inhibits intestinal alpha-glucosidase and slows down the final enzymatic stage of intestinal digestion of polysaccharides, oligosaccharides, and some disaccharides (maltose and sucrose)

Efficacyb: HbA1c ↓ 0.5%-1% (mainly ↓ postprandial glucose levels)

Contraindications: History of severe hypersensitivity reactions, IBD, colonic ulceration, conditions that may deteriorate due to increased intestinal gas formation, predisposition to intestinal obstruction, partial intestinal obstruction, cirrhosis, renal impairment (serum creatinine >2 mg/dL)

Frequent adverse effects: Flatulence, diarrhea, abdominal pain

Rare adverse effects: Ileus, hepatotoxicity

Risk of hypoglycemia: No if monotherapy

Effect on weight: Neutral

Miscellaneous advantages: No systemic effects

Miscellaneous disadvantages: Frequent GI adverse effects; frequent dosing; expensive

Other comments: Reduces postprandial glucose excursions. In case of hypoglycemia (eg, concomitant use of sulfonylureas), glucose (dextrose) recommended for treatment. GI adverse effects may be decreased by restricting dietary sucrose (table sugar)

Thiazolidinediones (TZD)

Drug and dosage

Pioglitazone: 15-30 mg PO once daily, administered without regard to meals. Dose can be increased in 15 mg increments with careful monitoring of adverse effects (eg, weight gain, edema, symptoms of heart failure). Max dose 45 mg once daily

Rosiglitazone: 4 mg PO once daily or in divided doses bid, administered without regard to meals. Dose can be increased up to 8 mg daily, as a single daily dose or in divided doses bid. Max dose 8 mg/d

Commentsa

Mechanism of action: Activates the nuclear transcription factor PPAR-gamma, ↑ insulin sensitivity

Efficacyb: HbA1c ↓ 0.5%-1.5%

Contraindications: History of severe hypersensitivity reactions, HF, serious hepatic impairment, active bladder cancer, history of bladder cancer; uninvestigated macroscopic hematuria, pregnancy

Frequent adverse effects: Edema, headaches

Rare adverse effects: HF exacerbation, bone fractures, anemia, possibly ischemic heart disease (rosiglitazone), possibly bladder cancer (pioglitazone)

Risk of hypoglycemia: No if monotherapy

Effect on weight: Modest gain

Miscellaneous advantages: Effectiveness may be more durable than sulfonylureas and metformin. ↑ HDL-C, ↓ triglycerides

Miscellaneous disadvantages: Rosiglitazone may ↑ LDL-C and is expensive

Other comments: Limit max dose of pioglitazone to 15 mg/d—and consider dose reduction of rosiglitazone—when used in combination with strong CYP2C8 inhibitors (eg, gemfibrozil)

Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins)

Drug and dosage

Sitagliptin: 100 mg PO once daily. Administer with or without food. If eGFR 30-50 mL/min, dose 50 mg once daily; if eGFR is <30 mL/min, dose 25 mg once daily

Linagliptin: 5 mg PO once daily. Administer with or without food. No dosage adjustment necessary for renal impairment

Saxagliptin: 2.5-5 mg PO once daily. Administer with or without food. If eGFR is ≤50 mL/min, dose 2.5 mg once daily. If concomitant use of strong CYP3A4/5 inhibitors, dose 2.5 mg once daily

Alogliptin: 25 mg PO once daily. Administer with or without food. If eGFR is 30-60 mL/min, dose 12.5 mg once daily. If eGFR is <30 mL/min, dose 6.25 mg once daily

Commentsa

Mechanism of action: Inhibition of DPP-4 activity leads to ↑ endogenous incretins (GLP-1 and GIP) after meals, ↑ glucose-dependent insulin secretion

Efficacyb: HbA1c ↓ 0.5%-0.8%

Contraindications: History of severe hypersensitivity reactions

Frequent adverse effects: Generally well tolerated

Rare adverse effects: Headaches, nausea, possibly pancreatitis

Risk of hypoglycemia: No if monotherapy

Effect on weight: Neutral

Miscellaneous advantages: Can be used in patients with advance renal disease

Miscellaneous disadvantages: Modest glucose-lowering efficacy, expensive

Other comments: Limited long-term safety data. Saxagliptin may increase risk of HF

