Hyperglycemia results from abnormal carbohydrate metabolism secondary to insulin deficiency, peripheral resistance to insulin action, or a combination of both. Hyperglycemia that exceeds the normal glucose range but does not meet the diagnostic criteria for diabetes mellitus is defined as prediabetes, which increases the risk for the development of diabetes.
Screening for type 2 diabetes mellitus in the general adult population is indicated because: (1) type 2 diabetes is often preceded by a prolonged asymptomatic hyperglycemic period in which microvascular and macrovascular damage may occur; (2) lifestyle interventions and medications have demonstrated the ability to delay or prevent onset of type 2 diabetes in persons with prediabetes, and (3) early intensive glucose control and management of hyperlipidemia and hypertension may prevent or reduce the progression of microvascular and macrovascular cardiovascular disease (CVD).
The American Diabetes Association (ADA) and the U.S. Preventive Services Task Force (USPSTF) include age, BMI, race/ethnicity, and other risk factors as part of their criteria for screening recommendations for type 2 diabetes (Table 1). These risk factors are associated with a high risk of incident diabetes.
Screening for type 1 diabetes is not recommended. Antibody screening in a high-risk person with a relative with type 1 diabetes should occur within the context of a clinical trial (www.diabetestrialnet.org).
Diabetes mellitus can be diagnosed by an abnormal result in one of three tests: hemoglobin A1c, fasting plasma glucose (FPG), or 2-hour plasma glucose (2-hr PG) after a 75-gram carbohydrate challenge during an oral glucose tolerance test (OGTT) (Table 2). An abnormal result in asymptomatic persons should be confirmed with repeat testing and/or two abnormal test results from the same sample (that is, fasting plasma glucose and hemoglobin A1c from same sample). A single random plasma glucose value greater than or equal to 200 mg/dL (11.1 mmol/L) in the setting of symptomatic hyperglycemia is diagnostic of diabetes.
The results of testing for diabetes differ depending on which test is done, FPG, 2-hr PG, or hemoglobin A1c. The 2-hr PG test has a higher sensitivity for the diagnosis of diabetes compared with FPG or hemoglobin A1c. The advantages and disadvantages of the tests must be considered when determining the best screening option for a patient (Table 3).
The underlying insulin abnormality, whether absolute or relative insulin deficiency, peripheral insulin resistance, or an overlap of both abnormalities, is important for classifying the type of diabetes mellitus and has implications for treatment options (Table 4).
Type 1 diabetes mellitus is characterized by a state of insulin deficiency secondary to the destruction of the insulin-producing beta cells in the pancreas. The destruction may be secondary to autoimmunity, idiopathic, or acquired.
Immune-mediated type 1 diabetes mellitus (type 1A) is the underlying cause in 5% to 10% of persons newly diagnosed with diabetes. The mechanism of the beta cell destruction is multifactorial and likely due to environmental factors in persons with genetic susceptibilities. Specific human leukocyte antigen (HLA) alleles demonstrate a strong association with immune-mediated type 1 diabetes. At diagnosis, one or more autoantibodies directed at the following targets are typically present: glutamic acid decarboxylase (GAD65), tyrosine phosphatases IA-2 and IA-2β, islet cells, insulin, and zinc transporter (Zn T-8). Owing to highly automated available assays, GAD65 and IA-2 autoantibodies are recommended for initial screening. GAD65 autoantibodies have a high prevalence (70%) at the time of diagnosis and may remain detectable for years.
Immune-mediated type 1 diabetes has a variable presentation that ranges from moderate hyperglycemia to life-threatening diabetic ketoacidosis (DKA). At the time of diagnosis, approximately 90% of the functioning beta cells have been destroyed. Initiating insulin at the time of diagnosis may decrease toxicity associated with extreme hyperglycemia allowing the beta cell to regain some ability to produce insulin. Although this “honeymoon period” can last several weeks to years, insulin use should be continued to decrease stress on the remaining functioning beta cells and prolong their lifespan. Insulin deficiency requires life-long use of insulin therapy.
Patients with immune-mediated type 1 diabetes also have an increased risk for other autoimmune disorders, including celiac disease, thyroid disorders, vitiligo, and autoimmune primary adrenal gland failure.
Late autoimmune diabetes in adults (LADA) is characterized by autoantibody development leading to beta cell destruction and ultimately insulin deficiency. Individuals with LADA are typically not insulin-dependent initially and are frequently misclassified as having type 2 diabetes. There is a slow progression toward insulin dependence over months to years after diagnosis in the setting of positive autoantibodies.
Idiopathic type 1 diabetes (type 1B) is characterized by variable insulin deficiency due to beta cell destruction without the presence of autoantibodies. Individuals with idiopathic type 1 diabetes may develop episodic DKA. There is typically a strong family history of type 2 diabetes in persons with idiopathic diabetes, and it is more common in Asian and African American patients, particularly with sub-Saharan African ancestry.
Beta cell destruction may occur from diseases affecting the pancreas or from the effect of drugs or infections (see Table 4). This may result in impaired insulin production or secretion with the subsequent development of type 1 diabetes.
The ineffective use of insulin by the peripheral cells to utilize glucose and fatty acids characterizes insulin resistance. Blood glucose levels remain in the normal range as long as the beta cells can increase insulin production. Hyperglycemia results from a relative insulin deficiency when the pancreas can no longer produce enough insulin. Obesity increases the risk for insulin resistance, which is also a component of the metabolic syndrome and predisposes to the development of type 2 diabetes.
Metabolic syndrome comprises a constellation of risk factors for development of type 2 diabetes and CVD, which includes abdominal obesity, impaired glucose metabolism, hyperlipidemia, and hypertension. Multiple organizations define metabolic syndrome differently (Table 5). The Endocrine Society recommends screening patients with risk factors for metabolic syndrome every 3 years to evaluate fasting plasma glucose, fasting lipid panel, blood pressure, and waist circumference. Calculation of the 10-year cardiovascular risk, using either the Framingham Risk Score or the American College of Cardiology (ACC)/American Heart Association (AHA) risk calculator, is recommended for patients with metabolic syndrome.
Most cases of diabetes (90% to 95%) meet the criteria for type 2 diabetes. Hyperglycemia accompanied by insulin resistance and/or relative insulin deficiency defines type 2 diabetes. The extent of beta cell dysfunction determines the degree of hyperglycemia, which may worsen over time with progressive decrease in insulin production. The pathogenesis of type 2 diabetes is multifactorial with influence from both genetic and environmental factors. Type 2 diabetes is commonly present in first-degree relatives of both individuals at high risk for or diagnosed with type 2 diabetes. There is also an increased risk in several ethnicities including: Hispanic/Latino, African American, American Indian, Asian American. Additional risk factors for diabetes risk include increasing age and decreased physical activity.
Type 2 diabetes classically presents in adults, although there is an increased incidence among children and adolescents as the rate of overweight/obesity increases in these populations. Type 2 diabetes has a gradual onset with most affected persons remaining asymptomatic for several years. At the time of diagnosis, these patients may already have microvascular and/or macrovascular CVD. Although the beta cell does not produce sufficient insulin to overcome insulin resistance and maintain euglycemia, there is adequate insulin production to suppress lipolysis and prevent DKA in type 2 diabetes. DKA in type 2 diabetes may rarely occur in the setting of extreme stress or illness.
