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Diabetes Mellitus, Type 2

Samir Malkani, MRCP (UK), MD and Sanaa Ayyoub, MD Reviewed 06/2022

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Subject: Diabetes Mellitus, Type 2

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

Monitor for hypoglycemia; adjust doses for renal/hepatic dysfunction and cognitive function; less aggressive glucose targets than 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.

  • In gestational diabetes, screen for diabetes/prediabetes with OGTT 6 to 12 weeks postpartum and every 3 years.




1.5 million new cases in the United States each year 


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


  • Peripheral insulin resistance and 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, antiretroviral therapy, atypical antipsychotics, organ transplant immunosuppressants)


  • Small causal effect of common polymorphisms; 50% concordance in monozygotic twins

  • Family history is strongly predictive of risk.


  • 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)

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

  • Sedentary lifestyle, visceral obesity


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

  • Metformin, α-glucosidase inhibitors, thiazolidinediones (TZDs), and glucagon-like peptide-1 receptor agonist (GLP-1 RA) in prediabetes


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



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


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


  • 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.


Initial Tests (lab, imaging)

Criteria for diagnosis 
  • 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, perform different test on same sample or a repeat the test.


Tight glucose control prevents long-term microvascular complications, but benefits on macrovascular outcomes are less apparent. Individuals likely to benefit from a more aggressive target are those without preexisting DM complications, with recent diagnoses of DM, and with long life expectancy. 
  • Use patient-centered approach.

  • Dietary modification, regular exercise, control of cardiovascular risk factors (blood pressure [BP] and lipids)

  • A1c targets—ADA recommendations (1) and ACP targets differ (2).

    • A1c <7.0: long life expectancy, no cardiovascular disease (CVD), short duration of DM, no history of hypoglycemia

    • A1c <8.0%: limited life expectancy, advanced micro- or macrovascular complications, extensive comorbidities, history of severe hypoglycemia or long-standing DM where lower goal is difficult to attain.

    • The ACP recommends an HbA1c between 7% and 8% in most patients (2).

    • ADA recommends preprandial glucose 80 to 130 mg/dL; postprandial glucose <180 mg/dL

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

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


  • 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, prescribe moderate to high intensity statin.

  • If >50 years old, low-dose aspirin if one additional CV risk factor and low GI bleed risk

  • Hypertension: goal BP <140/80 mm Hg

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


First Line

  • Reduces hepatic gluconeogenesis and multiple other mechanisms of action

  • Preferred due to high efficacy in lowering glucose, good safety profile, low hypoglycemia risk, low cost, and weight loss

  • Some studies suggest CV benefit; dosage: 500 to 2,000 mg in divided doses BID or extended release QD

  • Avoid in 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 vitamin B12 deficiency

  • In CKD for eGFR 30 to 45 reduce dose to ≤1,000 mg, stop if eGFR <30.

  • Severe diarrhea in 10% of patients, requiring switch to another agent

Second and Third Line

  • General principles

    • If HbA1c not at goal, add second/third agent.

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

    • Consider drug-specific side effects such as weight gain, hypoglycemia.

    • Cost of drug is an important consideration.

    • Seek patient input to optimize adherence.

  • GLP-1 RA (incretins)

    • Enhance glucose-dependent insulin release.

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

    • Small risk of acute pancreatitis. Use cautiously in CKD ≥ stage 4. May exacerbate gastroparesis. Most are injectable, expensive.

    • Contraindicated in personal/family history of medullary thyroid cancer or multiple endocrine neoplasia (MEN) type 2

    • Exenatide (Byetta): 5 to 10 μg SC BID or exenatide ER (Bydureon) 2 mg/week

    • Liraglutide (Victoza): 0.6 to 1.8 mg/day; improved CV outcomes  (3)

    • Dulaglutide (Trulicity): 0.75 to 4.50 mg weekly; improved CV outcomes  (3)

    • Lixisenatide (Adlyxin): up to 20 μg SC QD

    • Semaglutide injection (Ozempic): 0.25 to 1.00 mg weekly; improved CV outcomes (3); oral (Rybelsus) 3 to 14 mg daily neutral CV risk (4)

  • SGLT2 inhibitors

    • Inhibit renal glucose reabsorption

    • Cause weight loss, no hypoglycemia risk

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

    • Empagliflozin and canagliflozin improved CV mortality  (3).

    • Canagliflozin slowed progression of renal disease, death from renal causes in those with albuminuria and GFR of 30–90 (5).

