Diabetes Mellitus Type 1 in Adults

History

• Initial presentation varies depending on severity of manifestations and rate of β-cell destruction ^r3
  • Asymptomatic in some adults who may also present with modest fasting hyperglycemia ^c1
• Symptoms develop as hyperglycemia worsens, including: ^r3
  • Polyuria ^c2
  • Polydipsia ^c3
  • Polyphagia ^c4
  • Unexplained weight loss ^c5c6
    • Acute onset of diabetes is often heralded by weight loss, but patients with overweight or obesity can also develop type 1 diabetes
  • Weakness ^c7
  • Fatigue ^c8
  • Blurred vision ^c9
• DKA is an uncommon initial presentation in adults; adults frequently retain sufficient pancreatic β-cell function in the early stage of disease to prevent ketoacidosis ^c10

Physical examination

• Often, there are no signs with mild to moderate hyperglycemia ^c11
• Patients with symptomatic moderate to severe hyperglycemia at presentation show signs of volume depletion ^c12
  • Dry mucous membranes ^c13
  • Hypotension ^c14
  • Poor skin turgor ^c15
• Signs of complications
  • Increased blood pressure ^c16
  • Heart rate variability during deep inspiration, position change, or Valsalva maneuver ^c17
  • Microaneurysms, exudates, and/or macular edema on funduscopic examination ^c18c19c20
  • Decreased lower extremity sensation ^c21c22c23c24
  • Weak pedal pulses ^c25
  • Foot ulcers, deformities, or wounds ^c26c27c28c29

Causes

• Autoimmune (type 1A) ^c30
  • T cell–mediated autoimmune disease characterized by selective destruction of pancreatic beta cells ^c31
  • Disease emerges through a complex interrelation of genetic and environmental factors, most of which have yet to be identified
• Idiopathic (type 1B) ^c32
  • Pancreatic β-cell failure occurring without autoimmune destruction

Risk factors and/or associations

Primary diagnostic tools

• History and physical examination can suggest diabetes, but biochemical parameters are required for diabetes diagnosis ^c55
  • Testing for pancreatic islet autoantibodies and C-peptide level can help differentiate diabetes type and confirm a diagnosis of type 1 disease
• Laboratory confirmation of diabetes can be achieved with either of the following: ^r5r17
  • 2 diagnostic test results from among the following 3 tests, using the same or 2 different types of tests and the same or 2 different test samples:
    • Hemoglobin A1C measurement of at least 6.5% ^c56
      • Measurement of hemoglobin A1C can give an indication of duration of disease
    • Fasting plasma glucose measurement of at least 126 mg/dL (7 mmol/L) ^c57
    • 2-hour glucose measurement of at least 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test ^c58
      • More useful in asymptomatic patients, primarily when type 2 diabetes is suspected ^r18
  • 1 random plasma glucose measurement of 200 mg/dL or higher when classic symptoms of hyperglycemia or hyperglycemic crisis are present ^c59
    • Measuring the specific blood glucose level not only confirms the diagnosis but also directs further management of severe hyperglycemia
• After a diagnosis of diabetes is made and if clinical presentation suggests type 1, specific laboratory testing with assessment of pancreatic islet autoantibodies can confirm type 1 disease and allow for further classification ^r5r17c60
  • Consider alternative diagnosis of type 2 diabetes in patients aged older than 35 years with negative islet autoantibodies
• Measurement of C-peptide level can help differentiate diabetes type when pancreatic autoantibodies are negative, especially when measured beyond 3 years after initial diabetes diagnosis ^r1r17
• Evaluate comorbidities at time of diagnosis ^r3
  • Measure blood pressure, obtain fasting lipid panel, and measure urinary albumin excretion (urine albumin-creatinine ratio) ^c61c62c63
  • Obtain resting ECG for patients with hypertension or suspected cardiovascular disease ^r19c64
  • Refer to ophthalmologist for baseline dilated eye examination, starting 5 years after diagnosis ^c65

Laboratory

• Fasting glucose measurement ^c66c67c68
  • Diagnostic thresholds are as follows: ^r5
    • Fasting glucose reference range: less than 100 mg/dL (5.6 mmol/L)
    • Impaired fasting glucose: 100 to 125 mg/dL (5.6-6.9 mmol/L)
    • Diabetes mellitus: 126 mg/dL (7 mmol/L) or higher
  • Fasting requires no caloric intake for at least 8 hours
  • In absence of unequivocal symptomatic hyperglycemia, diabetes diagnosis must be confirmed by another abnormal test result; can be the same or different type of test and can be from the same or different test samples
• Random glucose measurement ^c69
  • A single measurement of 200 mg/dL (11.1 mmol/L) or greater when signs or symptoms of hyperglycemia are present confirms diagnosis of diabetes ^r5
• Hemoglobin A1C ^c70
  • Diagnostic threshold is 6.5% or greater ^r5
  • In absence of unequivocal symptomatic hyperglycemia, diabetes diagnosis must be confirmed by another abnormal test result; can be the same or different type of test and can be from the same or different test samples
  • Results may be altered in presence of some clinical conditions, causing problematic interpretation ^r5
    • Hemoglobinopathy
    • Iron deficiency
    • Hemolytic anemia
    • Thalassemia
    • Spherocytosis
    • Severe hepatic disease
    • Severe renal disease
    • Recent blood loss or transfusion
    • HIV treated with certain medications
    • Pregnancy and postpartum period
    • Erythropoietin therapy
• Oral glucose tolerance test ^c71
  • Performed 2 hours after oral ingestion of 75 g anhydrous glucose dissolved in water
  • Diagnostic thresholds are as follows: ^r5
    • Glucose tolerance reference range: less than 140 mg/dL (7.8 mmol/L)
    • Impaired glucose tolerance: 140 to 199 mg/dL (7.8-11.1 mmol/L)
    • Diabetes mellitus: 200 mg/dL (11.1 mmol/L) or greater
  • In absence of unequivocal symptomatic hyperglycemia, diabetes diagnosis must be confirmed by another abnormal test result; can be the same or different type of test and can be from the same or different test samples
  • Adequate carbohydrate intake of at least 150 g/day for 3 days before testing is necessary
• Pancreatic islet autoantibodies ^r3c72
  • Autoimmune markers indicative of type 1 diabetes include several different pancreatic islet autoantibodies (commercial laboratory assays measure all 4 types) ^{r20r21c73c74c75c76}
    • Autoantibodies against a glutamic acid decarboxylase isoform (GAD2, also known as GAD65): this is the most widely available and best characterized test ^c77c78
      • Such antibodies are detected in approximately 50% to 80% of patients at time of diagnosis with type 1 diabetes ^r20r21
      • Seroconversion usually precedes onset of clinical manifestations of disease, and result remains positive thereafter
    • Autoantibodies against certain protein tyrosine phosphatases that are cell membrane autoantigens, including those on islet cells (ie, PTPRN and PTPRN2, also known as islet antigen-2 and islet antigen-2β, respectively): detected in 30% to 70% of patients with newly diagnosed disease ^r20c79c80
    • Autoantibodies against a zinc transporter protein (SLC30A8, also known as ZnT8) (solute carrier family 30 member 8): test is largely available in research settings; antibodies are detected in 50% to 70% of patients with newly diagnosed disease ^r20r22
    • Autoantibodies to insulin ^r20c81
      • Detected in approximately 50% to 90% of patients with newly diagnosed disease ^r20
      • Must be measured before or within 2 weeks of commencing insulin therapy
  • Patients with clinical features compatible with type 1 diabetes and 1 or more positive islet autoantibodies are considered to have type 1 diabetes, regardless of insulin requirement at initial diagnosis ^r1
  • Absence of pancreatic autoantibodies does not rule out type 1 diabetes ^r1
    • Up to 5% to 10% of patients with new-onset type 1 diabetes in White European study populations have been found to lack islet antibodies ^r1
    • Pancreatic autoantibody titers diminish over time, which can produce false-negative results ^r23
• C-peptide ^r1c82
  • Surrogate marker for insulin secretion
  • Can be obtained if islet autoantibodies are absent and diabetes type remains unclear
  • Recommended test when diabetes type remains uncertain more than 3 years after initial diabetes diagnosis
  • Interpretation: ^r1
    • Less than 200 pmol/L or absent: indicative of type 1 diabetes ^c83
    • 200 to 600 pmol/L: indeterminate; consider repeat C-peptide measurement in 5 years and genetic testing for monogenetic diabetes in patients aged younger than 35 years with compatible features
    • Greater than 600 pmol/L: strongly suggestive of type 2 diabetes, especially in patients aged older than 35 years; consider genetic testing for monogenetic diabetes in patients aged younger than 35 years with suggestive features
• Additional laboratory tests recommended at diagnosis to screen for associated diseases and complications include: ^r3
  • Fasting lipid panel ^c84
  • Renal function tests for nephropathy ^c85
    • Estimated GFR ^c86
    • Urine albumin-creatinine ratio ^c87
  • Thyroid disease
    • TSH ^c88
    • Thyroid autoantibodies ^c89
      • Thyroid peroxidase ^c90
  • Celiac disease
    • IgA antitissue transglutaminase ^c91
    • Antiendomysial antibodies ^c92
  • Liver function tests ^c93

