> Table of Contents > Diabetes Mellitus, Type 2
Diabetes Mellitus, Type 2
Swathi A.N. Rao, MD
Sathya S. Krishnasamy, MD
image BASICS
DESCRIPTION
  • 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 metformin and glyburide are alternatives that do not cause adverse effects in some females (1,2)[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, altered gut microbiome. Genetic factors: monogenic (e.g., PPAR&ggr; and insulin gene mutations) and polygenic
  • Obesity, hemochromatosis
  • 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 hx of DM in first-degree relative, genetic factors, ethnicity (African American, Latino, Native American, Asian, and Pacific Islander)
  • Gestational diabetes or history of baby with birth weight ≥4 kg (9 lb), PCOS, obesity (BMI ≥25 kg/m2) and visceral adiposity, hypertriglyceridemia or low high-density lipoprotein, sedentary lifestyle, impaired fasting glucose (IFG)/impaired glucose tolerance (IGT)/metabolic syndrome (1)[A]
GENERAL PREVENTION
Weight loss of 5-10% body weight, exercise 150 minutes/week, decrease in fat and caloric intake. Follow USDA dietary recommendation of 14 g fiber/1,000 kcal; metformin, acarbose, or TZDs in high-risk prediabetics with cardiovascular risk factors (1)[A]
COMMONLY ASSOCIATED CONDITIONS
Hypertension, hyperlipidemia, metabolic syndrome, fatty liver disease, infertility, PCOS, acanthosis nigricans (1)[A]
image DIAGNOSIS
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
  • 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) or
  • 2-hour postprandial plasma glucose ≥200 mg/dL (11.1 mmol/L) after a 75-g glucose load after overnight fast of at least 8 hours
  • If equivocal, repeat testing (1,3)[A].
Follow-Up Tests & Special Considerations
Screen patients with history of gestational diabetes for persistent diabetes/prediabetes 6 to 12 weeks postpartum with OGTT, 1 year postpartum, and at least every 3 years thereafter (2,3)[A].
image TREATMENT
  • Use an individualized, patient-centered approach with attention to cost, comorbidities, and compliance.
  • A1C targets
    • A1C ≤6.5%: for nonpregnant adults with long life expectancy, no cardiovascular disease, DM for a short duration, and no hx of hypoglycemia. If not achievable safely, <7.0% (1,3)[A].
    • For those with a limited life expectancy, advanced micro- or macrovascular complications, extensive comorbidities, and history of hypoglycemia or long-standing DM goal A1C of 7-8% per AACE, <8% per ADA (1,3)[A]
    • Individualized goals for high glycators/variation in hemoglobin glycation index (4)[A]
  • FPG goal is <110 mg/dL (5.5 mmol/L) and 2-hour postprandial goal is <140 mg/dL (1)[A]. Per ADA, recommended 2-hour postprandial goal: 80 to 130 mg/dL and peak postprandial glucose <180 mg/dL (1)[A]
  • General approach
    • Individualized medical nutrition therapy by certified nutritionist and individualized exercise regimen with at least 150 minutes of moderate-intensity exercise per week
    • If A1C is <7.5%, oral monotherapy in the form of biguanides, GLP-1 receptor agonist, DPP-4 inhibitor, SGLT2 inhibitor, or &agr;-glucosidase inhibitor. Consider TZD, glinide, or sulfonylureas but with caution due to side effects.
    • If 7.5% < A1C <9.0%, metformin plus second medication, ideally weight-neutral or weight loss-promoting with low risk of hypoglycemia
    • If A1C ≥9.0%, initiate insulin alone or in combination with oral agents (1)[A].
GENERAL MEASURES
  • Comprehensive diabetic foot exam annually (3)[A].
  • Nephropathy: annual urine microalbumin to creatinine ratio and eGFR or albumin excretion rate (1,3)[A]
  • Retinopathy: dilated fundoscopic exam by ophthalmologist at diagnosis and every 2 years if normal, otherwise annually (3)[A]
  • If 40 to 75 years old, begin a statin—moderate intensity for low-risk and high-intensity statin if ≥7.5% ASCVD risk (3,5)[A].
  • Low-dose aspirin for all adults with CVD risk unless contraindicated.