Glucagon-like peptide 1 (GLP-1) agonists

Drug and dosage

Exenatide: Immediate release: Initial dose 5 microg SC bid within 60 min prior to 2 main meals (≥6 h apart). After 1 month dose may be increased to 10 microg bid. Extended release: 2 mg once weekly without regard to meals or time of day. Rotate injection sites weekly

Liraglutide: Initial dose 0.6 mg SC once daily for 1 week (dose intended to reduce GI symptoms but ineffective for glycemic control), then increase to 1.2 mg once daily. Dose may be increased to 1.8 mg once daily. Administer without regard to meals or time of day

Albiglutide: 30 mg SC once weekly. Dose may be increased to 50 mg once weekly. Administer without regard to meals or time of day. Rotate injection sites weekly

Dulaglutide: 0.75 mg SC once weekly. Dose may be increased to 1.5 mg once weekly. Administer without regard to meals or time of day. Rotate injection sites weekly

Lixisenatide: Initial dose 10 microg once daily for 14 days; on day15 increase to 20 microg once daily. Maintenance dose 20 microg once daily. If dose is missed, administer within an hour of next meal

Semaglutide: Initial dose 0.25 mg once weekly for 4 weeks. Increase to 0.5 mg once weekly for ≥4 weeks. If further glycemic control necessary, increase to max 1 mg once weekly

Commentsa

Mechanism of action: Stimulation of GLP-1 receptors leads to ↑ glucose-dependent insulin secretion; ↓ glucagon secretion; slow gastric emptying; ↑ satiety

Efficacyb: HbA1c ↓ 0.5%-1.5%

Proven CV benefit: Only liraglutide; semaglutide may be considered as it was shown to reduce MACE but at expense of stroke reduction rather than CV death. No CV benefit demonstrated with exenatide or lixisenatide

Reduction of CKD progression: Liraglutide and semaglutide

Contraindications: History of severe hypersensitivity reactions, history of pancreatitis, severe GI disease (eg, gastroparesis), history or family history of medullary thyroid carcinoma or MEN syndrome type 2; caution with severe renal impairment (exenatide contraindicated if eGFR <30 mL/min)

Frequent adverse effects: Nausea, vomiting, diarrhea, injection site reactions (eg, pruritus, swelling), headaches, dizziness, nervousness

Rare adverse effects: Possibly pancreatitis, possibly pancreatic cancer

Risk of hypoglycemia: No if monotherapy

Effect on weight: Modest to significant weight loss

Miscellaneous advantages: Once-weekly preparations can reduce treatment burden

Miscellaneous disadvantages: Injectable medications, expensive

Other comments: GI adverse effects more frequent early in the course of treatment. Administer SC injections in upper arm, thigh, or abdomen. Some patients develop high titers of antibodies that may ↓ glycemic response. Limited long-term safety data

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (flozins)

Drug and dosage

Canagliflozin: 100 mg PO once daily before first meal of day. Dose may be increased to 300 mg once daily. If eGFR is 45-59 mL/min, dose 100 mg once daily. Has also inhibitory effect on SGLT-1

Dapagliflozin: 5 mg PO once daily. Administer in the morning with or without food. Dose may be increased to 10 mg once daily

Empagliflozin: 10 mg PO once daily, may be increased to 25 mg

Sotagliflozin: Currently an investigational drug, under regulatory review by EMA and FDA for treatment of both type 1 and 2 DM. Has also inhibitory effect on SGLT-1

Commentsa

Mechanism of action: Promote renal excretion of glucose

Efficacyb: HbA1c ↓ 0.5%-0.8%

Proven CV benefit: Empagliflozin, canagliflozin, and dapagliflozin; empagliflozin has modestly stronger benefit