Most common

• Type 2 diabetes mellitus ^c94d1
  • Shares biochemical parameter of hyperglycemia with type 1 diabetes
  • Patients with type 2 diabetes may be asymptomatic, with hyperglycemia detected through screening or as an incidental finding
    • In symptomatic patients, hyperglycemia symptoms predominate (eg, polyuria, polydipsia)
  • Typically occurs in older adult patients and patients with overweight or obesity who often have a family history of type 2 diabetes
  • Differentiated from type 1 diabetes on the basis of clinical course over time, absence of pancreatic autoantibodies, and detectable or elevated C-peptide level
    • Clinical course of type 1 diabetes is characterized by ongoing, absolute insulin requirement that is lifelong, whereas insulin dependency is usually absent in early phase of type 2 diabetes
    • Younger age (less than 35 years) at initial diagnosis strongly favors type 1 diabetes; after age 35 years, type 2 diabetes is increasingly likely with absent pancreatic autoantibodies and older age ^r1
    • Lower BMI, unintentional weight loss, ketoacidosis, and severe hyperglycemia at presentation also favor type 1 diabetes ^r1
    • Type 2 diabetes most often responds to noninsulin antihyperglycemic agents (eg, metformin, glyburide) early in the course of disease
  • Genetic risk scores determined from common genetic variants can accurately discriminate between type 1 and type 2 diabetes in adults, but this testing is not commercially available yet ^r24
• Diabetes insipidus ^c95d2
  • Spectrum of diseases that display hypotonic polyuria and inability to concentrate urine owing to inadequate secretion of or impaired renal responsiveness to arginine vasopressin
  • Presenting symptoms of polyuria, polydipsia, and nocturia overlap with those of diabetes mellitus when the latter is associated with symptomatic hyperglycemia
  • Diagnosis of diabetes insipidus is suggested by a 24-hour urine volume greater than 3 L and low urinary osmolality; definitive diagnosis requires a water deprivation test
  • Most easily differentiated from diabetes mellitus on the basis of laboratory test results (eg, from plasma glucose level, oral glucose tolerance test, hemoglobin A1C)
• Monogenic diabetes/maturity-onset diabetes of youth ^{r25c96c97c98c99}
  • Autosomal dominant disorders causing β-cell dysfunction and impaired insulin secretion, with onset of hyperglycemia at young age (younger than 25 years)
  • Features include young age at presentation and strong family history of diabetes, but without typical features of type 2 diabetes (ie, absence of obesity, low-risk ethnic group)
  • Differentiated from type 1 diabetes by genetic testing, most commonly with identification of mutations in HNF1A (HNF1 homeobox A) or GCK (glucokinase), as well as by C-peptide level higher than 200 pmol/L ^r1
• Drug-induced diabetes ^c100
  • Drugs can have a toxic, irreversible effect on pancreatic beta cells (eg, pentamidine), typically inducing type 1 diabetes
  • Drugs promoting hyperglycemia (eg, glucocorticoids, thiazide diuretics, somatostatin analogues) may also induce diabetes (typically type 2) in a genetically susceptible person ^r26
  • Checkpoint inhibitors for cancer treatment have recently been associated with development of autoimmune disease, including fulminant type 1 diabetes; specific pathophysiology is unclear, and typical type 1 diabetes autoantibodies are frequently absent ^r5
  • Drug-induced diabetes is identified when hyperglycemia or ketoacidosis develops after an inciting drug is used ^r27

Admission criteria

DKA ^r38

• Plasma glucose level higher than 250 mg/dL with any of the following:
  • Arterial pH less than 7.3
  • Serum bicarbonate level lower than 15 mEq/L
  • Moderate ketonuria (more than 2+ on test strip) or ketonemia (3 mmol/L or greater)
• Volume depletion
• Acute kidney injury

Hypoglycemia with neuroglycopenia ^r38

• Any of the following:
  • Blood glucose level less than 50 mg/dL refractory to treatment (no prompt recovery of sensorium)
  • Coma, seizures, or altered behavior due to hypoglycemia

Uncontrolled diabetes ^r38

• At least 1 of the following:
  • Hyperglycemia with volume depletion
  • Hyperglycemia associated with metabolic deterioration
  • Recurrent fasting plasma glucose level higher than 300 mg/dL and refractory to outpatient treatment
  • Hemoglobin A1C 100% or more above the upper limit of reference range
  • Frequent episodes of severe hypoglycemia with blood glucose level lower than 50 mg/dL and refractory to outpatient treatment
  • Metabolic instability as evidenced by frequent swings between fasting hyperglycemia and hypoglycemia
  • Recurrent DKA not precipitated by infection or injury
  • Severe psychosocial issues that cause uncontrolled metabolic function and cannot be managed in an outpatient setting