  • Hypertension: goal BP <130/80 mm Hg (SBP <120 mm Hg preferred if tolerated). ACE inhibitor/ARB first-line antihypertensives (3)[A]
  • Vaccination: Follow CDC recommendations (1,3)[A]. Limit protein intake to 0.8 to 1 g/kg body weight/day for diabetics with early stages of CKD and to 1 g/kg body weight/day for those with advanced CKD (1,3)[A].
PATIENT EDUCATION
Diabetes self-management education and support by certified diabetes educator (1,3)[A].
MEDICATIONS
First Line
  • Biguanides
    • Metformin (Glucophage, Fortamet, Riomet, Glumetza): preferred first medication. 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, 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 (can merge with previous bullet)
    • Associated with GI side effects, vitamin B12 deficiency (3)[A].
  • Dipeptidyl peptidase-4 inhibitors
    • Weight neutral with minimal risk for hypoglycemia; dose adjustments in renal function decline with exception of linagliptin
    • Sitagliptin (Januvia): 100 mg/day
    • Saxagliptin (Onglyza): 2.5 mg/day, maximum 5 mg/day
    • Linagliptin (Tradjenta): 5 mg/day
    • Alogliptin (Nesina) 25 mg/day. Significant interactions with metformin (3)[A]
    • Linagliptin/metformin (Jentadueto): 2.5/500 mg PO BID, maximum 2.5/1,000 mg PO BID (3)[A]
  • Sulfonylureas
    • Caution with renal or liver disease, sulfa allergy, creatinine clearance <50 mL/min, elderly, 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 (3)[A]
    • Drugs that may potentiate effects of sulfonylureas: salicylates, clofibrate, warfarin (Coumadin), ethanol, and ACE inhibitors
  • Thiazolidinediones
    • Obtain baseline liver function tests: if abnormal, use with caution. Contraindicated in patients with NYHA Class III or IV heart failure.
    • Pioglitazone (Actos): 15 to 45 mg/day
    • P.295

    • Cumulative use of pioglitazone or rosiglitazone was not associated with the incidence of bladder cancer in a large, pooled multipopulation analysis (6)[A].
    • Duetact (pioglitazone hydrochloride and glimepiride): 30/2 mg PO daily with meal
    • Rosiglitazone (Avandia): 4 to 8 mg/day
Second Line
  • Insulin: rapid (aspart, lispro, glulisine); short (regular insulin); intermediate (neutral protamine hagedorn); long-acting (glargine, detemir); premixed (several types)
    • May be used in combination with certain oral agents. Combination basal/bolus insulin may be used (0.5 to 2 U/kg/day) after failure of oral agents.
    • Long-acting insulins have lower risk of hypoglycemia than short-acting insulin.
    • Insulin detemir (Levemir) or insulin glargine (Lantus): 10 units (or 0.1 to 0.2 units/kg) once daily in the evening or 2 divided doses (already mentioned). Onset of action 1 hour. No peak. Duration of action is 16 to 23 hours.
    • 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 (3)[B]
    • Concentrated human regular insulin (U-500) Eli Lilly: used for extreme insulin resistance (7)[B]
    • Toujeo Solostar pen (glargine U300) Sanofi-Aventis: used for insulin resistant patients. Improvement in nocturnal hypoglycemia compared to U100 glargine (8)[A]. Consider insulin pump therapy and V-Go in select patients (3)[A].
  • Amylinomimetic
    • Pramlintide (Symlin): 60 to 120 &mgr;g SC before every major meal
    • Prandial insulins (short-acting/rapid-acting) should be reduced by 50% if pramlintide is initiated to avoid hypoglycemia.
    • Avoid anticholinergics that slow intestinal absorption of nutrients (3)[A].
  • GLP-1 (glucagonlike peptide-1) receptor agonist (incretins)
    • Exenatide (Byetta): 5 to 10 &mgr;g SC BID within 60 minutes before meals and at least 6 hours apart. Extended-release formulation (Bydureon): 2 mg SC weekly
    • Liraglutide (Victoza): 0.6 mg/day SC for 1 week, then increase to 1.2, maximum 1.8 mg/day. Less expensive and better tolerated than exenatide; contraindicated in patients with personal or family history of medullary thyroid cancer or (MEN) type 2 (black box warning).
    • Liraglutide (Saxenda): 3 mg SC daily approved for treatment of obesity.
