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Diabetes Mellitus, Type 2

Samir Malkani, MD, MRCP–UK and Sanaa Ayyoub, MD Reviewed 06/2020
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Subject: Diabetes Mellitus, Type 2

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BASICS

DESCRIPTION

Diabetes mellitus (DM) type 2 is due to a progressive insulin secretory defect in the setting of insulin resistance. 
Geriatric Considerations

Monitor elderly for hypoglycemia; adjust doses for renal/hepatic dysfunction and cognitive function; less aggressive glucose targets than in younger patients

 
Pediatric Considerations

Incidence is increasing and parallels obesity epidemic.

 
Pregnancy Considerations

Diet, metformin, glyburide, and insulin are all options for treatment of gestational diabetes.

 

EPIDEMIOLOGY

Incidence

1.5 million new cases in the United States each year 

Prevalence

Estimated 30.3 million Americans (9.4% of the population); 90–95% are likely type 2. 

ETIOLOGY AND PATHOPHYSIOLOGY

  • Peripheral insulin resistance and/or defective insulin secretion with increased hepatic gluconeogenesis

  • Genetic factors: usually polygenic; rarely monogenic (e.g., peroxisome proliferator-activated receptor [PPAR] γ and insulin gene mutations)

  • Obesity (body mass index [BMI] ≥25 kg/m2) and visceral adiposity

  • Gut microbiome changes

  • Drug or chemical induced (e.g., glucocorticoids, highly active antiretroviral therapy [HAART], atypical antipsychotics, organ transplant immunosuppressants)

Genetics

  • Genome-wide association studies show many common variants confer small causal effect; 50% concordance in monozygotic twins

  • Family history is strongly predictive of risk.

RISK FACTORS

  • Parental history of type 2 diabetes

  • Gestational diabetes or history of baby with birth weight ≥4 kg (9 lb)

  • Polycystic ovarian syndrome (PCOS)

  • Hypertriglyceridemia or low high-density lipoprotein (HDL)—marker for insulin resistance

  • Ethnicity: African American, Latino, Native American, Asian, and Pacific Islander

  • Sedentary lifestyle, visceral obesity

  • Use of thiazides, antipsychotics, glucocorticoids, and statins

GENERAL PREVENTION

  • Maintenance of normal weight, or weight loss of 7% body weight, decrease intake of carbohydrates and overall calories. Moderate-intensity exercise and resistance training. Exercise 150 min/week.

  • Use of metformin, α-glucosidase inhibitors, thiazolidinediones (TZDs), and glucagon-like peptide-1 receptor agonist (GLP-1 RA) in select patients with prediabetes (1)[B]

COMMONLY ASSOCIATED CONDITIONS

Hypertension, dyslipidemia, metabolic syndrome, fatty liver disease, infertility, PCOS, acanthosis nigricans, hemochromatosis 

DIAGNOSIS

HISTORY

Polyuria, polydipsia, polyphagia, weight loss, weakness, fatigue, blurry vision, neuropathy, and frequent infections. Many individuals are asymptomatic. 

PHYSICAL EXAM

BMI, waist circumference, fundoscopic exam, oral exam, cardiopulmonary exam, abdominal exam for hepatomegaly, focused neurologic exam, and diabetic foot exam 

DIFFERENTIAL DIAGNOSIS

  • Type 1 DM—low or absent insulin C-peptide, positive β-cell autoantibodies, ketosis

  • DM is one of the features of Cushing syndrome, acromegaly, and glucagonoma.

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Criteria for diagnosis (1)[A
  • HbA1c ≥6.5% or

  • Hyperglycemic symptoms and random plasma glucose ≥200 mg/dL (11.1 mmol/L) or

  • Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) or

  • 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during oral glucose tolerance test (OGTT) with 75-g glucose load

  • If equivocal, repeat with a different test on the same sample or a repeat test in a separate sample.

Follow-Up Tests & Special Considerations

Screen patients with history of gestational diabetes for persistent diabetes/prediabetes with OGTT 6 to 12 weeks’ postpartum and every 3 years thereafter. 

TREATMENT

Tight control of type 2 diabetes prevents long-term microvascular complications, but benefits on macrovascular outcomes are not as apparent. Individuals likely to benefit from a more aggressive target (below) are those without preexisting DM complications, with recent diagnoses of DM, and with long life expectancy. Many medications have NOT been shown to improve long-term outcomes. 
  • Use patient-centered approach (individualized).

  • Cornerstone of therapy is lifestyle modification, with diet and exercise and control of cardiovascular risk factors (particularly blood pressure [BP] and lipids).

  • A1c targets—American Diabetes Association (ADA) recommendations (these are NOT universally accepted as not fully evidence based) (1)[C]. American College of Physicians targets differ (2).