Recommendations for specialist referral

• Certified diabetes educator for diabetes self-management education and ongoing support
• Registered dietitian for medical nutrition therapy
• Endocrinologist for uncertain diagnosis or treatment of labile glycemia (eg, recurrent hypoglycemia, persistent hyperglycemia, ketoacidosis)
• Nephrologist for persistent proteinuria, decreased GFR, labile blood pressure, or hyperkalemia
• Cardiologist for associated cardiovascular disease management
• Ophthalmologist to screen for or treat diabetic retinopathy
• Podiatrist for orthotic footwear and prevention or treatment of diabetic foot ulcers
• Mental health specialist for depression, self-harm, blatant disregard for self-care, severe anxiety, diabetes-related distress, suspicion for a serious mental illness, fear of hypoglycemia, repeated hospitalizations for DKA, intentional omission of insulin, or eating disorders ^r40
• Neuropsychologist or other specialist trained in assessing cognitive capacity if capacity changes significantly or is inadequate for decision-making and/or self-care
• Dentist for comprehensive dental and periodontal examination

Drug therapy

• Insulin ^{r51c101c102c103c104}
  • Overall, insulin regimen and dosing are highly individualized and based on age, duration of diabetes, comorbidities, history of diabetic complications, and risk of hypoglycemia
  • Preferred insulin regimen in American Diabetes Association/European Association for the Study of Diabetes consensus guidelines is a long-acting basal analogue (eg, detemir, glargine, degludec) combined with a rapid-acting or ultra-rapid-acting prandial analogue ^r1
  • Other less-preferred alternative insulin regimens include use of short-acting (regular), intermediate-acting NPH (neutral protamine Hagedorn [isophane insulin suspension]), and premixed insulin preparations; these regimens may be less labor intensive and/or have lower cost but generally lead to suboptimal glycemic control and higher risk of hypoglycemia
    • A recent systematic review and network meta-analysis concluded that long-acting insulin analogues were superior to intermediate-acting insulin in reducing hemoglobin A1C; fasting glucose; weight gain; and the incidence of major, serious, or nocturnal hypoglycemia in patients with type 1 diabetes ^r52
    • In contrast, a recent Cochrane review, using different inclusion, exclusion, and analytic criteria, found that there was lower risk of severe hypoglycemia with insulin detemir compared with NPH insulin, but otherwise no significant differences in clinical outcomes between detemir, glargine, degludec, and NPH insulin preparations ^r53
  • Suggested insulin initiation strategy at time of new diagnosis in insulin-naive patients is as follows: ^r43
    • Start with multiple daily injections consisting of a long-acting basal analogue dose combined with several prandial insulin doses before meals (basal-bolus strategy)
    • Step 1: determine total daily insulin dose
      • If initiating insulin therapy: typical total daily dose ranges from 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is commonly used
      • If intensifying insulin regimen: total daily dose equals sum of all current doses in a day
    • Step 2: determine daily basal insulin requirement (50% of total daily insulin dose from step 1)
    • Step 3: give basal insulin as a single subcutaneous dose once daily
    • Step 4: determine daily prandial insulin requirement (50% of total daily insulin dose from step 1)
    • Step 5: divide total daily prandial insulin requirement by 3 and administer as a subcutaneous dose of immediate analogue insulin before each meal
  • Insulin titration ^c105
    • Titrate insulin therapy to achieve individualized glycemic targets by changing doses and timing of administration in accordance with blood glucose measurements and patterns or by transitioning to continuous subcutaneous insulin infusion therapy
      • If fasting blood glucose target is not achieved, increase basal insulin dose by increments of approximately 10% to 20% every 2 to 3 days ^{r29c106c107c108}
      • If a 2-hour postprandial glucose measurement or a preprandial glucose measurement is higher than 180 mg/dL, increase the prandial dose for the next meal by 10% to 20%
      • If hypoglycemia occurs between meals after use of prandial insulin, reduce the next prandial insulin dose; if nighttime hypoglycemia occurs, reduce basal insulin or reduce prandial insulin taken before dinner
      • If fasting blood glucose level is lower than 70 mg/dL, reduce basal insulin by 10% to 20%
    • FDA-approved insulin dose calculators and decision support systems are available to assist with titration
  • Continuous subcutaneous insulin infusion via insulin pump with continuous glucose monitoring is preferred over multiple daily injections for most patients ^r42r43
    • Associated with modest improvements in hemoglobin A1C reduction and avoidance of nocturnal hypoglycemia
  • Use of insulin pens is generally preferred over syringe administration due to simplicity and ease of dosing if multiple daily injections are given
• Basal insulins ^r54c109c110
  • Basal insulin is designed to provide a constant low level of insulin to maintain euglycemia between meals and overnight ^r18
  • Necessary to suppress hepatic glucose production ^r55
  • Basal insulin is available in intermediate-acting and long-acting formulations; long-acting insulin analogues better mimic endogenous basal insulin secretion compared with intermediate-acting insulins (eg, isophane insulin) and may also reduce the risk of hypoglycemia, especially nocturnal hypoglycemia ^r55
  • Insulin degludec ^c111c112
    • Insulin Degludec Solution for injection; Adults: 33% to 50% of the total daily insulin dose subcutaneously once daily, initially. Adjust dose every 3 to 4 days based on metabolic needs, blood glucose, and glycemic control goal. Use short-acting, prandial insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
  • Insulin detemir ^{c113c114c115c116c117c118}
    • Insulin Detemir (Recombinant) Solution for injection; Adults: 33% to 50% of the total daily insulin dose subcutaneously once daily, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use short-acting, prandial insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
  • Insulin glargine ^{c119c120c121c122c123c124c125c126}
    • Insulin Glargine Solution for injection; Adults: 33% to 50% of the total daily insulin dose subcutaneously once daily, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use short-acting, prandial insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