The development of type 2 diabetes in high-risk individuals can be delayed or prevented with modifications to lifestyle (diet, exercise), pharmacologic intervention, or metabolic surgery. The goal of these interventions is weight loss and the reduction of insulin resistance. In the Diabetes Prevention Program (DPP), lifestyle modifications reduced the incidence of type 2 diabetes in persons with prediabetes by 58%. Thus, the ADA recommends the DPP goals of 7% weight loss over 6 months and at least 150 min/week of moderate-intensity exercise to reduce the risk of diabetes development. A diet rich in monounsaturated fat, whole grains, vegetables, whole fruits, and nuts is recommended.
Several pharmacologic interventions have demonstrated efficacy in diabetes risk reduction (Table 6). Safety data, cost, and long-term durability of each intervention must be considered for each individual patient. Metformin reduced the incidence of diabetes by 31% compared with placebo in the DPP. In addition, metformin has long-term safety data. The ADA and the American Association of Clinical Endocrinologists (AACE) recommend metformin initially for diabetes risk prevention in individuals with prediabetes, particularly in those with increasing hemoglobin A1c values despite lifestyle modifications who are younger than 60 years of age, are obese, or have a history of gestational diabetes.
The term “ketosis-prone diabetes” (KPD) incorporates several glycemic syndromes also known as ketosis-prone type 2 diabetes, “Flatbush diabetes,” type 1B diabetes, or atypical diabetes. These syndromes present with episodic DKA resulting from insulin deficiency but have variable periods of insulin dependence and independence.
For individuals with KPD, insulin therapy for the treatment of DKA is required until DKA has resolved and the beta cells are no longer impaired by glucose toxicity, if possible, and can produce sufficient amounts of insulin to suppress lipolysis. Given the variable clinical course exhibited with KPD, uncertainty prevails regarding the need for short-term and long-term insulin treatment regimens. Four classification systems have therefore been developed to provide predictive guidance on the length of insulin therapy. A longitudinal study demonstrated greater accuracy in predicting beta-cell reserve and insulin dependence 12 months after the initial episode of DKA with the Aβ system when compared to the other classification systems, with a sensitivity of 99% and specificity of 96%. With the Aβ system, autoantibody status (A) and beta-cell function (β) are key determinants affecting whether an individual will require long-term insulin. Longitudinal data from KPD cohorts indicate individuals without beta-cell reserve regardless of the antibody status (A+β− and A−β−) are more likely to have poor glycemic control and develop long-term insulin dependence after the development of DKA compared to individuals with preserved beta-cell function.
An increase in insulin resistance during the second and third trimester of pregnancy is a normal physiologic phenomenon driven by placental hormones. With impaired beta-cell function, insulin production will be inadequate to overcome the insulin resistance with subsequent development of hyperglycemia.
Gestational diabetes is defined as hyperglycemia during the second or third trimester in women without a prepregnancy diagnosis of type 1 or type 2 diabetes. Risk factors include age over 25 years, overweight/obesity, family history of type 2 diabetes, and high-risk racial/ethnic groups (Blacks, Hispanic/Latino Americans, South or East Asians, Pacific Islanders, and American Indians). Adverse maternal and neonatal outcomes related to gestational diabetes increase with worsening hyperglycemia. Complications include macrosomia, labor and delivery complications, preeclampsia, fetal defects, neonatal hypoglycemia, spontaneous abortion, and intrauterine fetal demise.
Given the increased prevalence of undiagnosed type 2 diabetes in the general population, the ADA recommends standard screening for any pregnant woman with diabetes risk factors at the initial prenatal visit. Women with hyperglycemia identified during the first trimester are classified as having type 2 diabetes instead of gestational diabetes. For all other pregnant women without a prior diabetes diagnosis, gestational diabetes screening should occur between gestation weeks 24 and 28. The screening method recommended varies among expert groups. The “one-step” OGTT involves blood glucose measurements at baseline (fasting) and 1 and 2 hours after a 75-g oral glucose load. One abnormal value above the cut-point is diagnostic of gestational diabetes. The “two-step” OGTT involves an initial blood glucose measurement 1 hour after a 50-g OGTT. If the blood glucose is abnormal, the second step is initiated. Glucose is measured at baseline (fasting) and 1, 2, and 3 hours after a 100-g oral glucose load. Two abnormal blood glucose values after the 100-g load are diagnostic for gestational diabetes.
Most women with gestational diabetes have glucose normalization after pregnancy, but they are at an increased risk for development of recurrent gestational diabetes and type 2 diabetes. The ADA recommends a 75-g OGTT 4 to 12 weeks postpartum to confirm resolution of hyperglycemia. If the initial postpartum screen is normal, life-long screening should continue every 1 to 3 years with a 75-g OGTT, hemoglobin A1c, or fasting plasma glucose.
Genetic defects impairing either insulin secretion or insulin action are rare forms of diabetes mellitus (see Table 4). Maturity-onset diabetes of the young (MODY) is characterized as an autosomal dominant monogenetic defect on different chromosomal loci resulting in six subtypes defined by the specific gene affected. Although insulin action remains normal in MODY, glucose sensing and insulin secretion are altered. Autoantibodies are absent. Individuals with MODY present with a clinical course that is frequently atypical of type 1 or type 2 diabetes. The onset of symptoms occurs before 25 years of age, and there is typically a strong family history of atypical diabetes in nonobese patients.
Excess hormone production associated with several endocrinopathies can also impair insulin secretion or insulin action-inducing hyperglycemia (see Table 4).
Effective diabetes management is best achieved through a patient-centered approach with patients and their caregivers developing individualized goals and treatment plans compatible with patient preferences, lifestyle requirements, comorbidities, and safety. Management should also incorporate patient education, self-monitoring of blood glucose, lifestyle modifications, and pharmacologic therapies.
Diabetes self-management education and support (DSMES) provides the knowledge and skills for patients to perform diabetes-related self-care and develop effective problem-solving strategies. The ADA recommends consideration of referral for DSMES at several critical periods in care: at time of diagnosis, annually to reassess needs during care transitions, and when self-management skills are impacted by health status changes. DSMES has been shown to improve outcomes, such as hemoglobin A1c and quality of life, and also reduce costs, as patients are able to reduce utilization of acute care and inpatient facilities for diabetes management.
Self-monitoring of blood glucose (SMBG) is recommended for patients on intensive insulin regimens (multiple-dose insulin regimens or insulin pump therapy). Specific regimens for SMBG monitoring are individualized and may include prior to meals, at bedtime, before and after exercise, and before operation of machinery. SMBG may be used to detect and correct hypoglycemia. SMBG may be informative when preprandial blood glucose values are at the target goal, but the hemoglobin A1c is above goal. Measuring postprandial blood glucose levels may identify undetected hyperglycemia.
In motivated patients on nonintensive insulin regimens, SMBG can be considered; however, the optimal testing frequency has not been determined in these patients. In patients with type 2 diabetes not using insulin, routine glucose monitoring may be of limited additional clinical benefit.
