• Diabetes mellitus (DM) refers to a syndrome of hyperglycemia resulting from many different causes (see “Etiology”). It is broadly classified into type 1 (T1DM) and type 2 DM (T2DM). The terms insulin-dependent and non-insulin-dependent diabetes are obsolete because when a person with type 2 diabetes needs insulin, he or she remains labeled as type 2 and is not reclassified as type 1. Immune-mediated type 1 DM (type 1A) represents 5% to 10% of newly diagnosed diabetics. Tables 1 and 2 provide a general comparison of the two types of DM. One difference is that type 1 has usually complete or near-total knockout of insulin reserves mediated solely by immunogenic responses from carriers of certain genotypes, whereas type 2 is of polygenetic origin and may have patients who may start with hyperinsulinemia but have insulin resistance and through environmental factors such as diet and sedentary lifestyle leads to an imbalance between glucagon and insulin levels, resulting in combination of causes toward hyperglycemia.
• Some type 1 diabetics also may exhibit high levels of glucagon, and not all type 1 diabetics have complete islet cell destruction.
• The classification of diabetes also includes:
  1. LADA: Latent autoimmune diabetes of adult onset (sometimes called type 1.5 DM). These individuals are typically not insulin dependent initially and are often misclassified as having type 2 DM.
  2. MODY: Maturity onset diabetes of youth. These have various genetic expressions and can be classified into various subtypes:
     1. MODY 1, 2, 3, 4, and 5 (with 3 being most prevalent: 70% incidence with HNF-1-alpha [12q24] genetic expression).
     2. MODY 7 and 8 (rare).
  3. Ketosis-prone diabetes: Relapsing/remitting beta cell function with slow deterioration over time. It presents with ketoacidosis requiring insulin, then regains beta cell function, and patient is able to discontinue insulin. This for is most common under age 40, in those of African or Afro-Caribbean origin, and in obese or overweight patients.
  4. Secondary diabetes:
     1. Pancreatic disease or resection (e.g., cystic fibrosis).
     2. Chronic excessive corticosteroid exposure or Cushing syndrome.
     3. Glucagonoma.
     4. Acromegaly.
     5. Other rare genetic disorders (e.g., mitochondrial diabetes MELAS syndrome).
  5. Rare autoimmune (e.g., type A and B insulin resistance syndrome).
  6. A classification of diabetes mellitus is shown in Box 1.
• Diabetes mellitus can be diagnosed by the following tests:
  1. A hemoglobin A_1c (HbA_1c) value ≥6.5% is considered diagnostic for diabetes. This test is preferred because of ease of administration and reliability.
  2. A fasting plasma glucose (FPG) ≥126 mg/dl, which should be confirmed with repeat testing on a different day. Fasting is defined as no caloric intake for at least 8 h.
  3. An oral glucose tolerance test (OGTT) with a plasma glucose ≥200 mg/dl 2 h after a 75 g (100 g for pregnant women) glucose load.
  4. Symptoms of hyperglycemia and a casual (random) plasma glucose ≥200 mg/dl are also indicative of DM. Classic symptoms of hyperglycemia include polyuria, polydipsia, and unexplained weight loss. At the time of diagnosis as a diabetic, B-cell function is at 25% to 30%.
• Individuals with glucose levels higher than normal but not high enough to meet the criteria for diagnosis of DM are considered to have “prediabetes,” the diagnosis of which is made as follows:
  1. A fasting plasma glucose 100 to 125 mg/dl; this is referred to as impaired fasting glucose.
  2. After OGTT, a 2-h plasma glucose of 140 to 199; this is referred to as impaired glucose tolerance. Patients with impaired glucose tolerance or prediabetes have B-cell function at 50% of normal.
  3. A hemoglobin A_1c value of 5.7% to 6.4%.
• Table 3 describes diagnostic categories for DM and at-risk states.

IDDM (insulin-dependent diabetes mellitus)

NIDDM (non-insulin-dependent diabetes mellitus)

Type 1 diabetes mellitus (insulin-dependent diabetes mellitus)

Type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus)

LADA (latent autoimmune diabetes of adult)

MODY (mature onset diabetes of youth)

• DM affects 9% to 10% of the U.S. population. Prevalence rates vary considerably by race/ethnicity. T1DM accounts for approximately 5% of diagnosed diabetes cases and is defined by the presence of one or more autoimmune markers.
• In the U.S., the overall pediatric incidence of T1DM is approximately 25 per 100,000 per year. Incidence a varies according to age (peaking in the pubertal years, ages 10 to 14), season (winter more than summer), geographic location (Finland and other Nordic countries more than equatorial regions), and race and ethnic group (U.S. non-Hispanic White persons more than Native Americans).¹
• Risk factors for type 1 DM are summarized in Table 4.
• There are three stages of type 1 DM. Patients in stage 1 have two or more diabetes-related autoantibodies, and those in stage 2 have developed asymptomatic dysglycemia but have normal other metabolic indices and do not require insulin treatment. Stage 3 is symptomatic clinical disease. Teplizumab is an anti-CD3 monoclonal antibody recently FDA approved to delay the onset of stage 3 type 1 DM in patients ≥8 years old who have stage 2 type 1 DM.^1a
• While incidence of diabetes in adolescents is mostly type 1, the rate of type 2 being diagnosed in adolescents has increased by 1.5 times in certain given areas. This seems to correlate with the epidemic of pediatric obesity.
• Table 5 summarizes epidemiologic determinants of and risk factors for type 2 DM.
• Incidence rate increases with age, varying from 2% in persons age 20 to 44 yr to 18% in persons 65 to 74 yr. T2DM can have a long presymptomatic phase, leading to a 4- to 7-yr delay in diagnosis. In the U.S. 1.2 million new cases of diabetes are diagnosed each yr, and 86 million have prediabetes. Currently, 30 million Americans have diabetes; with this current trend, it is predicted that by 2050, 1 out of 3 Americans will be diabetic.
• Diabetes accounts for 8% of all legal blindness in the U.S. and is the leading cause of end-stage renal disease (ESRD). Approximately 40% of patients in a given dialysis center are diabetic.
• Patients with diabetes are two to four times more likely than nondiabetic patients to experience development of cardiovascular disease (CVD).

