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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  • 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]. 



1.7 million new diagnoses/year in 2012 


  • 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.


  • 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)


50% concordance in monozygotic twins 


  • 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]


  • 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].


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



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


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


  • Type 1 DM

  • Cushing syndrome, acromegaly, and glucagonoma


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. 


  • 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].


  • 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.


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

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


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].


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


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



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


Normal lifespan with attention and prevention of comorbid 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


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]


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

  • Algorithm: Diabetes Mellitus, Type 2



  • 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


  • 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


  • 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


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.