Reduction of CKD progression: Canagliflozin, dapagliflozin, and empagliflozin

Contraindications: History of severe hypersensitivity reactions, severe renal impairment (canagliflozin, GFR <45 mL/min, dapagliflozin, GFR <30 mL/min), severe hepatic impairment, active bladder cancer

Frequent adverse effects: Vulvovaginal candidiasis, urinary frequency, polyuria

Rare adverse effects: Urinary tract infections, symptomatic hypotension (particularly in the elderly), hyperkalemia

Risk of hypoglycemia: No if monotherapy

Effect on weight: Modest weight loss

Miscellaneous advantages: Can decrease blood pressure. Empagliflozin has been shown to reduce mortality among patients with type 2 DM at high risk of CV events

Miscellaneous disadvantages: Uncertain long-term effect of chronic glycosuria, modest glucose-lowering efficacy, expensive, LDL-C levels may increase, careful use in conditions associated with risk of dehydration

Other comments: Correct volume depletion prior to administration. Limited long-term safety data. May reduce postprandial hyperglycemia by delaying intestinal glucose absorption

Warning: Recent FDA review applied to all sodium-glucose cotransporter-2 inhibitors pointed to risk of ketoacidosis and serious urinary tract infections (fewer than 100 cases reported over >1 year)

a Adapted from the American Diabetes Association and the European Association for the Study of Diabetes 2012 position statement.

b Predicted reduction of HbA1c levels with monotherapy (expressed in percentage points).

↑, increase; ↓, decrease; bid, 2 times a day; CKD, chronic kidney disease; CV, cardiovascular; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; EMA, European Medicines Agency; FDA, US Food and Drug Administration; GFR, glomerular filtration rate; GI, gastrointestinal; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HF, heart failure; IBD, inflammatory bowel disease; INN, international nonproprietary name; LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiovascular events; MEN, multiple endocrine neoplasia; PO, oral administration; PPAR-gamma, peroxisome proliferator-activated receptor gamma; tid, 3 times a day.

Figure 5.2-1. Intensive insulin therapy regimen with 4 insulin injections a day: a rapid-acting insulin analogue combined with a long-acting insulin analogue.

Figure 5.2-2. Intensive insulin therapy regimen with 4 insulin injections a day: a short-acting insulin combined with an intermediate-acting insulin (neutral protamine Hagedorn).

Figure 5.2-3. Treatment regimen with a premixed human insulin (short-acting insulin plus intermediate-acting insulin) administered twice a day.

AppendiXTop

Appendix 1 

Lowering HbA1c levels close to 7% has been associated with reductions in diabetic microvascular complications, and, less clearly, with long-term reductions of macrovascular disease. In patients with type 1 DM, the DCCT revealed that intensive insulin therapy (with at least 3 daily injections of insulin or treatment with an insulin pump) decreased rates of retinopathy, nephropathy, and neuropathy when compared with what was considered conventional-therapy at the time when this study was started (1 or 2 insulin injections per day).1 Most patients started the DCCT in their twenties, and after a mean follow-up of 6.5 years, the median HbA1c level was 7.2% in the intensive insulin therapy group and 9.1% in the conventional therapy group. In the EDIC study, the long-term observational study that followed the DCCT, decreased fatal and nonfatal cardiovascular events became apparent in the intensive insulin therapy group.2

In patients with type 2 DM, 4 large randomized trials have investigated the effect of glycemic control on the risk of microvascular and macrovascular complications. In the United Kingdom Prospective Diabetes Study (UKPDS 33), patients with newly diagnosed type 2 DM and a mean age of 53 years were assigned to an intensive glucose-lowering treatment or diet. After a follow-up of over 10 years, the median HbA1c level in the sulfonylureas or insulin group was 7.0%, while in the diet group, it was 7.9%.3 In the group treated with sulfonylureas or insulin, there was a 25% reduction in a composite outcome of microvascular events, a benefit mainly driven by fewer cases of retinal photocoagulation. In the UKPDS 34, patients whose body weight was >120% their ideal weight, and who received metformin, had a 36% reduction of all-cause mortality. The median HbA1c in the metformin group was 7.4%—a reduction not so different from the HbA1c levels achieved in the sulfonylureas or insulin arm, or in the diet arm—suggesting a beneficial effect of metformin beyond its hypoglycemic action.4 In the 10-year posttrial follow-up of the UKPDS, significant risk reductions for myocardial infarction (15%) and death from any cause (13%) become apparent in the sulfonylurea-insulin group. In the metformin group, the risk reductions for myocardial infarction (33%) and all-cause mortality (27%) persisted.5