• Physical examination varies with the presence of complications and may be normal in early stages
• Diabetic retinopathy:
  1. Nonproliferative (background diabetic retinopathy):
     1. Initially: Microaneurysms, capillary dilation, waxy or hard exudates, dot and flame hemorrhages, arteriovenous shunts
     2. Advanced stage: Microinfarcts with cotton wool exudates, macular edema
  2. Proliferative retinopathy: Characterized by formation of new vessels, vitreous hemorrhages, fibrous scarring, and retinal detachment
• Cataracts and glaucoma occur with increased frequency in patients with diabetes
• Diabetic macular edema: Swelling of the macula leading to loss of sharp vision in this part of the eye. People with this disorder usually already have retinopathy but may present separately as well
• Diabetic neuropathy:
  1. Distal sensorimotor polyneuropathy:
     1. Symptoms include paresthesia, hyperesthesia, or burning pain involving bilateral distal extremities in a “stocking glove” distribution. This can progress to motor weakness and ataxia
     2. Physical examination may reveal decreased pinprick sensation, decreased sensation to light touch, decreased vibration sense, and loss of proprioception. Motor disturbances such as decreased deep tendon reflexes and atrophy of interosseous muscles can also be seen
  2. Autonomic neuropathy:
     1. GI disturbances: Esophageal motility abnormalities, gastroparesis, diarrhea (usually nocturnal):
        1. Increased gastric emptying seen in type 2
        2. Decreased gastric emptying seen in type 1
     2. Genitourinary (GU) disturbances: Neurogenic bladder (hesitancy, weak stream, and dribbling), impotence
     3. Cardiovascular (CV) disturbances: Orthostatic hypotension, tachycardia, decreased heart rate variability (HRV). Decreased HRV is associated with increased cardiac mortality, independent of ejection fraction
  3. Polyradiculopathy: Painful weakness and atrophy in the distribution of ≥1 contiguous nerve root
  4. Mononeuropathy involving cranial nerves III, IV, or VI or peripheral nerves can also occur
• Diabetic nephropathy: Pedal edema, pallor, weakness, uremic appearance
• Nephrotic syndrome: Proteinuria, hypertriglyceridemia, edema
• Nephritis: Progressive degeneration of nephrons focal glomerulosclerosis

Type IV renal tubular acidosis, hyperkalemic nephropathy, interstitial nephritis, causing hyporeninemic hypoaldosteronism. It is important to keep in mind that NSAIDs, ACE inhibitors, trimethoprim, and heparin can all reduce aldosterone and can cause or exacerbate the condition. 50% of patients on dialysis have diabetes as primary diagnosis; whereas glycemia is important to prevent nephropathy, the most significant contributing factor is hypertension.

• Foot ulcers: Occur in 15% of individuals with diabetes (annual incidence rate 2%) and are the leading causes of hospitalization; they are usually secondary to a combination of factors, including peripheral vascular insufficiency, repeated trauma (unrecognized because of sensory loss), and superimposed infection.
  1. Patient symptoms are usually less than would be expected from clinical findings, due to loss of sensation related to peripheral neuropathy.
  2. Comprehensive foot exams include visual inspection, assessment of pedal pulses, and assessment of protective sensation using a 10-g monofilament to test sensation.
  3. Prevention of foot ulcers in an individual with diabetes includes strict glucose control, patient education, prescription footwear, intensive podiatric care, and evaluation for surgical interventions.
  4. Foot examination should be done annually on all diabetics.
• Neuropathic arthropathy (Charcot joints): Bone or joint deformities from repeated trauma (secondary to peripheral neuropathy; Fig. E1).
• Necrobiosis lipoidica diabeticorum: Plaque-like reddened areas with a central area that fades to white-yellow, found on the anterior surfaces of the legs (Fig. E2); in these areas, the skin becomes very thin and can ulcerate easily.
• Other diabetic skin manifestations with diabetes include:
  1. Scleroderma diabeticorum: Thickening of skin and epidermis giving skin a “leather-like texture”; typically affects type 2, mainly on upper back and neck.
  2. Dermatitis herpetiformis: Diffuse petechial rash associated with gluten insensitivity.
  3. Vitiligo: Associated with type 1 and type 2 and affects skin coloration due to autoimmune reaction to pigmentation (at times may be associated with adrenal insufficiency, especially in type 1 patients). Patients should use SPF 30 sunscreen to prevent sunburn.
  4. Acanthosis nigricans: Darkening of skin folds in neck and axilla, at times raised and velvety, thought to be associated with insulin resistance; other conditions such as Cushing and acromegaly can have this as well.
  5. Diabetic dermopathy: Appears as shiny round or oval lesions on thin skin of the lower extremity, also known as “shin spots”; these are usually not painful and do not require treatment.
  6. Eruptive xanthomatosis: Associated with uncontrolled blood sugars and extremely high triglycerides. There is a high risk for pancreatitis in patients with this finding; treatment is aimed at lowering blood sugars with insulin and fibrates.
  7. Digital sclerosis: Skin on toes fingers and hands become waxy, thick, and tight, with joint stiffness; treatment is aimed at lowering blood sugars and encouraging use of lotions and moisturizers.
  8. Bullosis diabeticorum: Rare disorder manifesting with blisters on hands, forearms, toes, and feet, usually painless. Lesions generally heal on their own.
  9. Box 2 summarizes cutaneous associations with diabetes mellitus.