Hemoglobin A1c generally correlates with average 3-month blood glucose level in patients without hemoglobinopathies or increased erythrocyte turnover; therefore, treatment efficacy can be measured by combining SMBG and hemoglobin A1c data (Table 7 and Table 8).
Another option is a continuous glucose monitoring system (CGMS), which can alert the user to retrospective and current trends of hypoglycemia and hyperglycemia. In addition, the FDA has approved two CGMS devices for real-time insulin dosing as well as monitoring. The goals in using a CGMS are to improve diabetes care by lowering hemoglobin A1c and avoiding hypoglycemia, which is critical for those with hypoglycemic unawareness. The ADA endorses CGMS use in adults (≥18 years of age) with type 1 diabetes who are not meeting glycemic targets. The Endocrine Society endorses the use of CGMS in patients with type 1 diabetes with an elevated hemoglobin A1c or an A1c level at goal when worn daily, since data demonstrate improved glycemic control with longer duration of CGMS use. In the future, CGMS may be indicated for patients with type 2 diabetes on intensive insulin regimens as well.
Persons with diabetes should receive age-appropriate vaccinations as recommended by the Advisory Committee on Immunization Practices guidelines. Additionally, patients with diabetes should receive influenza vaccinations annually, the pneumococcal polysaccharide vaccine (PPVS23), and the series of hepatitis B vaccinations. The CDC's recommended immunization schedule can be reviewed at: https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html. The ADA additionally suggests that patients with type I diabetes be screened for autoimmune thyroid disease at time of diagnosis and periodically thereafter.
Lifestyle changes are essential for the long-term management of diabetes and prevention of cardiovascular complications. While they should be individualized, diet and physical activity are critical components for patients with type 1 and type 2 diabetes.
Medical nutrition therapy with a registered dietitian provides individualized diabetes-specific education to promote healthy diet choices to achieve glycemic goals and weight management and has also been associated with reductions in hemoglobin A1c in patients with type 1 and type 2 diabetes. The ADA does not recommend a specific diet; however, evidence suggests that a decrease in overall carbohydrate intake results in improved glycemic control. In overweight and obese patients with type 2 diabetes, a goal of at least 5% weight loss is recommended and has been shown to improve glycemic control, although weight loss of 15% or more may be necessary to achieve the desired results.
Physical activity recommendations are the same as those of the DPP program: moderate to vigorous intensity aerobic activity for 150 minutes/week, vigorous-intensity aerobic activity for 75 minutes/week, or a combination of both. This has been shown to reduce hemoglobin A1c, decrease weight, improve a sense of wellbeing, and improve CAD risk factors. Resistance training is recommended two or more times per week. Older adults with diabetes should engage in flexibility and balance training two to three times per week, if possible. Prolonged sedentary behavior should be interrupted at 30-minute intervals with light activity or standing.
Weight loss medications (see MKSAP 18 General Internal Medicine) or metabolic surgery (see MKSAP 18 General Internal Medicine) are alternative options to consider if medical nutrition therapy and physical activity are unsuccessful. Metabolic surgery is recommended to treat type 2 diabetes in patients with BMI of 40 or greater (37.5 or greater in Asian Americans) and in patients with BMI of 35.0 to 39.9 (32.5-37.4 in Asian Americans) who do not achieve weight loss goals and improvement in comorbidities, including hyperglycemia, with medical interventions. Metabolic surgery may be considered for similar indications in adults with type 2 diabetes and BMI 30.0 to 34.9 (27.5-32.4 in Asian Americans).
Additional factors to consider and address in patients with diabetes mellitus include anxiety, depression, and diabetes-related distress. Screening for psychosocial issues and behavioral health conditions should occur at the time of diabetes diagnosis and periodically. These conditions can adversely affect glycemic control directly and through challenges with patient adherence to management plans.
Pharmacologic therapy should be individualized taking into consideration a person's age, state of health, weight, the pathophysiology of his/her hyperglycemia, specific risks/benefits of a potential therapeutic agent, medication cost, and the person's lifestyle and personal treatment goals. The hemoglobin A1c goals are generally not stringent in patients with significant comorbid conditions, macrovascular CVD, short life expectancy, long duration of diabetes, limited resources and social support, low health literacy/numeracy, nonadherence, and at high risk for complications from hypoglycemia. Most clinical practice guidelines, including the ADA, recommend target hemoglobin A1c thresholds based on a patient's state of health (see Table 7). In contrast, the VA/DoD guidelines for the management of type 2 diabetes recommend a hemoglobin A1c target range instead of a target threshold. The VA/DoD guidelines attempt to avoid intensification of pharmacologic therapy based solely upon marginal changes in hemoglobin A1c caused by known patient characteristics and laboratory limitations that could potentially cause greater harm than benefit in individuals with major comorbidities, microvascular complications, or advancing age.
The American College of Physicians (ACP) recommends a hemoglobin A1c level between 7% and 8% in most patients with type 2 diabetes, and clinicians should consider deintensifying pharmacologic therapy in patients who achieve hemoglobin A1c levels less than 6.5%. The rationale for these targets is based on evidence that collectively shows treating to targets of less than 7% compared with targets around 8% did not reduce death or macrovascular events over about 5 to 10 years of treatment but did result in substantial harms. More stringent targets may be appropriate for patients who have a long life expectancy (>15 years) and are interested in more intensive glycemic control with pharmacologic therapy despite the risk for harms, including but not limited to hypoglycemia, patient burden, and pharmacologic costs. ACP also recommends avoiding targeting an hemoglobin A1c level in patients with a life expectancy less than 10 years due to advanced age (80 years or older), residence in a nursing home, or chronic medical conditions because the harms outweigh the benefits in this population.
Several landmark studies provide guidance on glycemic goals and CVD risk reduction. Intensive glycemic control compared with standard control significantly reduces the incidence and progression of microvascular complications in patients with type 1 and type 2 diabetes, as demonstrated by the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS). Long-term follow-up demonstrated continued reductions in microvascular complications despite convergence in glycemic control between the study arms. Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), and the Veterans Affairs Diabetes Trial (VADT) further reinforced the association of reduced microvascular complications with tight glycemic control, but also highlighted that patients and providers must balance the risks/benefits of a labor-intensive regimen with the potential morbidity and mortality in specific populations.
Long-term follow-up evaluation of participants in the intensive insulin arms of the DCCT and UKPDS trials who were early in the course of diabetes demonstrated a significant reduction in CVD and mortality. In contrast, ACCORD, ADVANCE, and VADT evaluated tight glycemic control in older persons with more advanced type 2 diabetes and preexisting CVD or CVD risk factors. CVD was not significantly reduced in the ACCORD and ADVANCE trials. VADT demonstrated a significant reduction in cardiovascular events, but no change in cardiovascular or overall mortality.
Recently, the EMPA-REG Outcome trial, a randomized controlled trial (RCT), found that in patients with established CVD, empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduced the composite outcome (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke); it was primarily driven by a significant relative risk reduction in rates of cardiovascular death by 38%. There was also a significant reduction in all-cause mortality by 32% and hospitalization for heart failure by 35%. As a result of this trial, empagliflozin received FDA approval for reduction of cardiovascular death in adults with type 2 diabetes and CVD. Another SGLT2 inhibitor, canagliflozin, also demonstrated a reduction in cardiovascular events, but not cardiovascular death, in patients with type 2 diabetes at high risk for cardiovascular disease when compared to placebo in the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program.