    • Dapagliflozin slowed progression of renal disease, and reduced mortality from renal or CV causes, in patients with GFR 25-75 (6).

    • Increase in genital mycotic infections and UTI. Increased risk of euglycemic diabetic ketoacidosis (DKA); relatively expensive

    • Do not initiate therapy if eGFR <45.

    • Canagliflozin (Invokana): 100 to 300 mg/day

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

    • Low risk for hypoglycemia; reduce dose in renal impairment except linagliptin.

    • Weight neutral

    • No evidence for CV risk reduction (7).

    • 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 β-cell production of insulin

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

    • May cause weight gain, hypoglycemia

    • Inexpensive

    • Glipizide (Glucotrol): 2.5-40.0 mg/day

    • Glipizide extended-release: 5-20 mg/day

    • Glyburide (DiaBeta, Micronase): 1.25-20.00 mg/day, Glynase: 0.75-12 mg/day

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

  • TZD

    • Increases insulin sensitivity; activates PPARs

    • Pioglitazone reduces triglycerides (7); low cost

    • Can worsen heart failure symptoms

    • Increased risk of fractures/low bone mass

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

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

  • Insulin

    • Increases glucose disposal, inhibits hepatic glucose production

    • Potent glucose lowering; safe

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

    • Use as additional therapy after dual/triple therapy has been tried.

    • Weight gain. High hypoglycemia risk

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

    • Neutral effects on CV outcomes

    • Basal insulin start with 0.1 to 0.3 U/kg/day. Titrate up for desired result. Add mealtime (rapid/short acting) insulin if post meal 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 and lispro-aabc) 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 13 to 20 hours. Human regular U-500 (Humulin R U-500): duration 6 to 10 hours

    • Basal insulin analogs—glargine U-100 (Lantus, Basaglar): duration 22 to 24 hours; Glargine U-300 (Toujeo): duration 36 hours; detemir (Levemir): duration 21.5 hours. Degludec U-100, U-200 (Tresiba): duration 42 hours

    • 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)

  • Amylinomimetic

    • Delays gastric emptying, blunts glucagon, enhances satiety

    • Causes weight loss

    • Reduce prandial insulin by 50%.

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

  • α-Glucosidase inhibitors

    • Slows intestinal carbohydrate digestion

    • Avoid in renal insufficiency and bowel diseases.

    • Decreases 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.


For patients with BMI >35 kg/m2, consider bariatric surgery. 



Diabetes self-management education 


Normal lifespan with good management 


  • Emergencies: hyperosmolar coma, DKA

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

  • Microvascular: neuropathy, retinopathy, diabetic CKD

  • Ophthalmic: blindness, cataracts, glaucoma

  • GI: fatty liver disease, gastroparesis


American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2021;44:S1–S232.
Qaseem A, Wilt TJ, Kansagara D, et al; 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.
Acharya T, Deedwania P. Cardiovascular outcome trials of the newer anti-diabetic medications. Prog Cardiovasc Dis. 2019;62(4):342–348.
Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841–851.
Perkovic V, Jardine MJ, Neal B, et. al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–2306
Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–1446.
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.


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

  • Algorithm: Type 2 Diabetes, Treatment



  • E11.329 Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema

  • E11.331 Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema

  • E11.359 Type 2 diabetes mellitus with proliferative diabetic retinopathy without macular edema

  • E11.349 Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema

  • E11.351 Type 2 diabetes mellitus with proliferative diabetic retinopathy with macular edema

  • E11.321 Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema

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

  • E11.35 Type 2 diabetes mellitus with proliferative diabetic retinopathy

  • E11.339 Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema

  • E11.32 Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy

  • E11.51 Type 2 diabetes mellitus with diabetic peripheral angiopathy without gangrene

  • E11.34 Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy

  • E11.618 Type 2 diabetes mellitus with other diabetic arthropathy

  • E11.33 Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy

  • E11.341 Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema

  • E11.311 Type 2 diabetes mellitus with unspecified diabetic retinopathy with macular edema

  • E11.8 Type 2 diabetes mellitus with unspecified complications

  • E11.69 Type 2 diabetes mellitus with other specified complication

  • E11.52 Type 2 diabetes mellitus with diabetic peripheral angiopathy with gangrene


  • 44054006 Type 2 diabetes mellitus

  • 190388001 Multiple complications due to type 2 diabetes mellitus

  • 443694000 Type II diabetes mellitus uncontrolled

  • 313436004 Type 2 diabetes mellitus without complication


Individualize A1c targets based on life expectancy and comorbidities. Hypoglycemia poses more short-term danger than hyperglycemia.