Diabetes Mellitus, Type 2

Swathi A. N. Rao, MD and Sathya S. Krishnasamy, MD Reviewed 06/2017
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Subject: Diabetes Mellitus, Type 2

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BASICS

DESCRIPTION

  • Diabetes mellitus (DM) type 2 can manifest as nonketotic hyperglycemia and is due to a progressive insulin secretory defect in the setting of insulin resistance.

  • Significant contributing factor to blindness, renal failure, and lower limb amputations

Geriatric Considerations

Monitor elderly for hypoglycemia; adjust doses for renal/hepatic dysfunction and cognitive function. 

Pediatric Considerations

Incidence is increasing and parallels weight gain. 

Pregnancy Considerations

First-line drug is insulin (class B) but may consider glyburide after the 1st trimester. Metformin may be continued through 1st trimester (class B) 1[A]. 

EPIDEMIOLOGY

Incidence

1.7 million new diagnoses/year in 2012 

Prevalence

  • In 2012, 29.1 million Americans or 9.3% of the population had DM; men and women equally affected

  • 7.6% of non-Hispanic Caucasians, 12.8% of Hispanics, 13.2% of non-Hispanic African Americans, 9% of Asian Americans, and 15.9% of Native Americans.

ETIOLOGY AND PATHOPHYSIOLOGY

  • Peripheral insulin resistance

  • Defective insulin secretion

  • Increased gluconeogenesis

  • Genetic factors: monogenic (e.g., PPARγ and insulin gene mutations) and polygenic

  • Obesity

  • Gut microbiome

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

Genetics

50% concordance in monozygotic twins 

RISK FACTORS

  • Family history: first-degree relative

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

  • Polycystic ovary syndrome (PCOS)

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

  • Hypertriglyceridemia or low high-density lipoprotein (HDL)

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

  • Impaired fasting glucose (IFG)/impaired glucose tolerance (IGT)

  • Sedentary lifestyle

  • Genetic factors

  • Thiazides and fluoroquinolones associated with dysglycemia 1[A]

GENERAL PREVENTION

  • Weight loss of 5-10% body weight, exercise 150 min/week, and decrease in fat and caloric intake. Moderate-intensity exercise and resistance training are recommended. Follow USDA dietary recommendation of 14 g fiber/1,000 kcal; metformin, orlistat, α-glucosidase inhibitors, or TZDs (high-risk prediabetics with cardiovascular risk factors) 1[A].

  • Use of text messages and smart phone applications are also encouraged. Consider GoMeals or MyFitnessPal 1[A].

COMMONLY ASSOCIATED CONDITIONS

Hypertension, hyperlipidemia, metabolic syndrome, fatty liver disease, infertility, PCOS, acanthosis nigricans, hemochromatosis 2[A

DIAGNOSIS

HISTORY

Polyuria, polydipsia, polyphagia, weight loss, weakness, fatigue, blurry vision, and frequent infections 

PHYSICAL EXAM

BMI, funduscopic exam, oral exam, cardiopulmonary exam, abdominal exam for hepatomegaly, focused neurologic exam, and diabetic foot exam 

DIFFERENTIAL DIAGNOSIS

  • Type 1 DM

  • Cushing syndrome, acromegaly, and glucagonoma

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Criteria for diagnosis 1[A
  • HbA1c ≥6.5% is diagnostic.

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

  • Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) on 2 occasions 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 testing.

Follow-Up Tests & Special Considerations
Screen patients with history of gestational diabetes for persistent diabetes/prediabetes 6 to 12 weeks postpartum with OGTT and at least every 3 years thereafter. 

TREATMENT

  • Use patient-centered approach (individualized).

  • A1C targets

    • ▪ A1C ≪7.0: For those with a long life expectancy and no cardiovascular disease (CVD) who have had DM for a short duration and no history of hypoglycemia
    • ▪ A1C 8.0-8.5%: For those with a limited life expectancy, advanced micro- or macrovascular complications, extensive comorbidities, and a history of hypoglycemia or long-standing DM in whom the general goal are difficult to attain.
  • FPG goal is ≪110 mg/dL (5.5 mmol/L) and 2 hour postprandial goal is ≪140 mg/dL):

    • ▪ Use drugs from different classes to achieve adequate control and limit side effects.
    • ▪ Consider the addition of insulin if FPG is not controlled by oral agents 1,2[A].

GENERAL MEASURES

  • Diabetic foot exam at every visit

  • Nephropathy: annual urine microalbumin-to-creatinine ratio

  • Retinopathy: annual diabetic eye exam

  • If 40 to 75 years old, begin a statin—moderate intensity for low-risk and high-intensity statin if ≥7.5% ASCVD risk 2[A].

  • Hypertension: goal BP ≪140/80 mm Hg (SBP ≪130 preferred if tolerated)

  • Angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker: first-line hypertension drug. If contraindicated, consider calcium channel blocker.

  • Hepatitis B to unvaccinated adults age 19 to 59 years

  • Limit protein to 0.8 to 1 g/kg weight/day for diabetics with early stages of chronic kidney disease (CKD).

