Diabetes Mellitus, 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

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.

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.

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

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

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.

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

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