In contrast with UKPDS, the ADVANCE trial,6 the VADT,7 and the ACCORD trial8 included older patients with long-standing DM and at high risk for CVD. In these studies, intensive therapy (HbA1c levels of 6.5% in ADVANCE, 6.9% VADT, and 6.4% in ACCORD) delayed the progression of albuminuria but did not decrease the rates of other microvascular complications or cardiovascular mortality when compared with standard therapy (HbA1c levels of 7.3% in ADVANCE, 8.4% in VADT, and 7.5% in ACCORD).

1 The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993 Sep 30;329(14):977-86. PubMed PMID: 8366922.

2 Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005 Dec 22;353(25):2643-53. PubMed PMID: 16371630; PubMed Central PMCID: PMC2637991.

3 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53. Erratum in: Lancet 1999 Aug 14;354(9178):602. PubMed PMID: 9742976.

4 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53. Erratum in: Lancet 1999 Aug 14;354(9178):602. PubMed PMID: 9742976.

5 Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008 Oct 9;359(15):1577-89. doi: 10.1056/NEJMoa0806470. Epub 2008 Sep 10. PubMed PMID: 18784090.

6 ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560-72. doi: 10.1056/NEJMoa0802987. Epub 2008 Jun 6. PubMed PMID: 18539916.

7 Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360(2):129-39. doi: 10.1056/NEJMoa0808431. Epub 2008 Dec 17. Erratum in: N Engl J Med. 2009 Sep 3;361(10):1028. N Engl J Med. 2009 Sep 3;361(10):1024-5. PubMed PMID: 19092145.

8 Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545-59. doi: 10.1056/NEJMoa0802743. Epub 2008 Jun 6. PubMed PMID: 18539917; PubMed Central PMCID: PMC4551392.

Appendix 2 

Both the Eighth Joint National Committee for the management of hypertension (JNC 8) and the ADA recommend initiating pharmacologic antihypertensive treatment in adults with DM when systolic blood pressure is confirmed to be ≥140 mm Hg.1,2 There is evidence from randomized trials in patients with DM and hypertension that supports this recommendation, and indicates that treatment to systolic blood pressure levels <150 mm Hg reduces the risk for cardiovascular and cerebrovascular events, and also lowers mortality.3

In contrast, there is limited evidence for the benefits of aiming for lower blood pressure levels. A Cochrane systematic review evaluated if lower blood pressure targets (<130/85 mm Hg) in patients with DM were associated with reduction in mortality and/or morbidity compared with standard blood pressure treatment goals (<140-160/90-100 mm Hg).4 Only one study was found—the ACCORD BP trial—that investigated if intensive antihypertensive treatment targeting normal systolic blood pressure (ie, <120 mm Hg) in patients with type 2 DM reduces major cardiovascular events.5 Despite achieving significantly lower blood pressures (mean systolic blood pressure 119.3 mm Hg in the intensive-therapy group vs 133.5 mm Hg in the standard-therapy group), the only significant benefit in the intensive-therapy group was a reduction in the incidence of stroke, which, although statistically significant, had a small magnitude (absolute risk reduction of 1.1%; 91 people needed to be treated intensively during 4.7 years to prevent 1 additional stroke). The intensive-therapy group also had a significantly larger increase in the risk of serious adverse effects attributed to the antihypertensive medications, including hypotension, syncope, bradycardia or arrhythmia, hyperkalemia, angioedema, and renal failure (absolute risk increase, 2.0%; 1 excessive serious adverse event for every 50 patients treated intensively). The Cochrane systematic review also identified 4 trials that evaluated lower diastolic blood pressure targets and that failed to reduce the risk of stroke, myocardial infarction, or congestive heart failure.6 Based on the available evidence, a weak recommendation against treating blood pressure to normal levels (ie, <120/80 mm Hg) can be made.