  • Limit protein intake to 1 g/kg body weight/day for diabetic patients with advanced CKD.

PATIENT EDUCATION

  • Diabetes self-management education and support by certified diabetes educator

  • Lifestyle modifications with pharmacotherapy delays prediabetes progression to diabetes 1,2[A].

MEDICATION

First Line

  • Biguanides

    • Metformin (Glucophage, Fortamet, Riomet, Glumetza): preferred first medication because it promotes weight loss and improves insulin resistance. Dosage: 500 to 2,000 mg in divided doses or ER 1,000 to 2,000 mg every evening. Maximum effective dose 2,000 mg/day.
    • ▪ Avoid metformin and combination drugs containing 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 increased risk of lactic acidosis.
    • ▪ Caution with acute heart failure, alcohol abuse, elderly
    • ▪ Associated with GI side effects, vitamin B12 deficiency
  • Dipeptidyl peptidase-4 inhibitors

  • GLP-1 (glucagon-like peptide-1) receptor agonist (incretins)

    • Exenatide (Byetta, Bydureon): 5 to 10 μg SC BID within 60 minutes before meals and at least 6 hours apart
    • Liraglutide (Victoza): 0.6 mg/day SC for 1 week and then increase to 1.2, maximum 1.8 mg/day. Less expensive and better tolerated than exenatide; 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)
    • Albiglutide (Tanzeum): 30 to 50 mg SC q week in a single-dose pen
    • Dulaglutide (Trulicity) 0.75 to 1.5 mg weekly exenatide extended-release)): 2 mg/week
    • Lixisenatide (Lyxumia, Adlyxin) just approved by FDA—information forthcoming
    • ▪ Associated increased risk of acute pancreatitis with GLP-1 agonists and DPP4 inhibitors and caution with use in CKD ≥ stage 4 6[A]. GLP-1 analogs and Symlin require insulin adjustment and may exacerbate gastroparesis.
  • SGLT2 inhibitors

    • ▪ Inhibits glucose reabsorption by sodium glucose cotransporter-2 inhibition
    • Canagliflozin (Invokana) 100 to 300 mg single dose before breakfast; adjust dose with CKD.
    • Dapagliflozin (Farxiga) 5 to 10 mg daily; avoid use if eGFR ≪60.
    • Empagliflozin (Jardiance) 10 to 25 mg daily; avoid use if eGFR ≪45. Shown to reduce adverse cardiovascular morbidity and death—see EMPA-REG OUTCOME trial 7[A].
    • ▪ May cause hypotension, genital mycotic infections, UTI, impairment of renal function

Second Line

  • Insulin: rapid (aspart, lispro, glulisine), short (regular insulin), intermediate (neutral protamine hagedorn), long-acting (glargine, detemir), ultra long-acting (degludec)

    • ▪ May be used in combination with some oral agents
    • ▪ Humalog U200 available
    • ▪ Long-acting and ultra long-acting insulins have lower risk of hypoglycemia than short-acting.
    • Insulin detemir (Levemir) or insulin glargine (Lantus): 10 units (or 0.1 to 0.2 U/kg) once daily in the evening or 2 divided doses; added to oral agents. Onset of action 1 hour. No peak. Duration of action 16 to 23 hours. Biosimilar Basaglar now FDA-approved
    • ▪ Glargine U300 (Toujeo SoloStar) now available
    • Insulin degludec (Tresiba): U100 and U200 pens available. 0.2 to 0.4 U/kg in insulin-naïve patients or 1:1 conversion in insulin-experienced patients already on basal insulin. Combination basal/bolus insulin may be used (0.5 to 2 U/kg/day) after failure or oral agents.
    • ▪ Degludec/aspart 70/30 (Ryzodeg) now available
    • ▪ Human insulin inhalation powder (Afrezza). Given as a single inhalation before a meal, in combination with long-acting insulin; contraindicated in chronic lung disease; can cause edema when given with TZDs 8[B]
    • ▪ Consider insulin pump therapy and V-Go in select patients.
  • Amylinomimetic

    • Pramlintide (Symlin): 60 to 120 μg SC before every major meal
    • ▪ Prandial insulins (short-acting/rapid-acting) should be reduced by 50% if pramlintide is initiated to avoid hypoglycemia.
  • α-Glucosidase inhibitors

    • Acarbose (Precose): 25 to 100 mg TID
    • Miglitol (Glyset): 25 to 100 mg TID
    • ▪ Take at beginning of meals to decrease postprandial hyperglycemia.
  • Avoid in renal insufficiency and bowel diseases.