    • A1c <7.0: for those with a long life expectancy, no cardiovascular disease (CVD), diagnosed DM for a short duration, and no history of hypoglycemia

    • A1c <8.0%: for those with a limited life expectancy, advanced micro- or macrovascular complications, extensive comorbidities, and a history of severe hypoglycemia or long-standing DM in whom the general goal is difficult to attain

    • Many experts recognize more liberal targets (2).

    • ADA guidelines—preprandial glucose of 80 to 130 mg/dL and peak postprandial glucose of <180 mg/dL (1)[C]

  • Use drugs from different classes for complementary action and limit side effects. Use monotherapy with metformin (if not contraindicated), but if A1c is ≥9%, start with dual therapy; if A1c ≥10%, BG 300 mg/dL, and patient is symptomatic, consider adding injectable therapy with insulin with/without GLP-1 analog (1)[A].

  • Always consider side effect profile, CV benefit, and cost.

GENERAL MEASURES

  • Diabetic foot exam at every visit

  • Nephropathy: annual urine microalbumin-to-creatinine ratio and plasma creatinine (eGFR)

  • Retinopathy: annual diabetic eye exam

  • If 40 to 75 years old, begin a statin—moderate to high intensity based on atherosclerotic CVD (ASCVD) risk.

  • If >50 years old, low-dose aspirin if at least one additional CV risk factor and low risk for GI bleeding

  • Hypertension: goal BP <140/80 mm Hg (Tighter control may be considered on individual basis.)

  • Pneumococcal (PPSV23) for all adults and pneumococcal conjugate vaccine (PCV13) for patients >65 years (and some younger—see CDC) and annual influenza vaccine

MEDICATION

First Line

Monotherapy 
  • Metformin

    • Reduces hepatic glucose production and has multiple other mechanisms of action

    • Preferred as first line due to high efficacy in lowering glucose, good safety profile, low risk of hypoglycemia, and low cost; also promotes weight loss

    • Some studies suggest CVD benefit; dosage: 500 to 2,000 mg in divided doses or extended release QD or BID (1)[A]

    • Avoid metformin in renal insufficiency with eGFR <30, prior to radiocontrast agent use, surgery, and severe acute illnesses (e.g., liver disease, cardiogenic shock, pancreatitis, hypoxia) due to risk of lactic acidosis.

    • Caution with acute heart failure, alcohol abuse, elderly; associated with GI side effects, vitamin B12 deficiency (Monitor levels yearly.)

    • Can be used in chronic kidney disease (CKD) patients with eGFR ≥45; reduce dose to ≤1,000 mg with close monitoring in patients with eGFR 30 to 45.

    • About 10% of patients on metformin develop diarrhea. For these patients and other patients who have contraindications to metformin use, a different agent can be used as monotherapy.

Second Line

  • General principles for choosing additional medications

    • If HbA1c not at goal, add second agent. Start with dual therapy when initial HbA1c >9%.

    • If patient has CAD, heart failure, or CKD, consider drugs shown to improve outcomes with these conditions.

    • Consideration should be given to drug-specific side effects (such as weight gain, hypoglycemia).

    • Cost of drug is an important consideration.

    • Choose regimen with patient input to optimize adherence (mode of administration, complexity).

  • GLP-1 RA (incretins)

    • Stimulate glucose-dependent insulin secretion.

    • Promote weight loss, no risk of hypoglycemia; some improve CV outcomes.

    • Small risk of acute pancreatitis. Caution with use in CKD ≥ stage 4. May exacerbate gastroparesis. Most are injectable drugs, insulin dose may need reduction; relatively expensive

    • Should not be used in patients with personal history/family history of medullary thyroid cancer or multiple endocrine neoplasia (MEN) type 2 (black box warning)

    • Exenatide (Byetta): 5 to 10 μg SC BID within 60 minutes before meals and at least 6 hours apart or exenatide ER (Bydureon) 2 mg/week

    • Liraglutide (Victoza): 0.6 to 1.8 mg/day; reduced composite endpoint of cardiovascular death, nonfatal MI or nonfatal stroke; improved CV outcomes (3)

    • Dulaglutide (Trulicity): 0.75 to 1.50 mg weekly; improved CV outcomes (3)

    • Lixisenatide (Adlyxin): uptitration to 20 μg SC QD; available in combination (insulin glargine/lixisenatide)—15 to 60 U SC QD

    • Semaglutide (Ozempic): 0.25 to 1.00 mg weekly; improved CV outcomes (3); (Rybelsus) 3 mg to 14 mg orally daily

  • SGLT2 inhibitors

    • Inhibit renal glucose reabsorption

    • Cause weight loss, no hypoglycemia risk

    • Canagliflozin, dapagliflozin, and empagliflozin reduced heart failure admissions and reduced progression of renal disease (3).