    • Albiglutide (Tanzeum): 30 to 50 mg SC qwk in a single-dose pen
    • Dulaglutide (Trulicity) 0.75 to 1.5 mg weekly: 2 mg/wk Associated increased risk of acute pancreatitis with GLP-1 agonists and DPP4 inhibitors and caution with use in CKD ≥ stage 4. GLP-1 analogs and Symlin require insulin adjustment and may exacerbate gastroparesis (3,9)[A].
  • &agr;-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.
    • Drug binders, such as cholestyramine resin, should be taken at least 2 hours apart from &agr;-glucosidase inhibitors (3)[A].
  • 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 (3)[A]
  • Bile acid sequestrants
    • Colesevelam: 3.75 g/day or 1.875 g BID (3)[A]
  • Dopamine-2 agonists
    • Bromocriptine mesylate immediate release (Cycloset): 0.8 to 1.6 mg/day within 2 hours of awakening
    • Alters hypothalamic regulation of metabolism and reduces hepatic gluconeogenesis (10)[A].
    • May cause dizziness, nausea, fatigue, rhinitis (3)[A]
  • SGLT2 inhibitors
    • Inhibits glucose reabsorption by sodium glucose cotransporter-2 inhibition
    • Canagliflozin (Invokana):100 to 300 mg single dose before breakfast; adjust dose with renal function decline
    • Dapagliflozin (Farxiga): 5 to 10 mg daily; avoid use if eGFR <60
    • Empagliflozin (Jardiance): 10 to 25 mg daily; avoid use if eGFR <45
    • Xigduo (dapagliflozin-metformin): 5/100, 10/1,000 mg PO daily
    • May cause hypotension, genital mycotic infections, UTI, impairment of renal function, electrolyte abnormalities, elevated LDL, and DKA and increased fracture risk (canagliflozin) (3)[A]
  • Drug interactions: Thiazides cause IGT and fluoroquinolones can cause hyper- and hypoglycemia.
SURGERY/OTHER PROCEDURES
For patients with BMI >35 m2/kg, consider bariatric surgery (11)[B].
COMPLEMENTARY & ALTERNATIVE MEDICINE
Cinnamon may improve glycemic control, with improvements in A1C and FBG (12)[B].
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Office visit frequency per physician discretion, use telemedicine/mobile communications and home BG monitoring.
  • 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
  • Consider CGM as clinically indicated.
PROGNOSIS
There is evidence that intensive glycemic control in newly diagnosed diabetics may reduce long-term CVD rates.
REFERENCES
1. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American association of clinical endocrinologists and american college of endocrinology: clinical practice guidelines for developing a diabetes mellitus comprehensive care plan— 2015. Endocr Pract. 2015;21(Suppl 1):1-87.
2. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007;30 (Suppl 2):S251-S260.
3. Standards of medical care in diabetes—2015: summary of revisions. Diabetes Care. 2015;38(Suppl):S4.
4. Hempe JM, Liu S, Myers L, et al. The hemoglobin glycation index identifies subpopulations with harms or benefits from intensive treatment in the ACCORD trial. Diabetes Care. 2015;38(6):1067-1074.
5. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25)(Suppl 2):S1-S45.
6. Levin D, Bell S, Sund R, et al. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia. 2015;58(3):493-504.
7. Boldo A, Comi RJ. Clinical experience with U500 insulin: risks and benefits. Endocr Pract. 2012;18(1):56-61.
8. Ritzel R, Roussel R, Bolli GB, et al. Patient-level meta-analysis of the EDITION 1, 2 and 3: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes. Diabetes Obes Metab. 2015;17(9):859-867.
9. Fakhoury WK, Lereun C, Wright D. A meta-analysis 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.
10. Defronzo RA. Bromocriptine: a sympatholytic, d2-dopamine agonist for the treatment of type 2 diabetes. Diabetes Care. 2011;34(4):789-794.
11. 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.
12. Akilen R, Tsiami A, Devendra D, et al. Cinnamon in glycaemic control: systematic review and meta analysis. Clin Nutr. 2012;31(5):609-615.
See Also
&NA;
  • Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Hypertension, Essential
  • Algorithm: Type 2 Diabetes, Treatment
Codes
&NA;
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
Clinical Pearls
&NA;
Individualized, patient-centered approach to management.