The ADA suggests that the antihypertensive therapy for patients with DM should comprise a regimen that includes either an ACEI or an ARB.7 In contrast, the JNC 8 recommends that in the general nonblack diabetic population the initial antihypertensive treatment can include a thiazide-type diuretic, an ACEI, an ARB, or a calcium channel blocker (CCB).8 The JNC 8 also suggests that in the general black diabetic population a thiazide-type diuretic or a CCB should be tried first, while in the diabetic population with chronic kidney disease, either an ACEI or ARB are the agents of choice.9 It should be noted that a combination therapy is eventually required in most hypertensive patients with DM. Although many consider that the degree of blood pressure reduction is the major determinant for better cardiovascular outcomes (and not the choice of antihypertensive drug), some evidence suggests that ACEIs or ARBs may protect against progression of kidney disease10 and that ACEIs may reduce major cardiovascular events and mortality in patients with diabetes.11

1 James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507-20. doi: 10.1001/jama.2013.284427. Erratum in: JAMA. 2014 May 7;311(17):1809. PubMed PMID: 24352797.

2 American Diabetes Association. Standards of Medical Care in Diabetes – 2015. Diabetes Care 2015;38(Suppl 1):S1-S93.

3 James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507-20. doi: 10.1001/jama.2013.284427. Erratum in: JAMA. 2014 May 7;311(17):1809. PubMed PMID: 24352797.

4 Arguedas JA, Leiva V, Wright JM. Blood pressure targets for hypertension in people with diabetes mellitus. Cochrane Database Syst Rev. 2013 Oct 30;10:CD008277. doi: 10.1002/14651858.CD008277.pub2. Review. PubMed PMID: 24170669.

5 ACCORD Study Group, Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010 Apr 29;362(17):1575-85. doi: 10.1056/NEJMoa1001286. Epub 2010 Mar 14. PubMed PMID: 20228401; PubMed Central PMCID: PMC4123215.

6 Arguedas JA, Leiva V, Wright JM. Blood pressure targets for hypertension in people with diabetes mellitus. Cochrane Database Syst Rev. 2013 Oct 30;10:CD008277. doi: 10.1002/14651858.CD008277.pub2. Review. PubMed PMID: 24170669.

7 American Diabetes Association. Standards of Medical Care in Diabetes – 2015. Diabetes Care 2015;38(Suppl 1):S1-S93.

8 James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507-20. doi: 10.1001/jama.2013.284427. Erratum in: JAMA. 2014 May 7;311(17):1809. PubMed PMID: 24352797.

9 James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507-20. doi: 10.1001/jama.2013.284427. Erratum in: JAMA. 2014 May 7;311(17):1809. PubMed PMID: 24352797.

10 Wu HY, Huang JW, Lin HJ, et al. Comparative effectiveness of renin-angiotensin system blockers and other antihypertensive drugs in patients with diabetes: systematic review and bayesian network meta-analysis. BMJ. 2013 Oct 24;347:f6008. doi: 10.1136/bmj.f6008. Review. PubMed PMID: 24157497; PubMed Central PMCID: PMC3807847.

11 Cheng J, Zhang W, Zhang X, et al. Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis. JAMA Intern Med. 2014 May;174(5):773-85. doi: 10.1001/jamainternmed.2014.348. PubMed PMID: 24687000.