    • Empagliflozin and canagliflozin improved cardiovascular mortality outcomes (3).

    • Increase occurrence of genital mycotic infections and urinary tract infection. Increased risk of euglycemic diabetic ketoacidosis (DKA); relatively expensive

    • Do not initiate therapy if eGFR <45.

    • Canagliflozin (Invokana): 100 to 300 mg daily; increased risk for lower limb amputation

    • Dapagliflozin (Farxiga): 5 to 10 mg daily

    • Empagliflozin (Jardiance): 10 to 25 mg daily

    • Ertugliflozin (Steglatro): 5–15 mg daily

  • Dipeptidyl peptidase-4 (DPP-4) inhibitors

    • Inhibit the enzyme DPP-4, which deactivates endogenous incretins GLP-1 and GIP

    • Minimal risk for hypoglycemia; reduce dose in renal impairment with exception of linagliptin.

    • Weight neutral

    • Alogliptin and saxagliptin are associated with heart failure, but sitagliptin is not.

    • Clinical evidence shows no CV risk reduction (4).

    • Sitagliptin (Januvia): 100 mg/day

    • Saxagliptin (Onglyza): 2.5 or 5.0 mg daily

    • Linagliptin (Tradjenta): 5 mg/day

    • Alogliptin (Nesina): 25 mg/day

  • Sulfonylureas

    • Stimulate pancreatic β-cell production of insulin

    • Caution with renal or liver disease, sulfa allergy, creatinine clearance <50 mL/min

    • May cause modest weight gain, hypoglycemia

    • Low cost; widely available

    • Glipizide (Glucotrol): 2.5 to 40.0 mg/day; dosage >10 mg/day given BID before meals

    • Glipizide extended release: 5 to 20 mg/day

    • Glyburide (DiaBeta, Glynase, Micronase): 1.25 to 20.00 mg/day, glynase: 0.75 to 12.00 mg/day

    • Glimepiride (Amaryl): 1 to 8 mg/day

  • TZD

    • Increases insulin sensitivity; activates PPARs to increase glucose utilization

    • Pioglitazone reduces triglycerides (4); low cost

    • Obtain baseline liver function tests (LFTs). Use with caution if history of heart failure, worsening of heart failure symptoms.

    • Increased risk of fractures and low bone mass

    • Pioglitazone (Actos): 15 to 45 mg/day

    • Rosiglitazone (Avandia): 4 to 8 mg/day

  • Insulin

    • Activates insulin receptors, increases glucose disposal, inhibits hepatic glucose production

    • Potent glucose lowering effect; safe

    • Consider as initial therapy in those with A1c >10%, catabolic symptoms, ketosis.

    • Use as additional therapy if A1c not at goal after dual/triple therapy and GLP1-RA has been tried.

    • Can cause weight gain. High hypoglycemia risk. High cost. NPH and regular insulin are more affordable, safe, and effective.

    • Analogs have lower hypoglycemia risk than NPH and regular insulin.

    • Neutral effects on CV outcomes

    • Start with basal insulin at dose 0.1 to 0.3 U/kg/day. Titrate up to achieve desired blood glucose readings. Add mealtime (rapid/short acting) insulin if fasting glucose is at goal, but postmeal glucose is high. Mealtime starting dose can be 4 U or 10% of basal dose.

    • Rapid-acting analogs—lispro (Humalog), aspart (Novolog), glulisine (Apidra): duration of action 3 to 5 hours; ultrarapid (Fiasp) quicker onset

    • Inhaled insulin (Afrezza): rapid onset of action; duration of action 4.5 hours

    • Short-acting insulin—human regular (Humulin R/Novolin R/ReliOn R): duration of action 6 to 8 hours

    • Intermediate-acting insulin—human NPH (Humulin N/Novolin N/ReliOn N): duration of action 13 to 20 hours. Human regular U-500 (Humulin R U-500): duration of action 6 to 10 hours

    • Basal insulin analogs—glargine U-100 (Lantus, Basaglar): duration of action 22 to 24 hours; Glargine U-300 (Toujeo): duration of action 36 hours; detemir (Levemir): duration of action 21.5 hours. Degludec U-100, U-200 (Tresiba): duration of action 42 hours, does not need to be injected at same time each day

    • Premixed insulin products—NPH/regular 70/30 (Novolin 70/30, Humulin 70/30), 70/30 and 50/50 aspart mix (Novolog mix), 75/25 and 50/50 lispro mix (Humalog mix)

    • Mixed insulin must be taken with meals.

  • Amylinomimetic

    • Delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety (1)

    • Causes weight loss and lower insulin doses

    • Pramlintide (Symlin): 60 to 120 μg SC premeal

    • Reduce prandial insulin by 50%.