The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) RCT included subjects at risk for CVD and found that liraglutide, a glucagon-like peptide 1 (GLP-1) analogue, significantly reduced the primary composite outcome (cardiovascular death, nonfatal MI, or nonfatal stroke) by 13% compared with placebo (relative risk reduction). Liraglutide also significantly reduced cardiovascular death (22%) and all-cause mortality (15%) relative to placebo. Based on the LEADER data, the FDA approved liraglutide for the reduction of major cardiovascular events and cardiovascular deaths in adults with type 2 diabetes and CVD.
Due to destruction of the beta cells and subsequent insulin deficiency, life-long insulin therapy is required for persons with type 1 diabetes mellitus. Ideally, an intensive insulin regimen should be prescribed, which includes multiple daily doses of insulin (MDI) to mimic the physiologic action of the pancreas. The insulin regimen should include basal coverage to maintain glycemic control while fasting and between meals, prandial coverage, and supplemental insulin for correction of hyperglycemia. This can be accomplished with subcutaneous insulin injections, inhaled insulin preparations, or continuous subcutaneous insulin infusions (CSII) with an insulin pump.
Initial total daily insulin dosing ranges from 0.4 to 1.0 U/kg/day in patients with type 1 diabetes. Basal insulin typically encompasses approximately 50% of the total daily dose of insulin, with prandial insulin covering the remaining 50%. The available insulin formulations and their activity profiles are summarized in Table 9.
The timing and mode of prandial insulin delivery varies based on patient needs/preferences and dietary habits. MDI prandial dosing can be accomplished with fixed-dosing, carbohydrate counting, or modified carbohydrate counting. In general, 1 unit of insulin covers 10 to 20 grams of carbohydrates consumed. A modified carbohydrate counting method can be used when the grams of carbohydrates consumed cannot be accurately counted. With this method, regular or analogue insulin doses can be adjusted by 50% based on the portion of food consumed. For example, the dose for the size of the meal would be as follows: small (50%), regular (100%), large (150%). MDI should also incorporate supplemental insulin to correct hyperglycemia. A common method to calculate the correction dose of insulin is to give an additional 1 unit of regular or analogue insulin at the time of the premeal measurement for every glucose value 50 mg/dL (2.8 mmol/L) above the target glucose value in insulin-sensitive individuals and 1 unit for every 25 mg/dL (1.4 mmol/L) in insulin-resistant individuals. The supplemental insulin can be given with the prandial insulin in one injection. For example, an additional 3 units of insulin would be given with the prandial insulin if the target glucose was 120 mg/dL (6.7 mmol/L) and the current glucose was 270 mg/dL (15.0 mmol/L) in someone with type 1 diabetes.
Premixed insulin formulations combine intermediate-acting or long-acting basal insulin and rapid-acting or short-acting insulin in fixed concentrations. These formulations are typically administered twice daily and should be considered for those who are unable or unwilling to perform more frequent daily insulin injections. Premixed formulations can increase glycemic excursions, including hypoglycemia, since this is a non-physiologic regimen.
Inhaled insulin is a rapid-acting formulation for prandial dosing. The availability of inhaled insulin in cartridges with preset doses of insulin (4, 8, and 12 units) limits the flexibility of insulin dosing. Pulmonary function should be assessed at baseline and monitored because lung function may decline with use of inhaled insulin.
CSII provides continuous delivery of basal insulin and uses a bolus calculator programmed to achieve individual glycemic goals to calculate prandial and bolus correction doses. The Endocrine Society recommends CSII over MDI for all adults with type 1 diabetes who have not attained their hemoglobin A1c goal and for those who have attained their A1c goal but have large glycemic variability, severe hypoglycemia, or hypoglycemia unawareness. Additional considerations include a need for flexibility in insulin delivery, early morning hyperglycemia (“dawn phenomenon”), active lifestyle, or patient preference. There are CSII systems that will decrease or stop delivery of insulin if glucose levels fall below a threshold value that is set within the CSII system and will increase delivery if glucose levels are above a threshold value. Insulin delivery will be reinitiated or increased/decreased back to baseline when the threshold is no longer met.
Hypoglycemia and weight gain are risks associated with insulin use. The risk of hypoglycemia is lower with analogue insulin compared with regular insulin due to a shorter duration of action. Hypoglycemia caused by insulin stacking occurs when insulin dosing is too frequent and overlaps with the duration of action of a prior insulin injection. This can be avoided by allowing at least 3 to 4 hours between sequential injections of analogue insulin.
An adjunctive therapy approved for use with insulin in type 1 diabetes is pramlintide, an amylin analogue. Pramlintide can lead to improved glycemic control, decreased insulin doses, and weight loss through delayed gastric emptying, increased satiety, and decreased glucagon secretion.
As beta cell function declines, pharmacologic therapies must often be combined with lifestyle modifications to obtain glycemic control. Therapeutic options may include monotherapy or a combination of oral agents with injectable agents (Table 10).
The ADA recommends initiation of monotherapy if the A1c is less than 8% at the time of diagnosis. Metformin is the recommended first-line oral agent for newly diagnosed type 2 diabetes due to known effectiveness and low hypoglycemia risk. Gastrointestinal side effects of metformin are common and may be reduced by slow titration of doses, administration with food, and/or use of an extended release formulation. Lactic acidosis is a rare, potential risk associated with metformin use. Heart failure requiring pharmacologic treatment and hepatic dysfunction may increase the risk. An estimated glomerular filtration rate (eGFR) greater than 45 mL/min/1.73 m2 is recommended for metformin initiation to avoid potential lactic acidosis with kidney dysfunction. Clinicians should assess benefits and risks of continuing therapy in patients whose eGFR falls below 45 mL/min/1.73 m2 during therapy. Metformin is contraindicated at eGFR less than 30 mL/min/1.73 m2.
If an iodinated contrast agent is administered with an eGFR between 30 and 60 mL/min/1.73 m2, metformin should be held until kidney function is stable for 48 hours. Metformin should also be held in situations that may induce dehydration, such as vomiting or diarrhea. A reduction in vitamin B12 intestinal absorption occurs in up to 30% of patients on metformin whereas 5% to 10% develop vitamin B12 deficiency. Long-term metformin use may result in vitamin B12 deficiency, and annual B12 level testing is recommended.
Glycemic control should be assessed every 3 months with adjustments to therapy until the glycemic target is achieved, and every 6 months if at goal. There are limited data on comparative effectiveness to guide the addition of additional agents when glycemic goals are not met with metformin and lifestyle modifications; thus, many guidelines are based on expert opinion. If the hemoglobin A1c level is 9% or higher at the time of diagnosis or after 3 months of metformin therapy, the ADA recommends advancing to dual therapy defined as metformin combined with another therapeutic agent (see Table 9 and Table 10). AACE/ACE recommends initiation of metformin if the hemoglobin A1c level is less than 7.5% at diagnosis.