  • NPH (neutral protamine Hagedorn) ^{c127c128c129c130c131c132c133c134c135}
    • Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Adults: 50% of the total daily insulin dose subcutaneously once daily or divided twice daily, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use short-acting, prandial insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
• Prandial insulins ^r18c136c137
  • Rapid-acting and ultra-rapid-acting insulins more closely mimic physiologic insulin secretion after a meal owing to rapid onset and short duration of action; dosing to match meal intake results in less of a postprandial spike in blood glucose and reduced risk of late hypoglycemia ^r55
  • When used in a multiple daily insulin injection regimen, prandial doses (rapid-acting or ultra-rapid-acting analogues) are used to limit glucose excursions that occur after meals or snacks
  • Short-acting insulin
    • Regular insulin ^{c138c139c140c141c142c143c144c145c146c147c148c149c150}
      • Insulin Regular (Recombinant) Solution for injection; Adults: 50% of the total daily insulin dose subcutaneously divided 2 to 3 times daily approximately 30 minutes before meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
  • Rapid-acting insulin
    • Insulin aspart (Novolog insulin aspart products only) ^{c151c152c153c154c155c156c157}
      • Insulin Aspart (Recombinant) Solution for injection; Adults: 50% of the total daily insulin dose subcutaneously divided 5 to 10 minutes before meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
      • Novolog insulin aspart is not interchangeable with Fiasp insulin aspart.
    • Insulin glulisine ^{c158c159c160c161}
      • Insulin Glulisine Solution for injection; Adults: 50% of the total daily insulin dose subcutaneously divided 15 minutes before or within 20 minutes after start of meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
    • Insulin lispro ^{c162c163c164c165c166c167c168c169c170c171c172c173}
      • Insulin Lispro Solution for injection; Adults: 50% of the total daily insulin dose subcutaneously divided 15 minutes before or immediately after meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
  • Ultra-rapid-acting insulin
    • Insulin aspart (Fiasp insulin aspart products only) ^c174
      • Insulin Aspart (Recombinant) Solution for injection; Adults: 50% of the total daily insulin dose subcutaneously divided at the start of or within 20 minutes after starting meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
      • Fiasp insulin aspart is not interchangeable with Novolog insulin aspart.
    • Inhaled human insulin (Afrezza) ^c175
      • For insulin-naïve persons
        • Insulin (Human Recombinant) Inhalation powder; Adults: 4 units inhaled by mouth at each meal, initially. Use in combination with basal insulin. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal.
      • For conversion from subcutaneous prandial insulin
        • Insulin (Human Recombinant) Inhalation powder; Adults: 4 units inhaled by mouth at each meal for up to 4 units/dose prandial subcutaneous insulin; 8 units inhaled by mouth at each meal for 5 to 8 units/dose prandial subcutaneous insulin; 12 units inhaled by mouth at each meal for 9 to 12 units/dose prandial subcutaneous insulin; 16 units inhaled by mouth at each meal for 13 to 16 units/dose prandial subcutaneous insulin; 20 units inhaled by mouth at each meal for 17 to 20 units/dose prandial subcutaneous insulin; and 24 units inhaled by mouth at each meal for 21 to 24 units/dose prandial subcutaneous insulin. Use in combination with basal insulin. Increase the frequency of blood glucose monitoring when switching a patient's insulin regimen. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal.
• Rapid insulin analogues for continuous subcutaneous insulin infusion devices ^r51c176
  • When used in these devices, rapid-acting or ultra-rapid-acting insulin analogues serve as the equivalent of basal insulins
    • Insulin aspart (Novolog insulin aspart products only) ^c177c178
      • Insulin Aspart (Recombinant) Solution for injection; Adults: 40% to 60% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose 5 to 10 minutes before meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
    • Insulin aspart (Fiasp insulin aspart products only)
      • Insulin Aspart (Recombinant) Solution for injection; Adults: 40% to 60% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose at the start of or within 20 minutes after starting meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
    • Insulin glulisine ^c179
      • Insulin Glulisine Solution for injection; Adults: 40% to 60% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose 15 minutes before or within 20 minutes after starting meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
    • Insulin lispro ^c180
      • Insulin Lispro Solution for injection; Adults: 40% to 60% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose 15 minutes before or immediately after meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical total daily insulin dose is 0.4 to 1 unit/kg/day; 0.5 unit/kg/day is a typical starting total daily dose.
• Amylin mimetic ^r56c181
  • Pramlintide is the only noninsulin medication currently FDA approved to treat type 1 diabetes ^c182c183
    • Pramlintide Acetate Solution for injection; Adults: 15 mcg subcutaneously immediately before each major meal. May increase dose by 15 mcg/dose when no clinically significant nausea has occurred for at least 3 days. Max: 60 mcg/dose. If significant nausea persists at 45 or 60 mcg/dose, decrease dose to 30 mcg/dose; if 30 mcg/dose is not tolerated, consider discontinuation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  • Can be used as an adjunct to insulin (multiple daily injections or insulin pump) to reduce wide glycemic excursions and mitigate weight gain ^r57
  • Coformulations of pramlintide with insulin as well as possibility of use in insulin pump systems are currently under investigation ^r1
• Glucagon ^{r3c184c185c186}
  • Indicated for hypoglycemia; administered (subcutaneously, intramuscularly, or intranasally) by medical personnel or trained family member if patient is confused or comatose
  • Parenteral
    • Glucagon Hydrochloride Solution for injection; Adults: 1 mg IM, IV, or subcutaneously. May repeat dose if there has been no response after 15 minutes.
  • Intranasal
    • Glucagon Intranasal powder; Adults: 3 mg (1 actuation) into 1 nostril. May repeat dose if there has been no response after 15 minutes.