• Diabetes insipidus
• Stress hyperglycemia
• Diabetes secondary to hormonal excess, drugs, pancreatic disease

• Diagnosis of DM is made on the basis of the following tests:
  1. Fasting glucose ≥126 mg/dl on two occasions.
  2. Non-FPG ≥200 mg/dl and symptoms of DM.
  3. OGTT (75 g glucose load for nonpregnant individuals) with 2-h value >200 mg/dl.
  4. Glycosylated hemoglobin (HbA_1c) ≥6.5%. HbA_1c level reflects average glycemia over previous 3 mo or longer. In known diabetics, this test should be performed at least twice yearly in stable patients and more frequently when therapy changes or patients are not meeting glycemic goals. HbA_1c alone does not provide a measure of glycemic variability or hypoglycemia and is affected by the presence of hemoglobin variants, hemolysis, or blood loss.
• Measurement of autoantibodies glutamic acid decarboxylase (GAD65) and tyrosine phosphatase IA-2 are useful in suspected immune mediated type 1 DM (strong association).
• Screening for prediabetes and diabetes in asymptomatic patients (see Table 6):
  1. Should be considered in adults of any age who are overweight (body mass index [BMI] >25 kg/m²) or obese (BMI >30) and who have one or more additional risk factors for diabetes.
  2. In those who are without these risk factors, testing should begin at age 45 yr.
  3. If screen is normal, repeat testing should be carried out at least at 3-yr intervals.
  4. ADA recommends screening all Asian Americans with BMI 23 or higher every 2 yr.
• Detection and diagnosis of gestational diabetes mellitus (GDM):
  1. Screen for GDM using risk factor analysis and use of an OGTT. Pregnant women who are not known to have diabetes should be screened for gestational diabetes at 24 to 28 wks’ gestation with a “1-step” strategy with 75 g oral glucose tolerance test or a “2-step” approach with a 50-g (nonfasting) screen followed by a 100-g oral glucose tolerance test for those who screen positive. A diagnosis of GDM is made if any of the following levels of plasma glucose are exceeded: ≥92 mg/dl (5.1 mmol/L) when fasting, ≥80 mg/dl (10 mmol/L) at 1 h, or ≥153 mg/dl (8.5 mmol/L) at 2 h.
  2. Women with GDM should be screened for diabetes 6 to 12 wk postpartum and should be followed with subsequent screening for the development of diabetes or prediabetes at least every 3 yr. A woman who had GDM during pregnancy has 50% risk of developing diabetes later in life; this is dependent on ethnicity (e.g., Pima Indians, Hispanic, African American).
• Screening for diabetic nephropathy:
  1. Screening should be done at diagnosis and then yearly for type 2 diabetes and 5 yr after diagnosis, then yearly in type 1 diabetes. 18% of type 1 DM may have early kidney changes, and future guidelines may change screening to 1 yr after diagnosis if poorly controlled, then annually for both type 1 and type 2.
  2. Screening can be performed using an albumin:creatinine ratio (microalbumin) in a random spot urine collection or by measurement of a 24-h urine collection for albumin and creatinine clearance. The urine albumin to creatinine ratio (ACR) is independently associated with mortality at all levels of estimated glomerular filtration rate (eGFR) in older adults with diabetes.
  3. The diagnosis of microalbuminuria (ACR 30 to 299 mg/24 h) should be based on 2 to 3 elevated levels within a 3- to 6-mo period because there is a marked variability in day-to-day albumin excretion. Patients with overt macroalbuminuria (>300 mg albumin/24 h or albumin:creatinine ratio >300) should be followed by urine protein:creatinine ratio.
• A fasting serum lipid panel, serum creatinine, and electrolytes should be obtained yearly on all adult patients with diabetes.
• Self-monitoring of blood glucose (SMBG) is crucial for assessing the effectiveness of the management plan. The frequency and timing of SMBG varies with the needs and goals of each patient. In most patients with type 1 DM and pregnant women taking insulin, SMBG is recommended at least 3 times/day. In patients with type 2 DM not on insulin, recommendations are unclear for SMBG, but testing once or twice/day is acceptable in most patients. Glycemic control is best evaluated when SMBG is combined with HbA_1c testing.
• Continuous glucose monitoring (CGM; Fig. E4) is now starting to play a more prominent role in reducing the number of fingersticks. Dexcom CGM has been approved by FDA for use by patients to adjust insulin based on CGM readings. Randomized trials in persons with type 1 DM and high glycated hemoglobin levels have shown that the use of intermittently scanned CGMs with optional alarms for high and low blood glucose levels results in significantly lower glycated hemoglobin levels than levels monitored by fingerstick testing.^1b
• The use of insulin pump and CGM readings and computer software can adjust insulin automatically (known as the “artificial pancreas”).
• CGM can also be used in patients with type 2 on multiple daily injections.
• Limitations of CGM are that it cannot predict accuracy of blood glucose when <70 mg/dl.
• Screening for thyroid dysfunction (TSH level), vitamin B₁₂ deficiency, and celiac disease should be considered in type 1 diabetes due to the increased frequency of other autoimmune diseases in these individuals.
• Consider screening for autoimmune polyendocrine syndromes (APS-2):
  1. APS-2: Most commonly known as Schmidt syndrome, heterogeneous not linked to one gene (HDLA-DQ2, HDLA-DQ8, AND HLA-DR4). Patients can have IDDM, hyperthyroidism, other autoimmune conditions, B₁₂ deficiency, and myasthenia.