  • Meglitinides

    • Repaglinide (Prandin): 0.5 to 4 mg before meals; may be useful in patients with sulfa allergy or renal impairment
  • Diphenylalanine derivatives

    • Nateglinide (Starlix): 60 to 120 mg before meals TID
  • Bile acid sequestrants

  • Sulfonylureas

    • ▪ Caution with renal or liver disease, sulfa allergy, creatinine clearance ≪50 mL/min, pregnancy
    • Glipizide (Glucotrol): 2.5 to 40 mg/day. Dosage >10 mg/day given BID 30 minutes before meals
    • Glipizide extended-release: 5 to 20 mg/day
    • Glyburide (DiaBeta, Glynase, Micronase): 1.25 to 20 mg/day, Glynase 0.75 to 12 mg/day
    • Glimepiride (Amaryl): 1 to 8 mg/day
  • Thiazolidinediones

    • ▪ Obtain baseline liver function tests (LFTs); if abnormal, use with caution; routine monitoring of LFTs not recommended in those without liver disease; contraindicated in patients with NYHA Class III or IV heart failure
    • ▪ Increased risk of fractures and low bone mass 9[A]
    • Rosiglitazone (Avandia): 4 to 8 mg/day. Medication restrictions due to associated cardiac risks were relaxed in 2015.
    • ▪ May have role in stroke prevention in prediabetics 10[A]
    • Pioglitazone (Actos): 15 to 45 mg/day
    • ▪ There is associated increased risk of bladder cancer though risk appears small 11,12[A].

SURGERY/OTHER PROCEDURES

For patients with BMI >35 years, consider bariatric surgery 13[B]. 

COMPLEMENTARY & ALTERNATIVE MEDICINE

Cinnamon may improve glycemic control, with improvements in A1C and FBG 14[B]. 

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

  • Titrate oral medications every 3 months.

  • Monitor glucose, HbA1c, BP, body weight, lipid profile, and renal and liver function.

  • A1c twice a year for patients with well-controlled blood glucose and quarterly for patients with hyperglycemia or recent changes in therapy

PROGNOSIS

Normal lifespan with attention and prevention of comorbid complications 

COMPLICATIONS

  • Emergencies: hyperosmolar coma, diabetic ketoacidosis (DKA), Charcot joints

  • Atherosclerotic CVD, peripheral vascular disease, stroke

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

  • Ophthalmic: blindness, cataracts, glaucoma, retinopathy

  • GI: nonalcoholic fatty liver disease, gastroparesis, diarrhea

  • Neurologic: autonomic dysfunction

  • Foot ulcers and soft tissue infections

REFERENCES

American Diabetes Association. Standards of medical care in diabetes—2016. Diabetes Care.  2016;39(Suppl 1):S4–S5. [View Abstract on OvidInsights]
Garvey  WT, Mechanick  JI, Brett  EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity: executive summary. Endocr Pract.  2016;22(7):842–884. Available at https://www.aace.com/publications/guidelines.
Scirica  BM, Bhatt  DL, Braunwald  E, et al. Saxa-gliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med.  2013;369(14):1317–1326. [View Abstract on OvidInsights]
White  WB, Cannon  CP, Heller  SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med.  2013;369(14):1327–1335. [View Abstract on OvidInsights]
Green  JB, Bethel  MA, Armstrong  PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med.  2015;373(3):232–242. [View Abstract on OvidInsights]
Boldo  A, Comi  RJ. Clinical experience with U500 insulin: risks and benefits. Endocr Pract.  2012;18(1):56–61. [View Abstract on OvidInsights]
Fakhoury  WK, Lereun  C, Wright  D. A metaanalysis of placebo-controlled clinical trials assessing the efficacy and safety of incretin-based medications in patients with type 2 diabetes. Pharmacology.  2010;86(1):44–57. [View Abstract on OvidInsights]
MannKind Corporation Endocrinologic and Metabolic Drug Advisory Committee. AFREZZA® (insulin human [rDNA origin]) inhalation powder: an ultra-rapid acting insulin treatment to improve glycemic control in adult patients with diabetes mellitus. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm390865. Accessed December 7, 2016.
Schwartz  AV, Chen  H, Ambrosius  WT, et al. Effects of TZD use and discontinuation on fracture rates in ACCORD bone study. J Clin Endocrinol Metab.  2015;100(11):4059–4066.
Kernan  WN, Viscoli  CM, Furie  KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med.  2016;374(14):1321–1331. [View Abstract on OvidInsights]
Tuccori  M, Filion  KB, Yin  H, et al. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ.  2016;352:i1541. [View Abstract on OvidInsights]
Lewis  JD, Habel  LA, Quesenberry  CP, et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA.  2015;314(3):265–277. [View Abstract on OvidInsights]
Schauer  PR, Kashyap  SR, Wolski  K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med.  2012;366(17):1567–1576. [View Abstract on OvidInsights]
Akilen  R, Tsiami  A, Devendra  D, et al. Cinnamon in glycaemic control: systematic review and meta analysis. Clin Nutr.  2012;31(5):609–715. [View Abstract on OvidInsights]

SEE ALSO

  • Diabetes Mellitus, Type 1; Diabetic Ketoacidosis (DKA); Hypertension, Essential

  • Algorithm: Diabetes Mellitus, Type 2

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 diabetic 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

Target A1C ≪7.0 for those with a long life expectancy and no CVD, who have had DM for a short duration, and no history of hypoglycemia. 
 
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