Dual therapy should be initiated if the hemoglobin A1c level is 7.5% or higher at diagnosis or after 3 months of monotherapy. The ADA and AACE/ACE both recommend advancement to triple therapy if dual therapy fails to meet glycemic goals after 3 months. Triple therapy should be advanced to combination injectable therapy if glycemic goals are still unmet. This includes continued metformin and initiation of a GLP-1 receptor agonist or basal insulin if not already prescribed, initiation of basal insulin on background GLP-1 receptor agonist therapy, or initiation of a GLP-1 receptor agonist or prandial insulin on optimized background basal insulin. In most patients who need the greater glucose-lowering effect of an injectable medication, GLP-1 receptor agonists are preferred to insulin.
The ADA recommends that among patients with type 2 diabetes who have established atherosclerotic cardiovascular disease or indicators of high risk, established kidney disease, or heart failure, a sodium-glucose cotransporter 2 inhibitor or glucagon-like peptide 1 receptor agonist with demonstrated cardiovascular disease benefit is recommended as part of the glucose-lowering regimen independent of A1c measurement.
The use of sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes mellitus have been proven to reduce rates of acute myocardial infarction, stroke, and cardiovascular death. For patients with type 2 diabetes and clinical atherosclerotic cardiovascular disease (ASCVD), SGLT2 inhibitors may reduce hospitalization for heart failure. Based on strong evidence, these agents, typically empagliflozin (SGLT2 inhibitor) or liraglutide (GLP-1 receptor agonist), are recommended by the ADA for patients with diabetes and clinical ASCVD as part of the glucose control regimen. Weaker evidence supports the use of a SGT2 inhibitor in patients with ASCVD with heart failure or at high risk of heart failure.
Algorithms from the ADA and AACE/ACE provide guidance on initiation and dosing of basal and prandial insulin regimens (Table 11). The ADA recommends combination injectable therapy initially in the setting of symptomatic hyperglycemia (polydipsia, polyuria), hemoglobin A1c 10% or higher, or a glucose level of 300 mg/dL (16.6 mmol/L) or higher.
AACE/ACE recommends initiating insulin therapy with other agents if the initial hemoglobin A1c is more than 9% in a symptomatic individual. After optimizing the basal insulin dose, prandial insulin should be added prior to the largest meal if hyperglycemia persists. A basal-bolus insulin regimen, with prandial insulin prior to two or more meals, should be employed for continued hyperglycemia.
Ultralong-acting basal analogue insulins may be advantageous compared with long-acting basal analogue insulins due to a prolonged action profile (>24 hours), peakless insulin delivery, and decreased variability in action between and within individuals. The pharmacodynamic profile may decrease hypoglycemia in high-risk patients, improve glycemic fluctuations, and allow for flexibility in dosing beyond 24-hour time periods.
In patients with type 2 diabetes not at glycemic goal despite adherence to glucose monitoring and multiple treatment modalities, CSII may be considered.
Pharmacologic therapy should be prescribed for patients with gestational diabetes to improve perinatal outcomes if lifestyle interventions do not achieve glycemic targets. Insulin is the recommended therapy. While metformin or sulfonylurea therapy may be considered, both therapies cross the placenta, and there is no long-term safety data for their use during pregnancy. Additionally, sulfonylurea therapy has been associated with higher rates of neonatal macrosomia and hypoglycemia.
Several drugs can induce hyperglycemia through multiple mechanisms: increased hepatic glucose production, impaired insulin action, or decreased insulin secretion (Table 12). Whereas hyperglycemia with temporary drug therapies may resolve after discontinuation, many of these drugs are used indefinitely for chronic medical conditions. Persons at risk for hyperglycemia and the development of diabetes due to medications should be monitored periodically.
Tight inpatient glycemic control (80-110 mg/dL [4.4-6.1 mmol/L]) is not consistently associated with improved outcomes and may increase mortality. As a result, current inpatient glycemic goals strive to avoid complications from severe hypoglycemia and hyperglycemia, such as electrolyte abnormalities and dehydration.
Modifications to diet are necessary with consistent values above 140 mg/dL (7.8 mmol/L). If hyperglycemia persists, therapy should be initiated. Clinical status changes may increase the risk of adverse events associated with noninsulin therapies. Insulin is therefore preferred for inpatient management of hyperglycemia 180 mg/dL (10.0 mmol/L) and higher and adjusted to maintain a glucose level between 140 and 180 mg/dL (7.8-10.0 mmol/L) for most patients. Glucose values less than 140 mg/dL (7.8 mmol/L) may be reasonable in select noncritically ill patients if hypoglycemia is avoided, according to the ADA and AACE. In contrast, the American College of Physicians (ACP) does not recommend glucose values less than 140 mg/dL (7.8 mmol/L) due to increased hypoglycemia risk. Several factors may lead to inpatient hypoglycemia: altered mental status, fasting (expected or unexpected), illness, insulin–meal timing mismatch, poor oral intake, and alterations in hyperglycemia-inducing therapies.
In critically ill patients with type 1 and type 2 diabetes mellitus, intravenous insulin therapy is recommended. Intravenous insulin dose adjustments should be based on a validated algorithm that incorporates point-of-care (POC) monitoring every 1 to 2 hours.
For noncritically ill patients, subcutaneous insulin is appropriate. Persons with type 1 diabetes require continuous insulin therapy. Basal insulin must be provided to avoid development of DKA. Persons with type 2 diabetes with glucose values 180 mg/dL (10.0 mmol/L) or higher should also receive insulin therapy.
If the patient is eating, the ideal insulin regimen is a basal-bolus regimen with prandial coverage and correction boluses for premeal hyperglycemia. POC measurements and prandial insulin injections should occur prior to meal consumption. Postprandial insulin administration may be appropriate to allow for dose reduction with decreased oral intake for some persons or those with delayed gastric emptying. Overnight POC measurements are warranted if there are concerns for undetected hypoglycemia; otherwise glucose checks overnight should be avoided due to sleep disruption and increased risk of insulin stacking. The sole use of correction insulin (“sliding-scale insulin”) is not recommended since it is a reactive, nonphysiologic approach that leads to large glucose fluctuations.
Continuation of outpatient CSII therapy may be appropriate for those patients with normal mental status who can manage the device under the supervision of health care providers proficient in this technology. If a hospitalized patient becomes unable to safely manage CSII therapy, it should be discontinued and replaced with either a subcutaneous insulin regimen or intravenous insulin.
Continuation of outpatient oral or noninsulin injectable agents is not recommended when patients are admitted due to potential hemodynamic and/or nutritional changes that may occur. Insulin therapy should be initiated for glycemic management. As a patient nears hospital discharge with stability in nutritional status and hemodynamics, reinitiation of these agents may be considered if organ function has returned to baseline.
Stress associated with acute illness, enteral/parenteral nutrition, and hyperglycemia-inducing medications in the inpatient setting may induce glucose abnormalities in persons without diabetes.
Hyperglycemia management should follow the same guidelines as hospitalized patients with diabetes.
It is important to recognize that inpatient hyperglycemia may occur in the setting of previously unrecognized diabetes. An inpatient hemoglobin A1c measurement of 6.5% or higher is indicative of glucose abnormalities prior to the hospitalization, and these patients require discharge planning for management of newly diagnosed diabetes.
Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS) occur with extreme hyperglycemia and must be treated early and aggressively to avoid life-threatening consequences from dehydration and electrolyte abnormalities. Severe hyperglycemia is a consequence of insufficient insulin levels coupled with an increase in counterregulatory hormones. This impairs efficient glucose utilization and subsequently drives glycogenolysis and gluconeogenesis for fuel production.
DKA typically occurs in individuals with type 1 diabetes younger than 65 years of age. It is a relative or absolute insulin deficiency state resulting in unsuppressed lipolysis. Fatty acid oxidation occurs with subsequent ketone body production and development of metabolic acidosis. HHS typically occurs in individuals with type 2 diabetes who are older than 65 years of age. It is associated with a higher mortality rate compared with DKA. It is characterized as a partial insulin deficiency that is able to suppress lipolysis and prevent ketone body production, but unable to correct hyperglycemia or prevent the subsequent dehydration and electrolyte abnormalities. Younger patients with type 1 diabetes have a higher glomerular filtration rate, which allows a higher level of glucosuria compared with those with type 2 diabetes. As a result, HHS is associated with more extreme hyperglycemia compared to DKA (Figure 1).
Inciting factors for the development of DKA or HHS include infection, myocardial infarction, accidental or deliberate nonadherence to diabetes therapy, stress, trauma, and confounding medications (atypical antipsychotics, glucocorticoids, and SGLT2 inhibitors). DKA or HHS may be the initial presentation of a person with undiagnosed diabetes.
DKA and HHS may present with a multitude of symptoms and plasma glucose levels that can be normal to very high. Symptoms from DKA typically occur within 24 hours of onset, whereas symptoms from HHS may not appear for several days. DKA and HHS symptoms may include abdominal pain, nausea, polyuria, polydipsia, vomiting, weight loss, or shortness of breath. Extreme glucosuria causes an osmotic diuresis and severe volume depletion, which may be exacerbated by gastrointestinal losses of volume and electrolytes. The condition may progress to lethargy, obtundation, and death if the hyperglycemia, dehydration, and electrolyte abnormalities are not treated aggressively and early.
Initial evaluation includes the measurement of serum glucose levels, serum electrolytes, serum ketones, blood urea nitrogen and serum creatinine, plasma osmolality, complete blood count, arterial blood gases, urinalysis, and urine ketones. An electrocardiogram should also be reviewed. Cultures (blood, sputum, urine) and a chest radiograph may be obtained if an infection is suspected after a history is gathered and examination performed.
Multiple laboratory abnormalities are present with DKA and HHS. An increased anion gap metabolic acidosis is present in DKA secondary to production of acetoacetic acid and β-hydroxybutyrate. Although some patients with HHS may have an increased anion gap, typically with glucose levels above 400 to 600 mg/dL (22.2-33.3 mmol/L), they do not develop significant ketoacidosis as seen in DKA.
A moderate to severe reduction in serum bicarbonate levels is present in DKA, but levels may remain normal or mildly reduced (>20 mEq/L [20 mmol/L]) in HHS. Serum pH is typically greater than 7.3 in HHS. Hypertonic hyponatremia may occur in DKA and HHS with extreme hyperglycemia and osmotic shifts of water from intracellular to extracellular compartments. A normal or elevated sodium level indicates severe dehydration. Increased osmolality, frequently greater than 320 mOsm/kg H2O, is often present in HHS secondary to more severe hyperglycemia and water loss from osmotic diuresis compared with type 1 diabetes. Serum potassium levels may be elevated due to shifts from the intracellular to extracellular spaces due to ketoacidosis and the absence of sufficient insulin. Normal or low serum potassium levels indicate a depletion of body stores and require supplementation prior to insulin therapy to avoid cardiac arrhythmias. Stress may induce mild leukocytosis, but higher levels may indicate an infectious cause for DKA or HHS.
A multi-pronged approach is required to treat DKA and HHS (Table 13). Intravenous hydration is necessary for volume repletion. Electrolyte deficits, such as potassium, should be repleted. Hyperglycemia should be corrected preferably with intravenous insulin with hourly glucose measurements to guide dose adjustments. Frequent electrolyte measurements are necessary to guide repletion as hydration and insulin therapy continues. Most patients with DKA or HHS are managed in the ICU due to the high complexity of care required. Other conditions that contributed to the development of DKA or HHS, such as infection, should be treated.
A major cause of morbidity and mortality in persons with diabetes mellitus is cardiovascular disease (CVD). Diabetes is an independent risk factor for CVD. Other significant risk factors for CVD include hypertension, dyslipidemia, tobacco use, family history, and albuminuria. Simultaneous management of CVD risk factors is recommended to decrease morbidity and mortality. Screening interval guidelines for risk factors are listed in Table 14.
In patients with type 2 diabetes with established CVD, SGLT2 inhibitors or GLP-1 receptor agonists with proven CVD benefit are recommended as part of the antihyperglycemic regimen.
Hypertension contributes to the development of macrovascular and microvascular complications. The American Diabetes Association (ADA) defines hypertension as sustained blood pressures 140/90 mm Hg or higher. Citing concerns for increased treatment complications with a lower blood pressure target below 130/80 mm Hg, the ADA treatment goal for most persons is below 140/90 mm Hg. Those persons with known atherosclerotic cardiovascular disease or at high risk for CVD (10-year ASCVD risk ≥15%) should have a target of less than 130/80 mmHg. In contrast, guidelines from the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) and the American College of Cardiology/American Heart Association (ACC/AHA) and nine other organizations advocate for a treatment target below 130/80 mm Hg for most patients with diabetes. ADA recommended treatment strategies include lifestyle modifications (for blood pressure >120/80 mm Hg) and the addition of pharmacologic therapies for patients not achieving their target blood pressure. Initial recommended antihypertensive regimens include ACE inhibitors, angiotensin receptor blockers (ARBs), dihydropyridine calcium channel blockers, and thiazide diuretics. Multiple agents are frequently required to reach the blood pressure target. Underlying comorbidities should guide selection of therapeutic agents, such as the use of an ACE inhibitor or ARB in the presence of microalbuminuria.
Lipid management in diabetes frequently requires a combination of lifestyle modifications and pharmacologic agents. Patients aged 40 to 75 years with diabetes should be started on a moderate-intensity statin. If additional ASCVD risk factors are present, the Pooled Cohort Equations can be used to determine the 10-year ASCVD risk to determine if high-intensity statin therapy is indicated (see General Internal Medicine).
Antiplatelet therapy with aspirin (75-162 mg/day) is recommended by the ADA for secondary prevention in those persons with diabetes and ASCVD. Aspirin for primary prevention of ASCVD in persons with type 1 and type 2 diabetes may not provide universal benefit. Reflecting this uncertainty, the ADA recommends a patient discussion on the benefits of aspirin versus increased risk of bleeding before considering therapy. Primary prevention should be considered in patients with diabetes age 50 and older who do not have an increased risk of bleeding and have additional risk factors for ASCVD (tobacco use, dyslipidemia, hypertension, chronic kidney disease/albuminuria, or family history of premature ASCVD).
Retinopathy is the leading cause of preventable blindness among persons with diabetes between 20 and 74 years of age in developed countries. Risk factors for retinopathy include duration of diabetes, degree of hyperglycemia, hypertension, albuminuria, and dyslipidemia.