• Diet: The ADA does not recommend a special diet. However, newly diagnosed diabetics who are overweight or obese should be counseled to lose at least 5% of their body weight. Consultation with a registered dietitian is recommended.
  1. Calories:
     1. The patient with diabetes can be started on 15 calories/lb of ideal body weight; this number can be increased to 20 calories/lb for an active person and 25 calories/lb if the patient does heavy physical labor.
     2. The calories should be distributed as 45% to 65% carbohydrates, <30% fat, with saturated fat limited to <7% of total calories, and 10% to 30% protein (protein intake of 0.8 g protein/kg body weight/day for patients not treated with dialysis). Daily cholesterol intake should not exceed 300 mg.
     3. The emphasis should be on complex carbohydrates rather than simple and refined starches, and on polyunsaturated instead of saturated fats in a ratio of 2:1.
     4. The glycemic index compares the increase in blood sugar after the ingestion of simple sugars and complex carbohydrates with the increase that occurs after the absorption of glucose; equal amounts of starches do not give the same increase in plasma glucose (pasta equal in calories to a baked potato causes less of an increase than the potato); thus it is helpful to know the glycemic index of a particular food product.
  2. Fiber: Insoluble fiber (bran, celery) and soluble globular fiber (pectin in fruit) delay glucose absorption and attenuate the postprandial serum glucose peak.
     1. They also appear to reduce the increased triglyceride level often present in patients with uncontrolled diabetes. A diet high in fiber should be emphasized (20 to 35 g/day of soluble and insoluble fiber).
     2. Diet programs: In 2015, a meta-analysis review of all research revealed that weight loss was equal no matter which diet program patients were involved in.
     3. However, the only data to show evidence-based prevention of diabetes in prediabetics was the “Mediterranean diet.”
     4. The Mediterranean diet also showed a significant decrease in the percentage of established diabetics from needing insulin in the future and significant benefit in reducing cardiovascular events.
  3. Other principles:
     1. Modest sodium restriction to less than 2000 mg/day. If hypertension is present, restrict to <2400 mg/day; if nephropathy and hypertension are present, restrict to <2000 mg/day.
     2. Moderation of alcohol intake recommended (≤2 drinks/day in men, ≤1 drink/day in women).
     3. Nonnutritive artificial sweeteners are acceptable in moderate amounts.
        1. However, it has been shown that artificial sweeteners may actually increase insulin resistance by affecting the action of insulin at receptor level.
• Exercise: Increases the cellular glucose uptake by increasing the number of insulin receptors. The following points must be considered:
  1. Exercise program must be individualized and built up slowly. Consider beginning with 15 min of low-impact aerobic exercise three times per wk and increasing the frequency and duration to 30 to 45 min of moderate aerobic activity (50% to 70% of maximum age predicted heart rate) to 3 to 5 days/wk.
     1. In the absence of contraindications, resistance training three times per wk should be encouraged.
  2. Insulin is more rapidly absorbed when injected into a limb that is then exercised, and this can result in hypoglycemia.
  3. Physical activity can result in hypoglycemia if medication dose or carbohydrate consumption is not modified. Ingestion of additional carbohydrates is recommended if preexercise glucose levels are <100 mg/dl.
  4. Diabetes prevention program: Low-fat diet with exercise reduced diabetes by 58%. This encompassed diet of 1200 to 1800 kcal/day <30% from fat, exercise unsupervised and supervised, akin to brisk walking >150 min/wk of moderately intensity physical activity.
• Weight loss: To ideal body weight if the patient is overweight. Recent trials have shown that although weight loss has many positive health benefits for people with type 2 DM, such as slower decline in mobility, it does not reduce the number of cardiovascular events.
• Screening for nephropathy, neuropathy, and retinopathy: Annual serum creatinine and urine albumin excretion; initial comprehensive eye examination and at least annually thereafter.
• Diabetes self-management education: Could also address psychosocial issues.
• Self-monitoring of blood glucose should occur three to four times per day for patients using multiple insulin injections or on insulin pump therapy.
• Perform HbA_1c at least two times a year in patients who are meeting treatment goals and who have stable glycemic control.
  1. HbA_1c quarterly in patients whose therapy has changed or who are not meeting glycemic goals.
  2. The HbA_1c goal for nonpregnant adults in general is <7%.
  3. In the elderly, those with comorbidities, or those at risk for complications from hypoglycemia, a more moderate glycemic target (HbA_1c 7 to 8) may be appropriate.
  4. In elderly patients (>80 yr of age) with average life expectancy of 5 yr, a target HbA_1c <8.0 is reasonable. In patients >80 yr with comorbidities and life expectancy of 3 yr, a target HbA_1c of <9.0 may be appropriate.