  • α-Glucosidase inhibitors

    • Inhibit intestinal α-glucosidase, slow intestinal carbohydrate digestions/absorption (1)

    • Avoid in renal insufficiency and bowel diseases.

    • Take at beginning of meals to decrease postprandial hyperglycemia.

    • Acarbose (Precose): 25 to 100 mg TID

    • Miglitol (Glyset): 25 to 100 mg TID

  • Meglitinides

    • Mechanism similar to SU, but much shorter duration of action

    • Take at beginning of meals.

    • Repaglinide (Prandin): 0.5 to 4.0 mg TID

    • Nateglinide (Starlix): 60 to 120 mg TID

  • Combination therapy

    • Drugs from different classes with complementary mechanisms of actions can be combined

    • Many formulations are available with combination of two oral medications, and injectable combinations of insulin with GLP-RA agonists

ADDITIONAL THERAPIES

  • Bile acid sequestrants

  • Dopamine-2 agonists

    • Bromocriptine (Cycloset) 1.6 to 4.8 mg PO every am; mechanism of action uncertain

SURGERY/OTHER PROCEDURES

For patients with BMI >35 kg/m2, consider bariatric surgery (1)[A]. 

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

A1c twice a year for patients with well-controlled blood glucose and quarterly for patients with hyperglycemia or recent changes in therapy; periodic monitoring of lipids, renal functions, and urinary microalbumin 

PATIENT EDUCATION

Diabetes self-management education 

PROGNOSIS

Normal lifespan with prevention of complications 

COMPLICATIONS

  • Emergencies: hyperosmolar coma, DKA

  • ASCVD, peripheral vascular disease, stroke, foot ulcers, Charcot joints

  • Microvascular: peripheral neuropathy, proliferative retinopathy, erectile dysfunction, and diabetic CKD

  • Ophthalmic: blindness, cataracts, glaucoma

  • GI: nonalcoholic fatty liver disease, gastroparesis

  • Neurologic: autonomic dysfunction, insensate feet

REFERENCES

1
American Diabetes Association. Standards of medical care. Diabetes Care.  2019;42(Suppl 1):S1–S193.
2
Qaseem A, Wilt TJ, Kansagara D, et al; for Clinical Guidelines Committee of the American College of Physicians. Hemoglobin A1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: a guidance statement update from the American College of Physicians. Ann Intern Med.  2018;168(8):569–576.
3
Acharya T, Deedwania P. Cardiovascular outcome trials of the newer anti-diabetic medications. Prog Cardiovasc Dis.  2019;62(4):342–348.
4
Carbone S, Dixon DL, Buckley LF, et al. Glucose-lowering therapies for cardiovascular risk reduction in type 2 diabetes mellitus: state-of-the-art review. Mayo Clin Proc.  2018;93(11):1629–1647.

ADDITIONAL READING

SEE ALSO

  • Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Hypertension, Essential

  • Algorithm: Type 2 Diabetes, Treatment

CODES

ICD10

  • E11.9 Type 2 diabetes mellitus without complications

  • E11.319 Type 2 diabetes mellitus with unspecified diabetic retinopathy without macular edema

  • E11.21 Type 2 diabetes mellitus with nephropathy

  • E11.59 Type 2 diabetes mellitus with oth circulatory complications

  • E11.8 Type 2 diabetes mellitus with unspecified complications

  • E11.29 Type 2 diabetes mellitus w oth diabetic kidney complication

  • E11.22 Type 2 diabetes mellitus w diabetic chronic kidney disease

ICD9

  • 250.00 Diabetes mellitus without mention of complication, type II or unspecified type, not stated as uncontrolled

  • 250.50 Diabetes with ophthalmic manifestations, type II or unspecified type, not stated as uncontrolled

  • 250.40 Diabetes with renal manifestations, type II or unspecified type, not stated as uncontrolled

  • 250.70 Diabetes with peripheral circulatory disorders, type II or unspecified type, not stated as uncontrolled

  • 250.02 Diabetes mellitus without mention of complication, type II or unspecified type, uncontrolled

SNOMED

  • 44054006 Diabetes mellitus type 2 (disorder)

  • 422034002 Diabetic retinopathy associated with type II diabetes mellitus (disorder)

  • 420279001 Renal disorder associated with type II diabetes mellitus (disorder)

  • 422166005 peripheral circulatory disorder associated with type II diabetes mellitus (disorder)

  • 771000119108 Chronic renal impairment associated with type 2 diabetes mellitus

  • 313436004 Type II diabetes mellitus without complication

CLINICAL PEARLS

Individualize A1c targets based on life expectancy, preexisting DM complications, comorbidities, and individual patient preferences and values. Hypoglycemia poses more short-term danger than hyperglycemia. Exercise, diet, BP control, and CV risk reduction with statins are the cornerstones of DM treatment. 
 
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