Nondrug and supportive care

Glucose monitoring

• Blood glucose meter monitoring is indicated for all patients with type 1 diabetes; introduced at diagnosis ^r42c187c188
  • Point-of-care testing in which a small volume of capillary blood is placed on a test strip and inserted into a glucometer, providing a real-time digital display of blood glucose level
  • Glucose data are used by the patient to make immediate decisions about food, physical activity, and insulin dosing, and data are analyzed by the health care professional to tailor the treatment plan
  • Frequency of blood glucose monitoring is inversely correlated with hemoglobin A1C levels in patients with type 1 diabetes
  • Frequency is variable, depending on individualized patient needs and goals, but usually is 6 to 10 times per day ^r42
    • Before meals and snacks
    • At bedtime
    • Before and after exercise
    • At onset of hypoglycemia and after treatment of hypoglycemia until euglycemia is achieved
    • Before potentially hazardous tasks (eg, driving)
  • Additional testing may be needed owing to clinical condition (eg, illness, pregnancy)
• Continuous glucose monitoring ^c189
  • Testing technology in which a catheter with a glucose oxidase sensor is placed subcutaneously to measure and record interstitial glucose concentrations and provide a real-time display of glucose levels
  • Allows for close monitoring of blood glucose levels with insulin and lifestyle changes and eliminates burdens of frequent glucometer testing
  • Recommended as standard of care for all patients with type 1 diabetes treated with multiple daily injections of insulin or an insulin pump who are capable of using the device safely, either by themselves or with caregiver assistance ^r31r42
  • Most patients use personal continuous glucose monitoring devices, which provide real-time immediate feedback
    • Retrospective continuous glucose monitoring devices are also available for patients to wear for 72 hours as a short-term method to obtain information about glucose trends
  • Combined continuous subcutaneous insulin infusion and glucose monitoring systems deliver insulin and sample/measure interstitial fluid glucose levels and alter basal insulin dose on the basis of this; some automatically provide correction bolus doses
  • Combined continuous subcutaneous insulin infusion and glucose monitoring systems with threshold suspension functionality halt insulin delivery when the sensor glucose value reaches a predetermined lower threshold as a safety measure against an impending hypoglycemic event ^r42
  • Glucometric data analysis by the patient or health care professional is used to modify insulin doses
  • Glycemic outcomes associated with continuous glucose monitoring ^r58
    • Modest improvement in glycemic control (reduces hemoglobin A1C approximately 0.5%) ^r44r59
    • Reduced hypoglycemia, potentially facilitating safer intensification of glucose control ^r44r60
  • Patients using continuous glucose monitoring must still have access to glucometer monitoring in case of technical issues or in circumstances where blood glucose may change rapidly, leading to discrepancies ^r42
  • Inform patients that contact dermatitis can develop with continuous glucose monitoring devices that attach to the skin ^r1