• Type 1 DM: Lifelong insulin therapy is required for persons with type 1 DM. It should consist of basal coverage, prandial coverage, and supplemental insulin for correction of hyperglycemia. Initial total insulin dosing ranges from 0.4 to 1.0 U/kg/day, 50% of which is basal insulin and 50% prandial insulin. Examples of insulin regimens used in type 1 DM are described in Table 10.
• Type 2 DM: When the previous measures fail to normalize the serum glucose, oral hypoglycemic agents should be added to the regimen in T2DM. Treatment options in patients with type 2 diabetes should be tailored to try to target core diabetic defects and apply therapies that lower HbA_1c in a weight-neutral or weight-lowering fashion if possible; of course, cost of therapies needs to be considered as well. Contemporary guidelines stress the importance of a multifactorial approach that targets not only dysglycemia but also hypertension, dyslipidemia, and hypercoagulability.³ Clinical features of commonly used oral antihyperglycemic agents are summarized in Table 11. Commonly used injectable agents other than insulin are described in Table 12.
• Metformin: The primary mechanism of metformin is to decrease hepatic glucose production and improve insulin sensitivity. Because metformin does not produce hypoglycemia when used as a monotherapy, it is preferred initially for most patients. Metformin can reduce A1C by 1.0% to 1.5%. It is contraindicated in patients with severe renal insufficiency with an estimated glomerular filtrate rate <30 ml/min. Starting metformin in patients with GFR between 30 and 45 ml/min is also not recommended. The excess risk for lactic acidosis is however negligible in patients with mild to moderate reductions in kidney function.^3,4
• When metformin alone does not achieve the desired A_1C goal, the choice of a second drug is dictated by the comorbidities.
  1. For example, an SLGT2 inhibitor is preferred in patients with heart failure (HF) or cardiovascular kidney disease (CKD). In patients with cardiovascular disease (CVD) or at high risk for CVD, a preferred drug would be a glucagon-like peptide-1 (GLP-1) receptor agonist or a sodium-glucose cotransporter 2 (SGLT2) inhibitor; in obese patients, tirzepatide or an GLP-1 agent would be preferred. Whereas in most patients without HF, CVD, CKD, or obesity, lowering the HbA1c while minimizing hypoglycemia is the main goal of therapy and can be achieved with dipeptidylpeptidase-4 (DPP-4) inhibitors, GLP-1 agonists, SGLT-2 inhibitors.
• GLP-1 agonists: Dulaglutide (Trulicity), semaglutide (Ozempic, Rybelsus), liraglutide (Victoza), exenatide (Byetta, Bydureon), and lixisenatide (Adlyxin). These injectable agents are incretin mimetics that stimulate release of insulin from pancreatic beta cells and can be used as adjunctive therapy for patients with T2DM. GLP-1 agonists are not indicated in T1DM and are contraindicated in patients with severe renal impairment. Average A1C reduction is 1.0% to 2.0%. Advantages are weight loss, no hypoglycemia when used as monotherapy and reduced incidence of cardiovascular events and nephropathy. Side effects include injection site reactions, GI side effects (nausea, diarrhea, vomiting), increased risk of pancreatitis and thyroid C-cell carcinoma. Cost is a barrier to their use.
• Dual GIP / GLP-1 agonists: Tirzepatide (Mounjaro) is a novel, once weekly, injectable peptide with agonist activity at both the GIP and GLP-1 receptors. It increases insulin secretion, decreases glucagon secretion, increases insulin sensitivity, delays gastric emptying, and reduces food intake. In randomized trials in patients with type 2 diabetes, tirzepitide reduced A₁C and body weight more than semaglutide, insulin degludec (Tresiba), or insulin glargine (Lantus).⁵ Average weight loss is 7 to 13 Kg. The most common side effects included GI adverse events (nausea, comiting, diarrhea, abdominal pain). A₁C reduction is 2.0% to 2.5%.
• Sodium-glucose cotransporter 2 (SGLT₂) inhibitors: Canagliflozin (Invokana), dapagliflozin (Farxiga), empagliflozin (Jardiance), and sotagliflozin (Zynquista). These medications decrease glucose reabsorption, increase urinary glucose excretion, and lower HbA_1c 0.5% to 1.0%). Empagliflozin has been shown to slow progression of renal disease in type 2 diabetics with CVD. SGLT₂ inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular disease among patients with stable heart failure. Sotagliflozin therapy initiated before or shortly after discharge in patients with diabetes and recent worsening heart failure resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure versus placebo in a recent trial.⁶ Potential advantages include weight loss (up to 3.5% of BMI) and mild lowering of blood pressure (2 to 4 mm Hg). Side effects include increased risk of genital mycotic infections, UTIs, and volume depletion. Renal function should be evaluated before starting SGLT₂ inhibitors and periodically thereafter. Temporary discontinuation of these meds is recommended in cases of reduced oral intake or fluid loss. Higher cost and limited drug formulary availability are limiting factors.
• DPP-4 inhibitors:Sitagliptin (Januvia), linagliptin (Tradienta), saxagliptin (Onglyza), vildagliptin (Galyus and others), and alogliptin (Nesina, Vipidia). These medications raise blood incretin levels, thereby inhibiting glucagon release and lowering blood glucose levels. When used alone or with metformin, they do not cause hypoglycemia. They have modest efficacy (hemoglobin A_1C reductions of 0.5% to 1%, neutral effect on weight). Linagliptin does not require a dosage adjustment in renal insufficiency. Sitagliptin can be used in any degree of kidney disease but needs to be dosed based on GFR and creatinine levels.
• Thiazolidinediones (pioglitazone and rosiglitazone) increase insulin sensitivity and have been used in the therapy of type 2 diabetes. A1C reduction is 1.0% to 1.5%. Serum transaminase levels should be obtained before starting therapy and monitored periodically. Thiazolidinediones, in general, result in moderate weight gain and increase the risk for heart failure and osteoporosis/fractures. Rosiglitazone has an FDA black box warning for heart failure exacerbations and myocardial ischemia. Pioglitazone and rosiglitazone cause increased incidence of bladder cancer. Use thiazolidinediones with caution with calcium channel blockers, especially amlodipine (can cause fluid retention and edema).
• Acarbose and miglitol: These agonists inhibit pancreatic amylase and small intestinal glucosidases, thereby delaying carbohydrate absorption in the gut and reducing associated postprandial hyperglycemia. The major side effects are flatulence, diarrhea, and abdominal cramps.
• The meglitinides nateglinide and repaglinide and the bile acid sequestrant colesevelam can also be used to lower glucose levels but are expensive and generally poorly tolerated.
• Pramlintide is a synthetic analog of human amylin, which is synthesized by pancreatic beta cells and cosecreted with insulin in response to food intake. It suppresses glucagon secretion and slows stomach emptying and can be used as an adjunctive treatment for patients with T1DM or T2DM who inject insulin at mealtime. Nausea is its major side effect. This therapy has been largely replaced with use of GLP-1 analogs.
• Sulfonylureas: Sulfonylureas interact with ATP-sensitive potassium channels in the beta-cell membrane to increase insulin secretion and work best when given before meals. They reduce A1C by 1.0% to 1.5%. All sulfonylureas are contraindicated in patients who are allergic to sulfa. Use of sulfonylureas confers a greater risk of hypoglycemia than the other agents. Preferred agents in this class are glimepiride and glipizide. Sulfonylureas are now being considered for use as last or later resort or when cost is of major concern for the patient and when other therapies cannot be incorporated or are contraindicated.
• Combination therapy of various hypoglycemic agents is commonly used when dual therapy results in inadequate glycemic control.