Diabetic retinopathy changes are classified as nonproliferative (occurs within the retina) or proliferative (occurs in the vitreous or retinal inner surface). Nonproliferative retinopathy findings may include microaneurysms, dot and blot hemorrhages, hard exudates (lipid deposition), soft exudates or cotton-wool spots (ischemic superficial nerve fibers), venous bleeding, and intraretinal microvascular abnormalities. Neovascularization due to chronic ischemia characterizes proliferative retinopathy, which may cause intraocular hemorrhage, retinal detachment, and vision loss.
Macular edema may occur with nonproliferative and proliferative retinopathy.
Screening guidelines were developed for early detection of asymptomatic abnormalities to allow for treatment interventions to prevent vision loss (see Table 14).
Optimal control of blood pressure, glucose, and lipid parameters can prevent and delay the progression of retinopathy. Panretinal laser photocoagulation can treat high-risk proliferative diabetic retinopathy and severe nonproliferative retinopathy. In addition, intravitreal injections with anti-vascular endothelial growth factor (anti-VEGF) to reduce vision loss associated with proliferative retinopathy is not inferior to panretinal laser photocoagulation. Retinopathy may develop or accelerate during pregnancy or with rapid glycemic improvements, and may require laser photocoagulation to decrease the risk of vision loss. Macular edema is preferentially treated with anti-VEGF intravitreal injections to improve vision loss. Anti-VEGF injections require monthly injections for at least 12 months followed by intermittent injections to prevent recurrent macular edema.
Diabetic nephropathy is the leading cause of end-stage kidney disease (ESKD). Diabetes is typically present for 5 to 10 years prior to the development of nephropathy. Individuals with a first-degree relative with ESKD due to diabetic nephropathy have increased risk of progressing to ESKD themselves.
Measurement of estimated glomerular filtration rate (eGFR) and screening for the presence of microalbuminuria is recommended for early detection of kidney disease (see Table 14). Urinary albumin excretion can be determined from a random urine collection as an albumin-creatinine ratio (UACR). An elevated UACR level (≥30 mg/g creatinine) should be confirmed by multiple measurements over 3 to 6 months due to possible temporary elevations from biological variability, illness, hyperglycemia, heart failure, hypertension, exercise, and menstruation. Annual measurements of eGFR and UACR may identify progression of nephropathy and guide therapeutic decisions. More frequent assessments may be necessary with worsening kidney function. An eGFR less than 30 mL/min/1.73 m2 warrants a referral to a nephrologist.
Uncontrolled hyperglycemia and hypertension are risk factors for diabetic nephropathy; thus treatment to attain glucose and blood pressure goals is recommended. The ADA recommends an ACE inhibitor or an angiotensin receptor blocker (ARB) as first-line therapy to slow progression of nephropathy and prevent CVD in nonpregnant persons with diabetes, hypertension, a reduced eGFR (<60 mL/min/1.73 m2), and an elevated UACR (≥300 mg/g creatinine). An ACE inhibitor or an ARB is also recommended for treatment of an elevated UACR between 30 and 299 mg/g creatinine in nonpregnant persons with hypertension. Treatment with an ACE inhibitor or ARB is not recommended for patients with diabetes who have a normal blood pressure, a UACR level less than 30 mg/g creatinine, and an eGFR level greater than 60 mL/min/1.73 m2. For patients with type 2 diabetes and chronic kidney disease, the ADA recommends that physicians consider use of a sodium-glucose cotransporter 2 inhibitor (typically empagliflozin) or glucagon-like peptide 1 receptor agonist (typically liraglutide) as part of the antihyperglycemic regimen to reduce risk of chronic kidney disease progression and cardiovascular events.
Diabetic neuropathy involves damage to nerves or nerve roots due to hyperglycemia. Symptoms are dependent on the affected nerve(s) and may be focal or diffuse in nature. Neuropathy may occur peripherally and/or affect the autonomic nervous system. Glycemic control may prevent peripheral neuropathy and cardiac autonomic neuropathy in individuals with type 1 diabetes and can delay progression of neuropathy in type 2 diabetes.
Diabetic peripheral neuropathy (distal symmetric polyneuropathy) typically has an ascending presentation with a “stocking and glove” distribution. It may involve damage to both small and large nerve fibers. Symptoms from small nerve fiber damage include pain, burning, and tingling. Small nerve fiber abnormalities can be detected on examination by assessment of pinprick and temperature sensations. Abnormalities in position sense, vibration, and light touch are indicative of large nerve fiber damage and convey an increased risk for foot ulcerations. Assessment of large nerve fiber damage can be achieved by assessing ankle reflexes and with a 128-Hz tuning fork and a 10-g monofilament. Since diabetic peripheral neuropathy may be asymptomatic, screening should occur for early detection to prevent limb loss (see Table 14).
Autonomic neuropathy may affect one or multiple organs with symptoms varying based on the affected organ. Symptoms may include hypoglycemia unawareness, gastroparesis, constipation, diarrhea, erectile dysfunction, and bladder dysfunction. Symptoms from cardiac autonomic dysfunction may include orthostatic hypotension, resting sinus tachycardia, and exercise intolerance. Cardiac autonomic neuropathy is an independent risk factor for sudden death.
The goal of treatment of diabetic neuropathy is symptom control. The ADA recommends pregabalin, duloxetine, or gabapentin (not FDA approved) as initial therapy for neuropathic pain. Other agents that may provide symptom relief but are not FDA approved include tricyclic antidepressants, venlafaxine, carbamazepine, and capsaicin. The primary treatment of orthostatic hypotension is nonpharmacologic and includes diet, use of compression stockings, and changing positions slowly. Medications that cause or worsen the orthostatic changes should be discontinued and other agents (fludrocortisone, midodrine, or droxidopa) added for refractory symptoms. Small and frequent low-fat, low-fiber meals may improve symptoms of gastroparesis. Metoclopramide is the only prokinetic agent approved by the FDA for the treatment of gastroparesis. Given the risk of side effects, including dystonia, careful assessment of risks and benefits should be undertaken before prescribing (see MKSAP 18 Gastroenterology and Hepatology).
Diabetic amyotrophy is a rare condition affecting the lumbosacral plexus that may occur secondary to infarction or immune vasculopathy. Presentation is acute and associated with severe asymmetric pain or proximal weakness in a leg with associated muscle wasting. Partial remission may occur over many months. Treatment is supportive.
Mononeuropathies and nerve compression syndromes (carpal tunnel syndrome, peroneal palsy) can occur in patients with diabetes. Mononeuropathies frequently resolve without intervention within a few months. Compression syndromes may respond to conservative management, or surgery may be necessary for symptom relief.
Significant morbidity and mortality are associated with lower extremity ulcers and amputations (see MKSAP 18 Infectious Disease). The ADA recommends performing a comprehensive foot evaluation at least annually to identify risk factors for ulcers and amputations. The examination should include inspection of the skin, assessment of foot deformities, neurological assessment (10-g monofilament testing with at least one other assessment: pinprick, temperature, vibration), and vascular assessment including pulses in the legs and feet. Patients with evidence of sensory loss or prior ulceration or amputation should have their feet inspected at every visit. Risk factors for ulcer include hyperglycemia, peripheral artery disease, history of foot ulcer or amputation, foot deformity, peripheral neuropathy, impaired vision, tobacco use, and diabetic nephropathy. Vascular assessment should occur in persons with absent pedal pulses or symptoms concerning for claudication. Foot care specialists should be involved in the care of high-risk individuals. Patients should be educated on the importance of daily foot inspections and properly fitting footwear.