Medical nutrition therapy ^c190

• Individualized nutrition counseling, preferably provided by a registered dietitian, is recommended for all patients
• Patients using multiple daily injections or continuous subcutaneous insulin infusion need instruction on how to adjust insulin doses based on planned carbohydrate, fat, and protein intake ^r40
  • Participation in an intensive flexible insulin therapy education program using the carbohydrate-counting meal-planning approach can result in improved glycemic control capable of reducing hemoglobin A1C levels by 0.3% to 1% ^r61
• Patients using fixed insulin regimens need guidance on consistent carbohydrate intake with respect to timing and amount ^c191
• Regardless of insulin regimen, nutrition therapy assists with devising a meal plan based on metabolic needs, preferences, physical activity, and schedule
• Patients with overweight and obesity should aim to achieve and maintain minimum weight loss of 5% ^r40
• Guidance is available to assist with management of diabetes during fasting for Ramadan and during intercurrent illness ^r62r63c192
• Macronutrient consideration ^r40
  • Ideal distribution of calories among carbohydrates, fats, and proteins for patients with type 1 diabetes to optimize glycemic control is unknown, but there is no universal ideal macronutrient distribution
  • Individualize macronutrient distribution based on the dietary reference intake recommendations for healthy eating, metabolic goals, and total caloric needs
    • Emphasize nonstarchy vegetables, minimize added sugars and refined grains, and avoid highly processed foods ^r64
  • Carbohydrates
    • Monitoring carbohydrate intake, by carbohydrate counting or experience-based estimation, is recommended for patients using intensive insulin regimens to adjust insulin doses ^c193
    • Evidence is insufficient to advise a specific amount of carbohydrate intake; however, reducing overall carbohydrate intake may improve glycemic control ^r64
    • Carbohydrate intake should emphasize high-fiber (at least 14 g per 1000 kcal), nutrient-dense, minimally processed carbohydrate sources
    • Carbohydrates from vegetables, fruits, whole grains, legumes, and dairy products are preferred over other sources that contain added fats, sugars, or sodium
    • Reduce consumption of sugar-sweetened and non-nutritive sweetened beverages and encourage water as an alternative
  • Fats
    • Recommended total fat intake is 20% to 35% of total calories (same as for general population)
    • Emphasis is on consumption of monounsaturated healthy fats and avoidance of saturated and trans fats ^{r65c194c195c196}
  • Proteins
    • Emphasize protein in conjunction with low saturated fat intake (eg, fish, egg whites, beans) ^c197
    • Ideal protein intake
      • For patients without diabetic nephropathy, the evidence is inconclusive regarding the ideal protein intake for optimizing glycemic control or improving cardiovascular risk; therefore, protein intake should approximate the recommended daily allowance for the general population (0.8 g/kg of body weight) ^r66
      • For people with diabetic nephropathy (either micro- or macroalbuminuria), dietary protein restriction is not recommended because it does not alter glycemic measures, cardiovascular risk measures, or the course of GFR decline ^r67r68
        • For patients with non–dialysis-dependent diabetic kidney disease, the recommended daily dietary protein intake is the same as that for the general population (0.8 g/kg of body weight)
        • For patients receiving dialysis, consider higher levels of dietary protein intake
• Micronutrients ^r65
  • Routine supplementation is not recommended because there is no clear evidence of benefit for patients with diabetes who do not have underlying deficiencies
  • A healthful diet can usually provide sufficient micronutrients
• Alcohol ^r40c198
  • Alcohol should be consumed in moderation, if at all (ie, 1 or fewer drinks per day for females, 2 or fewer drinks per day for males)
  • Ingestion of alcohol can increase the risk of delayed hypoglycemia, especially in conjunction with insulin therapy
• Sodium ^r40
  • Recommended total sodium intake is less than 2300 mg/day (same as for general population) ^c199
  • Further sodium reduction is recommended for concurrent hypertension

Physical activity counseling ^c200

• Benefits of physical activity for adults with type 1 diabetes include improvements in physical fitness and muscle strength,^r69 and protection against cardiovascular disease^r70
• Pre-exercise medical clearance is unnecessary for patients before beginning low- or moderate-intensity physical activity not exceeding the demands of brisk walking or everyday living, unless symptoms of cardiovascular disease are present ^r71r72
  • Pre-exercise medical clearance is recommended for patients attempting to begin a vigorous exercise program or increasing from a relatively sedentary level of activity to a more vigorous level of exercise and for patients with symptoms of cardiovascular disease regardless of exercise intensity level ^r71r73
• Provide individualized exercise prescription with the following general guidance: ^r74
  • Goal for optimal health benefit for most patients is 150 minutes of moderate intensity (50%-70% of maximum heart rate) aerobic exercise per week, spread out over at least 3 days per week; more than 2 consecutive days without exercise should be avoided ^r67r68
  • Patients should engage in resistance exercise 2 to 3 sessions per week on nonconsecutive days
  • Older adults also benefit from flexibility and balance training 2 to 3 times per week
  • Interrupt prolonged sitting every 30 minutes with short bouts of physical activity ^r72
• Strategies to prevent exercise-induced hypoglycemia include: ^r74
  • Aiming for blood glucose level of 100 mg/dL or higher at start of exercise ^c201
  • Adjusting insulin or carbohydrate intake in 1 of the following ways:
    • Reducing the prandial insulin dose for the meal or snack preceding exercise
    • Reducing basal insulin rates (in continuous subcutaneous insulin infusion device)
    • Consuming additional carbohydrates during prolonged physical activity
  • Increasing frequency of self-monitoring of blood glucose to detect hypoglycemia during and after activity

Smoking cessation ^c202d3

• Patients with diabetes who also smoke or have been exposed to secondhand tobacco smoke are at greater risk for microvascular complications of diabetes, cardiovascular disease, and sudden death
• Patients should avoid cigarettes and other tobacco products, including e-cigarettes
• Offer patients counseling, pharmacologic measures, or both to assist with cessation

Diabetes self-management education and support ^c203c204c205

• Ongoing processes of facilitating the knowledge, skill, and ability necessary for the patient to participate in diabetes self-care
• Particularly critical at diagnosis when not meeting targets, when therapeutic or life changes occur, or when complications develop ^r1
• Education and support can be provided through 1-to-1 counseling and education, informal ongoing learning resources, and structured education programs ^r1
• Mandatory educational topics consist of instruction on how to recognize and treat hypoglycemia, sick day management, blood glucose testing, and carbohydrate counting
• Referral to digital coaching and digital self-management interventions can be effective
• For intensive insulin therapy, instruct patients on how to match prandial insulin dose to carbohydrate intake, preprandial blood glucose level, and anticipated activity
• Participation in an intensive insulin therapy education program can result in improved glycemic control when the carbohydrate-counting meal-planning approach is used