  1. Insulin is indicated for the treatment of all T1DM and for T2DM patients whose condition cannot be adequately controlled with diet and oral agents. The American College of Endocrinology and the American Association of Clinical Endocrinologists recommend initiation of insulin therapy in patients with type 2 diabetes and an initial HbA_1c level >9%, or if the diabetes is uncontrolled despite optimal oral glycemic therapy. Insulin therapy may be initiated as augmentation, starting at 0.1 to 0.2 unit/kg of body weight, or as replacement, starting at 0.6 to 1.0 unit/kg. Tables 13 and 14 summarize onset, peak, and duration of action of currently available insulin preparations. The risks of insulin therapy include weight gain, hypoglycemia, and in rare cases, allergic or cutaneous reactions.
  2. Replacement insulin therapy should mimic normal release patterns.
     1. Approximately 50% to 60% of daily insulin can be given as a long-acting insulin (NPH, Ultralente, glargine, detemir) injected once or twice daily.
     2. The remaining 40% to 50% can be short-acting (regular) or rapid-acting (lispro, aspart, glulisine) to cover mealtime carbohydrates and correct increased current glucose levels.
     3. NPH and older basal insulins can be mixed with rapid-acting insulins like Humalog and regular; all newer basal insulins cannot be mixed in one syringe.
     4. Basal-bolus regimens are now preferred on injection of long-acting basal at bedtime or in AM to target fasting glycemia between 80 and 130, and rapid-acting mealtime insulins to target lower postprandial blood glucose <140 mg/dl.
     5. New combinations of basal insulins with GLP-1 analogs are now available:
        1. Soliqua: Combines glargine insulin and lixisenatide in one pen. Patients taking <30 units start at 15 units and patient taking >30 units start at 30 units and are titrated every 3 to 4 days until fasting blood glucose levels are between 80 and 130 mg/dl. One should not exceed 60 units of glargine insulin.
        2. Xultophy 100/3.6 is degludec insulin and liraglutide combination in one pen. Dosing is based on Tresiba dose. Patients start at 16 units and increase by 2 units every 5 to 7 days to target fasting glycemia between 80 and 130 mg/dl, and dose cannot exceed 50 units. The use of this combination may eliminate or reduce prandial insulin needs and limits weight gain caused by insulin.
• Continuous subcutaneous insulin infusion (CSII, or insulin pump [Fig. E4]) provides comparable or slightly better control than multiple daily injections. It should be considered for diabetes presenting in childhood or adolescence and during pregnancy. The guidelines for insulin pump therapy from the American Association of Diabetes Educators include “frequent and unpredictable fluctuations in blood glucose” and “patient perceptions that diabetes management impedes the pursuit of personal or professional goals.” Use of insulin pumps are today coupled with CGM monitoring and with software in which the computer is making the automatic adjustments to glucose levels, constituting what is referred to as an “artificial pancreas.” This allows for fewer fluctuations of glycemia. Newer hybrid closed-loop systems combine an insulin pump, a continuous glucose monitoring device, and control algorithms that automate insulin delivery to maintain glucose levels within predetermined ranges and avoid hypoglycemia or hyperglycemia.¹
• Antiplatelet therapy: Low-dose aspirin (ASA; 81 mg/day) has been proven to lower the risk of subsequent myocardial infarction, stroke, or vascular death in secondary prevention studies. The ADA recommends low-dose aspirin for primary prevention in diabetic patients with one additional cardiovascular risk factor, including age older than 50 yr, cigarette smoking, hypertension, obesity, albuminuria, hyperlipidemia, and family history of coronary artery disease. Clopidogrel can be used in patients with atherosclerotic cardiovascular disease (ASCVD) and a documented aspirin allergy. The ADA does not recommend aspirin therapy in diabetics younger than 50 yr of age at low risk for coronary artery disease.
• Lipid management: Measure fasting lipid profile at least annually in adults.
  1. All patients with diabetes with one or more additional risk factors for CVD should be on statin therapy together with lifestyle modification regardless of baseline lipid levels.
  2. Diabetic patients aged 40 to 75 with LDL cholesterol of 70 to 189 mg/dl and without clinical ASCVD should receive at least moderate-intensity statin therapy and consider high-intensity statin therapy if 10-yr ASCVD risk is ≥7.5%.
  3. Ezetimibe can be added to moderate-intensity statin therapy in those who cannot tolerate high-intensity statin therapy.
  4. Combination therapy with statin and fenofibrate is not recommended but may be considered in those with triglyceride levels equal or greater than 204 mg/dl. If triglycerides are not at goal with combination of statin and fibrate, then prescription fish oil is advised if triglyceride levels still exceed 300 mg/dl.
  5. PCK-9 inhibitors may be considered in diabetics with CAD risk when statins are insufficient and in those who cannot tolerate statins, have had cardiovascular events, and cannot achieve A_1c to target goal.
• Hypertension: Antihypertensive therapy is recommended to keep systolic blood pressure (BP) <140 and diastolic BP <90 mm Hg. Use of ACE inhibitors or angiotensin receptor blockers (ARBs) to decrease albuminuria and for prevention of progression of kidney disease should be considered regardless of presence of hypertension. Combination therapy with an ACE inhibitor and an ARB should be avoided due to increased risk of adverse effects among patients with diabetic nephropathy. In older adults a treatment goal of <130/70 mm Hg is not recommended due to higher mortality and morbidity.
• Bariatric surgery should be considered in adults with BMI >35 kg/m² and type 2 diabetes, especially if the diabetes is difficult to control with lifestyle and pharmacologic therapy. Five-yr outcome data showed that, among patients with type 2 DM and a BMR of 27 to 43, bariatric surgery plus intensive medical therapy was more effective than intensive medical therapy alone in decreasing, or in some cases resolving, hyperglycemia.⁷
• Hypoglycemia-a plasma glucose concentration low enough to cause symptoms or signs-is a rare occurrence in individuals without diabetes but is common in sulfonylurea-, glinide-, or insulin-treated diabetes.
• The plasma glucose concentration is normally maintained in a relatively narrow range, 72 to 144 mg/dl (4.0 to 8.0 mmol/L), owing to a fine balance between glucose influx (exogenous glucose delivery and endogenous glucose production) and glucose efflux (glucose utilization by insulin-sensitive tissues, such as the skeletal muscle, and insulin-insensitive tissues, particularly the brain).
• A classification of hypoglycemia in diabetics is shown in Table 15. Hypoglycemia results from an imbalance between glucose influx and glucose efflux due to either excessive glucose removal from the circulation, deficient glucose delivery into the circulation, or both.
• Hypoglycemia in diabetes is typically the result of the interplay of therapeutic hyperinsulinemia and compromised defenses against falling glucose levels resulting in hypoglycemia-associated autonomic failure (HAAF), including defective glucose counterregulation and impaired awareness of hypoglycemia (Fig. E5).
• An attenuated sympathoadrenal response to falling glucose levels, the key feature of HAAF, is induced by recent antecedent hypoglycemia, sleep, or prior exercise, and is reversible by short-term scrupulous avoidance of hypoglycemia.
• Iatrogenic hypoglycemia is associated with both morbidity and fatality in type 1 and type 2 diabetes mellitus. Risk factors for hypoglycemia are summarized in Table 16. Treat hypoglycemia in a conscious person with glucose tab or gel 15 to 20 g and intramuscular injection of glucagon if unconscious. Patient and family members should be instructed on the administration of glucagon for individuals at significant risk for severe hypoglycemia. A sick day management protocol for diabetic patients is described in Box 3.