Hypoglycemia is defined as a glucose value less than 70 mg/dL (3.9 mmol/L). Glucose values less than 54 mg/dL (3.0 mmol/L) are serious and clinically significant. Severe hypoglycemia is any glucose value at which a person requires external assistance to correct the glucose.
Hyperadrenergic symptoms (sweating, tremors, anxiety, tachycardia) are the normal physiologic response to the development of hypoglycemia. Counterregulatory hormones (glucagon, epinephrine, norepinephrine, cortisol, and growth hormone) are subsequently released by the body to correct hypoglycemia. Neuroglycopenic signs (altered mental status, dysarthria, confusion) are associated with severe hypoglycemia. Obtundation, seizures, and death may occur if severe hypoglycemia is not corrected rapidly.
Hypoglycemia can become a rate-limiting step in achieving glycemic goals for many persons. Severe recurrent hypoglycemia is associated with acquired cognitive deficits and can lead to dementia. Therapies must be adjusted to eliminate hypoglycemia, and glycemic goals should be individualized to accommodate targets that can be safely achieved.
Several factors contribute to hypoglycemia including a mismatch of food consumption and insulin delivery, increased physical exertion, weight loss, worsening kidney impairment, abnormalities in gastrointestinal motility and absorption, and accidental/intentional overdose of insulin. Older adults are also at an increased risk for hypoglycemia.
Hypoglycemia can also occur with the use of oral anti-diabetic agents due to incorrect dosages, drug-drug interactions, and intercurrent illnesses that alter the metabolism or excretion of drugs.
Hypoglycemia treatment in an alert person includes consumption of 15 to 20 grams of a fast-acting carbohydrate followed by a self-monitored blood glucose (SMBG) measurement 15 to 20 minutes later. If the glucose has not improved, repeat treatment with 15 grams of carbohydrates should occur. After glucose normalization (>70 mg/dL [3.9 mmol/L]), a meal or snack should be consumed to avoid recurrent hypoglycemia. Glucagon should be provided to those persons at risk for developing clinically significant hypoglycemia (<54 mg/dL [3.0 mmol/L]) and used by close contacts if the person is not able to safely consume carbohydrates to correct hypoglycemia. Glucagon is available in intramuscular, intranasal, and subcutaneous preparations.
Relative hypoglycemia characterizes symptoms of hypoglycemia in the setting of plasma glucose values greater than 70 mg/dL (3.9 mmol/L). This may occur with a large, rapid decrease in glucose or rapid normalization of glucose with treatment intensification in an individual with prolonged plasma glucose values above 200 mg/dL (11.1 mmol/L). Relative hypoglycemia can be prevented by avoiding large glycemic excursions and by slow correction of long-standing hyperglycemia to goal to allow a longer adjustment period.
Hypoglycemia without concomitant diabetes is uncommon and warrants further assessment. A hypoglycemia evaluation should commence if the criteria for Whipple triad are met: neuroglycopenic symptoms, hypoglycemia at or below 55 mg/dL (3.1 mmol/L), and resolution of symptoms with glucose ingestion. Laboratory measurement of glucose must confirm true hypoglycemia, as point-of-contact (POC) glucose values are not reliable in this scenario. Hypoglycemia in persons without diabetes may be attributable to the following causes: drugs, alcohol, illness, organ dysfunction (kidney or liver), hormonal deficiencies (adrenal insufficiency), malnutrition, and pancreatogenous insulinoma or noninsulinoma (endogenous hyperinsulinemic hypoglycemia that is not caused by an insulinoma).
Although there may be overlap in presentation, hypoglycemia typically occurs in the fasting or in the postprandial state. Diagnostic blood and urine studies should be obtained during a hypoglycemic episode in which Whipple triad has been demonstrated. If a spontaneous episode is not witnessed, measures should be implemented to recreate circumstances that normally induce hypoglycemia (fasting or ingestion of a typical meal that causes an episode in that particular patient). Imaging studies for tumor localization should only occur after confirmation of endogenous hyperinsulinism from the diagnostic blood and urine studies.
A prolonged fast, up to 72 hours, should be initiated if the hypoglycemia typically occurs while fasting.
Five blood specimens are drawn simultaneously every 6 hours: glucose, C-peptide, insulin, proinsulin, β-hydroxybutyrate. Insulin antibodies and an oral hypoglycemic agent screen should also be measured at the beginning of the fast. Blood specimen collection should increase to every 1 to 2 hours when the glucose measurement is less than 60 mg/dL (3.3 mmol/L).
Testing is complete when one of the following parameters is met: plasma glucose 45 mg/dL (2.5 mmol/L) or below with neuroglycopenia, or plasma glucose less than 55 mg/dL (3.1 mmol/L) if Whipple triad was documented previously. POC glucose values and hyperadrenergic symptoms should not be used to determine the end of the fast. Blood specimens should be collected again at the end of the 72-hour time period if neither of the above criteria has been met.
The interpretation of the diagnostic testing results is found in Table 15. To decrease the cost of this procedure, the plasma glucose should be sent to the laboratory as soon as possible, and if it is less than 60 mg/dL (3.3 mmol/L), the other four blood samples should be sent.
Postprandial hypoglycemia typically occurs within 5 hours of the last meal. Altered gastrointestinal anatomy, as occurs after Roux-en-Y gastric bypass surgery, is frequently the cause of the postprandial hypoglycemia. Meals consisting of simple carbohydrates (pancakes, syrup, juice) are frequently the culprit. A mixed-meal test consisting of the types of food that normally induce the hypoglycemia should be performed to determine the cause. Baseline laboratory studies including glucose, C-peptide, insulin, and proinsulin should be obtained prior to meal consumption. These tests should be repeated every 30 minutes for 5 hours. If neuroglycopenia occurs, the tests should be repeated prior to administration of carbohydrates. To decrease the cost of this procedure, the plasma glucose should be sent to the laboratory as soon as possible, and if it is less than 60 mg/dL (3.3 mmol/L), the other three blood samples should be sent.
Screening should also occur for insulin antibodies and oral hypoglycemic agents if symptomatic hypoglycemia occurs. Interpretation of the results is similar to those obtained during fasting hypoglycemia (see Table 15).
Treatment generally consists of small frequent mixed meals with a balance of protein, fat, and carbohydrates.
Hypoglycemia unawareness is characterized by insufficient release of counterregulatory hormones and an inadequate autonomic response to hypoglycemia. Prior episodes of hypoglycemia increase the risk of developing hypoglycemia unawareness. Treatment involves relaxation of glycemic targets and modifications of hypoglycemia-inducing diabetes therapies to avoid continued hypoglycemia. Avoidance of hypoglycemia for several weeks may reverse hypoglycemia unawareness in some persons and result in the return of adrenergic symptoms with glucose levels less than 70 mg/dL (3.9 mmol/L). A continuous glucose monitoring system may be beneficial in appropriate individuals to provide early detection of impending severe hypoglycemia for early intervention.