Appendix 3

A Cochrane systematic review found that adults with type 2 DM who participated in group-based training programs had significant improvements in DM control when compared with patients not undergoing these educational interventions.1 In this review, a meta-analysis of 7 clinical trials showed a statistically significant reduction of HbA1c of 0.8% at the end of 12 to 14 months of follow-up. There was also an overall reduced need for diabetes medications, and clinically small but statistically significant reductions of body weight and systolic blood pressure. More limited evidence suggests that individual patient education has a beneficial effect on glycemic control in patients with type 2 DM, specifically among those with baseline HbA1c levels greater than 8%.2

1 Deakin T, McShane CE, Cade JE, Williams RD. Group based training for self-management strategies in people with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003417. Review. Update in: Cochrane Database Syst Rev. 2015;6:CD003417. PubMed PMID: 15846663.

2 Duke SA, Colagiuri S, Colagiuri R. Individual patient education for people with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD005268. doi: 10.1002/14651858.CD005268.pub2. Review. PubMed PMID: 19160249.

Appendix 4 

In a meta-analysis of 3 randomized controlled trials by the Cochrane Collaboration group, dietary advice plus exercise was associated with a statistically significant mean decrease in HbA1c of 1.0% at 12 months. There were not enough data to reliably recommend one dietary intervention versus another, and no data were found on the effect of diet on micro- or macrovascular diabetic complications, mortality, or quality of life.1 Recently, the Look AHEAD trial failed to demonstrate significant reductions in cardiovascular morbidity and mortality among overweight or obese patients with type 2 DM randomized to an intensive lifestyle intervention. Nevertheless, other positive effects were observed with this intervention, including significant improvements of glycemic control, weight loss, lower systolic blood pressure, reductions in sleep apnea and depression, and improvements in quality of life. The use of insulin and antihypertensive medications was also lower in the intensive lifestyle intervention group.2

1 Nield L, Moore HJ, Hooper L, et al. Dietary advice for treatment of type 2 diabetes mellitus in adults. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004097. Review. PubMed PMID: 17636747.

2 Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013 Jul 11;369(2):145-54. doi: 10.1056/NEJMoa1212914. Epub 2013 Jun 24. Erratum in: N Engl J Med. 2014 May 8;370(19):1866. PubMed PMID: 23796131; PubMed Central PMCID: PMC3791615.

Appendix 5 

A Cochrane systematic review explored whether CSII is better than multiple insulin injections in patients with type 1 DM.1 This review found that there was a small but statistically significant difference in HbA1c reduction favoring CSII (weighted mean difference, -0.3%). Quality of life measures suggested that CSII was preferred over multiple injections. Adverse events were not well reported in the included trials, and no information was available on mortality, late DM complications, or costs. Although only few severe hypoglycemic events were reported (and the use of different scales made it inappropriate to conduct a meta-analysis), the data suggested that CSII may be better than multiple injections for reducing the incidence of severe hypoglycemia.2 Another Cochrane systematic review and meta-analysis revealed that CGM sensor-augmented insulin pump therapy (real-time CGM in patients with type 1 DM starting insulin pump therapy) was associated with a statistically significant larger decline in the HbA1c level compared with patients using multiple insulin injections and self-monitoring blood glucose levels (mean difference in change in HbA1c level -0.7% from baseline).3 Information on DM complications, mortality, and costs was not available. There were no studies in pregnant women with type 1 DM or in patients with hypoglycemia unawareness.4

1 Misso ML, Egberts KJ, Page M, O'Connor D, Shaw J. Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD005103. doi: 10.1002/14651858.CD005103.pub2. Review. PubMed PMID: 20091571.

2 Misso ML, Egberts KJ, Page M, O'Connor D, Shaw J. Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD005103. doi: 10.1002/14651858.CD005103.pub2. Review. PubMed PMID: 20091571.

3 Langendam M, Luijf YM, Hooft L, Devries JH, Mudde AH, Scholten RJ. Continuous glucose monitoring systems for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2012 Jan 18;1:CD008101. doi: 10.1002/14651858.CD008101.pub2. Review. PubMed PMID: 22258980.

4 Langendam M, Luijf YM, Hooft L, Devries JH, Mudde AH, Scholten RJ. Continuous glucose monitoring systems for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2012 Jan 18;1:CD008101. doi: 10.1002/14651858.CD008101.pub2. Review. PubMed PMID: 22258980.

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