• Diabetic retinopathy occurs in nearly 15% of patients with diabetes after 15 yr of diagnosis and increases 1%/yr after diagnosis. Glycemic, lipid, and blood pressure controls are essential to reduce the risk and progression of diabetic retinopathy. An annual comprehensive eye exam by an ophthalmologist or optometrist should begin at the time of diagnosis for those with T2DM and after 5 yr in those with T1DM. Retinal laser photocoagulation and vitrectomy are effective treatment modalities. Prevention is best accomplished by strict glucose and BP control. Early blockade of the renin-angiotensin system has been shown to slow progression of retinopathy in patients with type 1 diabetes.
• The frequency of neuropathy in patients with type 2 diabetes approaches 70% to 80%. It can be subdivided into sensorimotor neuropathy and autonomic neuropathy. Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, is effective and FDA approved for relief of diabetic peripheral neuropathy. Pregabalin and gabapentin (900 to 3600 mg/day) are also effective for the symptomatic treatment of peripheral neuropathic pain. Topical capsaicin, 5% lidocaine transdermal patches, amitriptyline, and carbamazepine are also modestly effective. Use of high-dose vitamin combination of B₁₂, B₆ with alpha lipoic acid may help with nerve preservation and worsening of neuropathy, but will have no immediate effect on pain.
• Diabetic gastroparesis is most often seen in patients who have had diabetes for at least 10 yr and typically have retinopathy, neuropathy, and nephropathy. Major manifestations are postprandial fullness, nausea, vomiting, and bloating. Pharmacologic therapy involves prokinetic agents (metoclopramide). Endoscopic injection of botulinum toxin into the pylorus and gastric electrical stimulation (using f electrodes placed laparoscopically in the muscle wall of the stomach antrum and connected to a neurostimulator) represent newer approaches to nonpharmacologic therapy.
• Nephropathy: The first sign of renal involvement in patients with DM is most often microalbuminuria, which is classified as incipient nephropathy. Before the current period of intensive glycemic control and blood pressure with ACE inhibitors and angiotensin receptor blockade, it was suggested that 25% to 45% of diabetic patients would develop clinically evident renal disease (proteinuria) and 4% to 17% would progress to end-stage renal disease. In the current era of intensive glycemic and blood pressure control and ACE/ARB use, clinically evident diabetic nephropathy has declined to 9% and end-stage renal disease 2% to 7%. Use of ACE inhibitor or ARB is not recommended in diabetics with normal blood pressure, no microalbuminuria (urine albumin to creatinine ratio less than 30 mg/g creatinine) and normal renal function (eGFR >60 ml/min/1.73 m²).
• Infections are generally more common in patients with diabetes because of multiple factors, such as impaired leukocyte function, decreased tissue perfusion secondary to vascular disease, repeated trauma because of loss of sensation, and urinary retention secondary to neuropathy.
• Prevention/delay of type 2 diabetes: Fewer than 10% of older adults with prediabetes progress to diabetes in 6.5 yr.⁸ Patients with prediabetes should achieve weight loss of 5% to 10% of body weight and increase physical activity to at least 150 min/wk of moderate activity such as walking. Metformin therapy may be considered in those at high risk, especially if they have hyperglycemia (HbA_1c ≥6) despite lifestyle interventions.
• The Mediterranean diet has been shown to prevent type 2 diabetes in patients with prediabetes and can delay the need of insulin use in type 2 diabetes in up to 50% of patients.
• Use of metformin in prediabetics can prevent onset of diabetes in up to 30% of patients, independent of diet.

