Diabetes Mellitus, Type 2

Peripheral insulin resistance and/or 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, highly active antiretroviral therapy [HAART], atypical antipsychotics, organ transplant immunosuppressants)

Genome-wide association studies show many common variants confer small causal effect; 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)—marker for insulin resistance

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

Sedentary lifestyle, visceral obesity

Use of thiazides, antipsychotics, glucocorticoids, and statins

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

Use of metformin, α-glucosidase inhibitors, thiazolidinediones (TZDs), and glucagon-like peptide-1 receptor agonist (GLP-1 RA) in select patients with prediabetes (1)[B]

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, repeat with a different test on the same sample or a repeat test in a separate sample.

Use patient-centered approach (individualized).

Cornerstone of therapy is lifestyle modification, with diet and exercise and control of cardiovascular risk factors (particularly blood pressure [BP] and lipids).

A1c targets—American Diabetes Association (ADA) recommendations (these are NOT universally accepted as not fully evidence based) (1)[C]. American College of Physicians targets differ (2).

• A1c <7.0: for those with a long life expectancy, no cardiovascular disease (CVD), diagnosed DM for a short duration, and no history of hypoglycemia

• A1c <8.0%: for those with a limited life expectancy, advanced micro- or macrovascular complications, extensive comorbidities, and a history of severe hypoglycemia or long-standing DM in whom the general goal is difficult to attain

• Many experts recognize more liberal targets (2).

• ADA guidelines—preprandial glucose of 80 to 130 mg/dL and peak postprandial glucose of <180 mg/dL (1)[C]

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

Always consider side effect profile, CV 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, begin a statin—moderate to high intensity based on atherosclerotic CVD (ASCVD) risk.

If >50 years old, low-dose aspirin if at least one additional CV risk factor and low risk for GI bleeding

Hypertension: goal BP <140/80 mm Hg (Tighter control may be considered on individual basis.)

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

Metformin

• Reduces hepatic glucose production and has multiple other mechanisms of action

• Preferred as first line due to high efficacy in lowering glucose, good safety profile, low risk of hypoglycemia, and low cost; also promotes weight loss

• Some studies suggest CVD benefit; dosage: 500 to 2,000 mg in divided doses or extended release QD or BID (1)[A]

• Avoid 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 risk of lactic acidosis.

• Caution with acute heart failure, alcohol abuse, elderly; associated with GI side effects, vitamin B₁₂ deficiency (Monitor levels yearly.)

• Can be used in chronic kidney disease (CKD) patients with eGFR ≥45; reduce dose to ≤1,000 mg with close monitoring in patients with eGFR 30 to 45.

• About 10% of patients on metformin develop diarrhea. For these patients and other patients who have contraindications to metformin use, a different agent can be used as monotherapy.

General principles for choosing additional medications

• If HbA1c not at goal, add second agent. Start with dual therapy when initial HbA1c >9%.

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

• Consideration should be given to drug-specific side effects (such as weight gain, hypoglycemia).

• Cost of drug is an important consideration.

• Choose regimen with patient input to optimize adherence (mode of administration, complexity).

GLP-1 RA (incretins)

• Stimulate glucose-dependent insulin secretion.

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

• Small risk of acute pancreatitis. Caution with use in CKD ≥ stage 4. May exacerbate gastroparesis. Most are injectable drugs, insulin dose may need reduction; relatively expensive

• 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)

• Exenatide (Byetta): 5 to 10 μg SC BID within 60 minutes before meals and at least 6 hours apart or exenatide ER (Bydureon) 2 mg/week

• Liraglutide (Victoza): 0.6 to 1.8 mg/day; reduced composite endpoint of cardiovascular death, nonfatal MI or nonfatal stroke; improved CV outcomes (3)

• Dulaglutide (Trulicity): 0.75 to 1.50 mg weekly; improved CV outcomes (3)

• Lixisenatide (Adlyxin): uptitration to 20 μg SC QD; available in combination (insulin glargine/lixisenatide)—15 to 60 U SC QD

• Semaglutide (Ozempic): 0.25 to 1.00 mg weekly; improved CV outcomes (3); (Rybelsus) 3 mg to 14 mg orally daily

SGLT2 inhibitors

• Inhibit renal glucose reabsorption

• Cause weight loss, no hypoglycemia risk

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

• Empagliflozin and canagliflozin improved cardiovascular mortality outcomes (3).