Immunizations

• Provide routinely recommended vaccinations as indicated by age ^r75
• American Diabetes Association supports following the recommendations of CDC and Advisory Committee on Immunization Practices ^r75
  • The following immunizations are highly recommended for adult patients with diabetes:
    • COVID-19 vaccine series according to CDC recommendations ^r76
    • Annual influenza vaccination with inactive or recombinant vaccine; live attenuated influenza vaccine should not be given ^c206
    • Pneumococcal vaccine
      • PPSV23 (pneumococcal vaccine polyvalent) is recommended with 1 dose at ages 19 to 64 years and an additional dose at 65 years or older ^c207c208
      • PCV13 (pneumococcal conjugate vaccine) is no longer routinely recommended at age 65 years and older because of declining incidence of pneumonia due to those strains
    • Hepatitis B vaccine (2- or 3-dose series) for patients aged younger than 60 years; consider for those aged 60 years and older based on individual patient risk ^c209c210
    • HPV vaccine for adults aged 26 years and younger; consider for adults aged 27 through 45 years ^c211
    • Zoster vaccine for adults aged 50 years and older (2-dose Shingrix, even if previously vaccinated) ^c212
    • Tetanus, diphtheria, pertussis booster every 10 years ^c213
    • Respiratory syncytial virus vaccine in adults aged 60 years and older

Comorbidities

• Hypertension ^{c220c221c222d4}
  • Treatment of hypertension reduces cardiovascular events and microvascular complications; however, a specific blood pressure goal for patients with diabetes has been uncertain; suggested targets vary by professional society ^r29r34
  • American Diabetes Association, American College of Cardiology/American Heart Association, and others generally recommend a target blood pressure lower than 130/80 mm Hg for patients with diabetes
    • Individualize treatment but do not target to less than 120/80 mm Hg, as this is associated with adverse events ^r33
  • Association of British Clinical Diabetologists and Renal Association UK recommend blood pressure target of lower than 140/90 mm Hg for patients without microalbuminuria and lower than 130/80 mm Hg for those with microalbuminuria (urine albumin to creatinine ratio greater than 3 mg/mmol) ^r100
    • Target blood pressure of 120/80 mm Hg is recommended for adults younger than 30 years, and 140/90 mm Hg, for those older than 65 years
    • It may be appropriate to target a diastolic blood pressure of lower than 80 mm Hg in selected patients aged 30 to 65 years with higher lifetime risk due to earlier age at onset of type 1 diabetes
    • A higher target of 150/90 mm Hg may be appropriate for frail adults aged older than 75 years
  • Treatment
    • Advise all patients with blood pressure higher than 120/80 mm Hg to undertake lifestyle changes for reducing blood pressure, such as: ^r33
      • Weight loss for those with overweight or obesity ^{c223c224c225c226}
      • DASH diet (Dietary Approaches to Stop Hypertension) or variations thereof; such diets include reducing sodium intake and increasing potassium intake ^c227
      • Moderation of alcohol intake ^{c228c229c230c231}
      • Increased physical activity
    • Start pharmacotherapy in addition to lifestyle changes for patients with blood pressure higher than 130/80 mm Hg ^r33
      • For patients with diabetes and hypertension but without albuminuria for whom cardiovascular disease prevention is the primary goal, any of the following drug classes may be considered: ACE inhibitor, angiotensin receptor blocker, thiazide diuretic, or dihydropyridine calcium channel blocker
      • For patients with hypertension, diabetes, and early-stage heart failure, treatment with a thiazide-type diuretic or an ACE inhibitor is more effective than treatment with a calcium channel blocker in preventing progression to symptomatic heart failure ^r101
      • For patients with diabetes, albuminuria, and hypertension, start either an ACE inhibitor or an angiotensin receptor blocker, but not both; titrate to maximum tolerated dose ^r100
      • Multidrug therapy (ie, thiazide diuretic and ACE inhibitor/angiotensin receptor blocker at maximal doses) is often required to achieve blood pressure target ^r33
        • If blood pressure is 150/90 mm Hg or higher, start pharmacotherapy with 2 agents in addition to lifestyle modifications
• Dyslipidemia ^c232d5
  • There is a lack of consensus among medical professional organizations regarding the use of numeric lipid goals
    • American Diabetes Association^r33 and American Heart Association^r102 do not specify a numeric LDL-C goal
    • American Association of Clinical Endocrinologists recommends an LDL-C goal less than 100 mg/dL for patients with diabetes and no other atherosclerotic cardiovascular disease or major risk factors (high risk), less than 70 mg/dL for patients with 2 or more major risk factors for atherosclerotic cardiovascular disease (very high risk), and less than 55 mg/dL for patients with established cardiovascular disease (extreme risk) ^r29r37
  • Treatment
    • Lifestyle modifications for dyslipidemia are recommended for all patients with diabetes, regardless of whether pharmacotherapy is used, including:
      • Medical nutrition therapy (low saturated fat, low trans fat, low cholesterol, increased omega-3 fatty acids, increased fiber)
      • Weight loss, if necessary
      • Increased physical activity
      • Smoking cessation
    • Intensify lifestyle modifications and optimize glycemic control for patients with triglyceride levels 150 mg/dL or higher and/or HDL-C levels lower than 40 mg/dL (males) or 50 mg/dL (females) ^r33
    • Pharmacotherapy
      • Statin therapy is first line drug therapy for patients with dyslipidemia; because adults with type 1 diabetes are at substantial risk for coronary artery disease, moderate- or high-intensity statin therapy is indicated ^r102
        • Primary prevention ^r33
          • Moderate-intensity statin therapy is indicated for adults aged 40 to 75 years with diabetes mellitus without known atherosclerotic cardiovascular disease ^r103
          • High-intensity statin therapy to reduce the LDL-C by 50% of baseline or greater and to target an LDL-C goal of less than 70 mg/dL is indicated for adults aged 40 to 75 years who are at higher risk (1 or more atherosclerotic cardiovascular disease risk factors)
          • Addition of ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor to maximum tolerated statin therapy is reasonable for these patients, especially those with multiple atherosclerotic cardiovascular disease risk factors and an LDL-C of 70 mg/dL or greater
          • Initiation of statin therapy may be reasonable for adults aged 20 to 39 years with diabetes and additional atherosclerotic cardiovascular disease risk factors or long-standing diabetes (ie, 20 or more years)^r103r33
          • Initiation of moderate-intensity statin therapy is reasonable for adults older than 75 years with diabetes based on individual risks and benefits; it is reasonable for those who are already on statin therapy to continue beyond age 75 years ^r36r104
        • Secondary prevention
          • High-intensity statin therapy to target an LDL-C reduction of 50% or more from baseline with a goal of less than 55 mg/dL is recommended for patients with diabetes and atherosclerotic cardiovascular disease
          • Addition of ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor is recommended if goals are not achieved on maximum tolerated statin therapy
      • Patients who are intolerant of statin therapy who require cholesterol-lowering therapy can be treated with bempedoic acid or PCSK9 inhibitor therapy with monoclonal antibody treatment or inclisiran siRNA ^r33
• Chronic kidney disease ^c233d6
  • Chronic kidney disease in patients with diabetes may occur as a complication of diabetes itself or have other causes
  • Patients with diabetes and kidney disease have substantially elevated mortality rates, which are primarily caused by cardiovascular disease ^r105
  • Treatment with an ACE inhibitor or an angiotensin receptor blocker is recommended for patients with albuminuria (urine albumin–creatinine ratio 30 mg/g creatinine or higher) and/or eGFR less than 60 mL/minute/1.73 m² to prevent the progression of kidney disease and reduce cardiovascular events ^r106
  • As GFR declines, insulin dose adjustments are required because of reduced renal insulin clearance
  • Risks of hypoglycemia and hypoglycemia unawareness are greater for patients with chronic kidney disease; hemoglobin A1C targets may need to be relaxed for those with diabetes and kidney disease
• Coronary artery disease ^r33c234
  • Use American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease risk calculator to assess 10-year atherosclerotic cardiovascular disease risk and to guide therapy ^r33r102
  • Promote lifestyle modifications to reduce cardiovascular risk, including: ^r107r108
    • Smoking cessation
    • Maintaining body weight within reference range
    • Regular physical activity
    • Consumption of a balanced diet replete with fruits and vegetables, low in saturated fat and sodium, and enriched with whole grains
  • Maintaining optimal glycemic control may prevent cardiovascular events and reduces risk of recurrent events
  • Treat risk factors such as hypertension and dyslipidemia
  • Antiplatelet therapy with low-dose aspirin is recommended for secondary prevention in patients with a history of cardiovascular disease and may be considered for primary prevention for patients at increased risk for cardiovascular events; use clopidogrel in event of aspirin allergy ^r33
    • Also consider ACE inhibitor or angiotensin receptor blocker for patients with known cardiovascular disease
  • Routine screening for coronary artery disease is not recommended for asymptomatic patients
  • Obtain resting ECG for patients with hypertension or suspected cardiovascular disease; exercise ECG can also be used as an initial screening test
  • Exercise ECG may be considered for cardiovascular risk assessment for patients with cardiac symptoms or an abnormal resting ECG
  • Coronary artery calcium measurement may be considered for patients aged 40 years or older
• Psychosocial disorders
  • Diabetes distress (also called diabetes-related distress) is the experience of being overly burdened by the ongoing behavioral demands of managing the disease (eg, medication dosing, frequency, and titration; monitoring blood glucose level, food intake, and eating patterns; physical activity) ^r109
    • Refer such patients to diabetes education or to a mental health specialist if areas of diabetes care are adversely impacted
  • Depression ^c235
    • Highly prevalent in patients with diabetes (approximately 21% of patients diagnosed with type 1 diabetes are affected by depression) ^r110
    • Associated with increased risk of myocardial infarction and mortality
    • Depression and diabetes distress are associated with poor self-care, nonadherence to treatment plan, and poor glycemic control
    • Screen patients annually and refer to a mental health specialist for assessment and treatment
  • Anxiety ^r110c236
    • Anxieties unique to diabetes include fear of complications and hypoglycemia
    • Screen for anxiety about insulin injections or infusion, complications, and hypoglycemia when it appears to interfere with self-management behaviors ^r40
    • Refer to a mental health specialist patients who report fear, dread, or irrational thoughts or show anxiety symptoms such as avoidance behaviors, excessive repetitive behaviors, or social withdrawal
  • Disordered eating ^r40c237
    • Omitting insulin to promote glycosuria to lose weight is the most commonly reported disordered eating behavior
    • Screen for disordered eating when hyperglycemia and weight loss are unexplained
      • One validated screening tool is the Diabetes Eating Problems Survey,^r111 which includes questions regarding insulin adjustment specifically for the purposes of weight reduction