• Patients with diabetes should be advised to have annual ophthalmologic examinations. In T1DM, ophthalmologic visits should usually begin 5 yr after diagnosis, whereas T2DM patients should be seen from disease onset. Fig. 6 illustrates a flow chart useful in determining the timing of initial ophthalmic examination after a diagnosis of diabetes mellitus.
• Podiatric care can significantly reduce the rate of foot infections and amputations in patients with DM. Noninfected neuropathic foot ulcers require debridement and reduction of pressure.
• Nephrology consultation in all cases of proteinuria, hyperkalemia, uncontrolled BP, and when GFR has decreased to <30 ml/min/1.73 m².

• Because normalization of serum glucose level is the ultimate goal, every patient with diabetes should measure his or her blood glucose with commercially available glucometers unless contraindicated by senility or blindness.
• Continuous glucose monitoring is now commercially available for all types of diabetics on multiple daily injections of insulin. The advantage of CGM is that it not only gives a patient a value, but it shows a rate of change at that moment and predicts impending hyperglycemia or hypoglycemia, allowing a patient to react appropriately. Among patients with poorly controlled type 2 DM treated with basal insulin without prandial insulin, CGM, as compared with blood glucose meter monitoring results in significantly lower HbA_1c levels.⁸
• Underinsured children and those with psychiatric illness are at greater risk for acute complications in T1DM and require frequent monitoring and aggressive risk management with diet, exercise, and periodic laboratory evaluation.
• Significant sustained weight loss using bariatric surgery has been reported as effective in achieving remission of type 2 diabetes in morbidly obese patients. Bariatric surgery may be considered for adults with BMI >35 kg/m² and T2DM, especially if diabetes or associated comorbidities are difficult to control with lifestyle and pharmacologic therapy.
• Cigarette smoking predicts incident type 2 diabetes. For a smoker at risk for diabetes, smoking cessation should be coupled with strategies for diabetes prevention and early detection.
• Glycemic control in hospitalized patients: The American College of Physicians (ACP) recommends against using intensive insulin therapy to strictly control blood glucose in nonsurgical intensive care unit (SICU)/medical intensive care unit (MICU) in patients with or without DM. The ACP recommends a target blood glucose level of 130 to 180 mg/dl if insulin therapy is used.
• Studies have shown that tight glycemic control in SICU patients can reduce infection rates and ICU stay. This was not seen in MICU patients. However, there is evidence showing that patients using continuous IV insulin infusions to keep tight glycemic control after open heart surgery reduces sternal wound infection rates.
• Having diabetes for longer than 10 yr is associated with doubled risk for dementia at age 70.⁸

Diabetes Mellitus Type 1 (Patient Information)

Diabetes Mellitus Type 2 (Patient Information)

Diabetic Foot (Related Key Topic)

Diabetic Gastroparesis (Related Key Topic)

Diabetic Ketoacidosis (Related Key Topic)

Diabetic Polyneuropathy (Related Key Topic)

Diabetic Retinopathy (Related Key Topic)

Gestational Diabetes Mellitus (Related Key Topic)

Hyperglycemic Hyperosmolar Syndrome (Related Key Topic)