• Increase occurrence of genital mycotic infections and urinary tract infection. Increased risk of euglycemic diabetic ketoacidosis (DKA); relatively expensive

• Do not initiate therapy if eGFR <45.

• Canagliflozin (Invokana): 100 to 300 mg daily; increased risk for lower limb amputation

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

• Minimal risk for hypoglycemia; reduce dose in renal impairment with exception of linagliptin.

• Weight neutral

• Alogliptin and saxagliptin are associated with heart failure, but sitagliptin is not.

• Clinical evidence shows no CV risk reduction (4).

• 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 pancreatic β-cell production of insulin

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

• May cause modest weight gain, hypoglycemia

• Low cost; widely available

• Glipizide (Glucotrol): 2.5 to 40.0 mg/day; dosage >10 mg/day given BID before meals

• Glipizide extended release: 5 to 20 mg/day

• Glyburide (DiaBeta, Glynase, Micronase): 1.25 to 20.00 mg/day, glynase: 0.75 to 12.00 mg/day

• Glimepiride (Amaryl): 1 to 8 mg/day

TZD

• Increases insulin sensitivity; activates PPARs to increase glucose utilization

• Pioglitazone reduces triglycerides (4); low cost

• Obtain baseline liver function tests (LFTs). Use with caution if history of heart failure, worsening of heart failure symptoms.

• Increased risk of fractures and low bone mass

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

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

Insulin

• Activates insulin receptors, increases glucose disposal, inhibits hepatic glucose production

• Potent glucose lowering effect; safe

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

• Use as additional therapy if A1c not at goal after dual/triple therapy and GLP1-RA has been tried.

• Can cause weight gain. High hypoglycemia risk. High cost. NPH and regular insulin are more affordable, safe, and effective.

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

• Neutral effects on CV outcomes

• Start with basal insulin at dose 0.1 to 0.3 U/kg/day. Titrate up to achieve desired blood glucose readings. Add mealtime (rapid/short acting) insulin if fasting glucose is at goal, but postmeal 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) 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 of action 13 to 20 hours. Human regular U-500 (Humulin R U-500): duration of action 6 to 10 hours

• Basal insulin analogs—glargine U-100 (Lantus, Basaglar): duration of action 22 to 24 hours; Glargine U-300 (Toujeo): duration of action 36 hours; detemir (Levemir): duration of action 21.5 hours. Degludec U-100, U-200 (Tresiba): duration of action 42 hours, does not need to be injected at same time each day

• 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)

• Mixed insulin must be taken with meals.

Amylinomimetic

• Delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety (1)

• Causes weight loss and lower insulin doses

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

• Reduce prandial insulin by 50%.

α-Glucosidase inhibitors

• Inhibit intestinal α-glucosidase, slow intestinal carbohydrate digestions/absorption (1)

• Avoid in renal insufficiency and bowel diseases.

• Take at beginning of meals to decrease 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

• Many formulations are available with combination of two oral medications, and injectable combinations of insulin with GLP-RA agonists

Bile acid sequestrants

• Colesevelam: 3.75 g/day or 1.875 g BID

Dopamine-2 agonists

• Bromocriptine (Cycloset) 1.6 to 4.8 mg PO every am; mechanism of action uncertain

Emergencies: hyperosmolar coma, DKA

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

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

Ophthalmic: blindness, cataracts, glaucoma

GI: nonalcoholic fatty liver disease, gastroparesis

Neurologic: autonomic dysfunction, insensate feet

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

Algorithm: Type 2 Diabetes, Treatment

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 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