Special populations

• Older adults
  • Standard glycemic targets are appropriate for healthy older adults who are functionally and cognitively intact with a significant life expectancy ^r112
    • Hemoglobin A1C: below 7.0% to 7.5%
    • Bedtime blood glucose level: 80 to 180 mg/dL
    • Fasting blood glucose level: 80 to 130 mg/dL
  • Less stringent glycemic targets are appropriate for older adults in intermediate health with multiple medical comorbidities or mild to moderate functional or cognitive impairments ^r113
    • Hemoglobin A1C: below 8.0%
    • Bedtime blood glucose level: 100 to 180 mg/dL
    • Fasting blood glucose level: 90 to 150 mg/dL
  • For older adults with very complex/poor health (end-stage chronic conditions or severe functional or cognitive impairments), in long-term care, or at the end of life, focus should be avoiding hypoglycemia and symptomatic hyperglycemia rather than specific A1C targets ^r114
  • Avoid hypoglycemic events in older adults with diabetes, as these increase risk of cognitive decline ^r113
    • Routinely ask patients and caregivers about hypoglycemia and hypoglycemia unawareness
    • Simplifying insulin regimens (ie, with use of premixed insulins) may be appropriate to avoid errors and hypoglycemic events
    • Consider continuous glucose monitoring to minimize hypoglycemia
  • Older adults continue to require some form of basal insulin even if they are not eating meals ^r113
  • Older adults commonly need extra assistance with monitoring and insulin injections because deficits in self-care capacity, mobility, and autonomy can adversely impact glycemic control ^r113
  • Encourage adequate nutrition, protein intake, and exercise, including aerobic activity, weight-bearing exercise, and/or resistance training
  • Individualize screening and treatment of other comorbidities and complications for older patients
• Pregnant patients
  • Pregestational type 1 diabetes affects 0.1% to 0.2% of all pregnancies ^r3
  • Manage patients with preexisting diabetes who are planning a pregnancy or who become pregnant in a multidisciplinary care setting, if available
  • Offer preconception counseling to all patients with diabetes and reproductive potential as part of routine care ^r35
    • Include:
      • Comprehensive nutrition assessment and counseling
      • Lifestyle recommendations
      • Comprehensive diabetes self-management education, including glycemic targets
      • Counseling on diabetes in pregnancy
      • Supplementation with prenatal vitamins with folic acid
      • Comprehensive medical evaluation
      • Appropriate screening for diabetes and pregnancy-related complications and comorbidities, genetic diseases, and infectious diseases
        • Refer for baseline ophthalmologic examination in first trimester and monitor every trimester and for 1 year post partum as indicated by degree of retinopathy
      • Immunizations
      • Contraceptive planning
  • Some medications commonly used for both diabetes and its complications are teratogenic and should be discontinued before conception or during pregnancy, including: ^r35
    • Statins
    • ACE inhibitors
    • Angiotensin receptor blockers
  • Diabetes is associated with increased risk of preeclampsia; prescribe low-dose aspirin during second and third trimesters to reduce risk ^r35
    • Doses of 100 to 150 mg/day are recommended; however, a dose of 162 mg/day may be acceptable (ie, 2 of the 81-mg tablets, which is the low-dose aspirin available in the United States)
    • Aspirin doses of less than 100 mg are not effective in reducing risk of preeclampsia
  • Glycemic targets for pregnant patients with type 1 diabetes
    • American Association of Clinical Endocrinologists targets ^r29
      • Hemoglobin A1C: lower than 6% if it can be accomplished without significant hypoglycemia
      • Preprandial, bedtime, and overnight glucose levels: 60 to 95 mg/dL
      • 1-hour postprandial glucose: 110 and 140 mg/dL
      • 2-hour postprandial blood glucose level: 100 to 120 mg/dL
    • American Diabetes Association targets ^r35
      • Hemoglobin A1C: 6% or lower
      • Fasting blood glucose level: lower than 95 mg/dL
      • 1-hour postprandial blood glucose level lower than 140 mg/dL
      • 2-hour postprandial blood glucose level lower than 120 mg/dL
  • Pregnancy changes maternal insulin sensitivity, which results in altered insulin requirements ^r35
    • First-trimester insulin requirements are typically lower, whereas second- and third-trimester requirements are typically higher, owing to increasing insulin resistance
    • Risk of hypoglycemia is increased in the first trimester, and hypoglycemia awareness may be reduced
    • Pregnancy is a ketogenic state, and DKA can occur at lower blood glucose levels than in nonpregnant patients
    • Either multiple daily injections or insulin pump technology can be used
    • Preprandial and postprandial self-monitoring of blood glucose is recommended
    • When used as an adjunct to preprandial and postprandial blood glucose monitoring, continuous glucose monitoring can help achieve glycemic targets and reduce macrosomia and neonatal hypoglycemia
• Hospitalized patients ^r32
  • Obtain hemoglobin A1C for all admitted patients if no previous readings in the past 3 months
  • Exogenous insulin is required regardless of nutritional intake and should be administered using validated protocols that allow for adjustments based on glycemic fluctuations
    • Consult with specialized diabetes or glucose management team whenever available
  • Maintain a glucose level between 140 and 180 mg/dL in most critically and noncritically ill patients
    • More stringent glucose targets between 110 and 140 mg/dL may be appropriate for select patients (eg, those with previous cardiac surgery, stroke, or acute ischemic cardiac events), provided that the target can be achieved without significant hypoglycemia
    • A target range of 100 to 180 mg/dL may be acceptable in noncritically ill patients
    • Glucose levels higher than 250 mg/dL may be acceptable in terminally ill patients with a short life expectancy
  • Avoid iatrogenic hypoglycemia (less than 70 mg/dL) ^r32
    • Inpatient hypoglycemia is associated with higher complication rates and greater mortality
    • Identify potential triggers of hypoglycemia and manage preemptively when possible
      • Triggers include emesis, reduced oral intake, new NPO status, reduction in glucocorticoid doses, interruption or change in enteral/parenteral feedings, change in infusion rate of IV solutions that contain dextrose, or inappropriate timing of short-acting insulin in relation to meals
    • Hemoglobin A1C level at admission can predict risk for in-hospital hypoglycemia for older patients; levels lower than 7% are associated with highest rate of hypoglycemic episodes ^r115
    • Continuous glucose monitoring is recommended for inpatients at high risk for hypoglycemia ^r116r117
      • Use in combination with periodic point-of-care blood glucose testing to validate the accuracy of continuous glucose monitoring
  • Patients in non-ICU settings ^r32
    • Clinically stable patients with good nutritional intake are preferably given scheduled multiple daily subcutaneous injections of insulin with basal, prandial, and correctional components
    • A basal plus bolus correction insulin regimen is the preferred treatment for noncritically ill patients with poor oral intake or those who have NPO status
    • Home insulin regimen can be continued, but most often, the usual insulin schedule must be modified because of altered insulin needs due to the effects of illness, any alterations in renal function, and change in nutritional intake
    • Self-management of insulin dosing is appropriate for clinically stable, alert patients who successfully use continuous subcutaneous insulin infusion devices at home ^r118
    • Prolonged use of sliding scale insulin regimens is inadvisable
    • Daily adjustments in insulin dosing are made based on blood glucose patterns, as needed
      • Adjust basal insulin dose according to fasting glucose levels (titrate up if fasting level is higher than 140 mg/dL)
      • Adjust nutritional (prandial) insulin based on the glucose level before each meal
  • Patients in ICU setting ^r32
    • Administer IV insulin infusions using validated written or computerized protocols (where available) that allow for predefined adjustments in the insulin infusion rate based on glycemic fluctuations and insulin dose
  • Perioperative patients
    • Target glucose range for the perioperative period is 100 to 180 mg/dL^r32; attempts to achieve tighter perioperative glucose control lead to unacceptable rates of hypoglycemia^r119
    • Measure blood glucose level every 4 to 6 hours while NPO and provide additional doses of short- or rapid-acting insulin as needed to limit hyperglycemia
  • Patients receiving enteral/parenteral feedings ^r32
    • Provide basal, prandial, and correctional insulin; basal insulin must continue even if feedings are held or discontinued
    • Dosing can be determined based on preadmission basal insulin dose
    • NPH (neutral protamine Hagedorn)–based or basal bolus regimens are recommended for patients receiving enteral nutrition ^r120
    • Tube feedings: use 1 unit of insulin for 10 to 15 g of carbohydrate
    • Enteral bolus feeding: give 1 unit of regular or immediate-acting insulin per 10 to 15 g of carbohydrate before each feeding
    • Continuous peripheral or central parenteral delivery: add 1 unit of regular insulin per 10 g of dextrose; insulin may be added to the solution and administered parenterally
    • Administer correctional doses, based on point-of-care blood glucose measurements, every 6 hours in all cases using regular insulin or an immediate-acting insulin
    • Continuous enteral or parenteral feeding results in a constant postprandial state and attempting to reduce blood glucose levels to lower than 140 mg/dL will greatly increase the risk of hypoglycemia

At-risk populations

• First-degree relatives of patients with type 1 diabetes have 5- to 10-fold elevated risk of developing diabetes when compared with the general population (approximately 5% cumulatively) ^r12c262

Screening tests

• Immune-mediated diabetes accounts for most cases of type 1 diabetes and is characterized by detectable autoimmune markers including islet cell autoantibodies and autoantibodies to glutamic acid decarboxylase, insulin, islet antigen-2 and islet antigen-2β, and zinc transporter 8
  • Stage 1 of type 1 diabetes is defined by the presence of 2 or more of these autoimmune markers and is presymptomatic
• Screening can be considered for first-degree relatives of patients with type 1 diabetes and may identify those who are at risk for developing the disease ^r142c263
  • Screening, coupled with education about disease symptoms and close observation, may enable earlier identification of type 1 diabetes onset ^r142
    • In addition, clinical studies are evaluating various methods of preventing type 1 diabetes in patients with islet autoantibodies
  • Widespread screening of low-risk asymptomatic individuals is not recommended but may be available in the context of clinical research trials or specific screening programs that are available in Europe and the United States ^r5
• Presymptomatic type 1 diabetes can be identified by testing for autoantibodies to insulin, glutamic acid decarboxylase, islet antigen 2, or zinc transporter 8
  • Presence of multiple islet autoantibodies indicates risk for subsequently developing clinical diabetes; testing for dysglycemia may aid in evaluating near-term risk ^r5
• In patients in whom multiple islet autoantibodies are identified: ^r143
  • Monitor for disease progression with hemoglobin A1C approximately every 6 months and 75-g oral glucose tolerance test annually; can individualize frequency of monitoring
  • Consider referral to a specialized center for evaluation and/or consideration of a clinical trial or therapy aimed at delaying development of clinical diabetes