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neuropathy, and frequent infections

PHYSICALEXAM

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

DIFFERENTIALDIAGNOSIS

Type 1 DM—low or absent insulin, pancreatic autoantibodies, ketosis

DM is one of the features of Cushing syndrome, acromegaly, and glucagonoma.

DIAGNOSTIC TESTS & INTERPRETATION

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 two 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.

TREATMENT

It is uncertain as to whether and to what extent tight control of Type 2 diabetes prevents long-term macroand microvascular complications (2),(3)[A]. Individuals most likely to benefit from a more aggressive target (below) are those without preexisting complications of diabetes, with recent diagnoses of DM, and with otherwise long life expectancy. Most medications have NOT been shown to improve long-term outcomes.

Use patient-centered approach (individualized).

Cornerstone of therapy is lifestyle modification and control of cardiovascular

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risk factors (particularly blood pressure and lipids).

Most oral agents lower A1c 0.5–1%. Most oral agents and insulin cause weight gain.

A1C targets—according to ADA(recommendations NOT universally accepted as not fully evidence-based) (1)[C]:

–A1C <7.0: for those with a long life expectancy and no cardiovascular disease (CVD) who has had DM for a short duration and no history of hypoglycemia

–A1C <8.0%: for those with a limited life expectancy, advanced microor macrovascular complications, extensive comorbidities, and a history of hypoglycemia or long-standing DM in whom the general goal is difficult to attain

–ADAguidelines—preprandial glucose of 80 to 130 mg/dLand peak postprandial glucose of <180 mg/dL(1)[C]

–Many experts recognize more liberal targets than above as appropriate for

many individuals (2),(3)[A].

ADA: 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. Use monotherapy unless A1c is ≥9% → dual therapy; if A1c ≥10%, BG 300 mg/dL, and patient is symptomatic → insulin plus additional therapy (1)[A]

GENERALMEASURES

Diabetic foot exam at every visit

Nephropathy: annual urine microalbumin-to-creatinine ratio if not on ACEinhibitor

Retinopathy: annual diabetic eye exam

If 40 to 75 years old, begin a statin—moderate to high intensity based on ASCVD risk.

Low-dose aspirin in patients ≥50 years old with at least one additional CV risk factor and without risks for GI bleeding

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

Pneumococcal (PPSV-23) for all adults and pneumococcal conjugate vaccine (PCV-13) for patients >65 years (and some younger—see CDC) and annual influenza vaccine

PATIENT EDUCATION

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Diabetes self-management education and support by certified diabetes educator

Lifestyle modifications with or without pharmacotherapy delays prediabetes progression to diabetes (1)[A].

MEDICATION

First Line

Biguanides

–Metformin: preferred first medication for most because it likely reduces risk of death and 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 (1,3)[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 CKD patients with eGFR ≥45; can use reduced dose of ≤1,000 mg with close monitoring in patients with eGFR 30 to 45 (4)[A]

Dipeptidyl peptidase-4 inhibitors

–Weight neutral with minimal risk for hypoglycemia; dose adjustments in renal function decline with exception of linagliptin.

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

–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

–Glucagon-like peptide-1 (GLP-1) receptor agonist (incretins). Risk of acute pancreatitis with GLP-1 agonists and DPP4 inhibitors. Caution with use in CKD ≥ stage 4. May exacerbate gastroparesis. Cause modest weight loss. GLP-1 analogs require insulin adjustment if patient on insulin.

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

–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)

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–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

–Albiglutide (Tanzeum): 30 to 50 mg SC q week in a single-dose pen

–Dulaglutide (Trulicity): 0.75 to 1.50 mg weekly

–Lixisenatide (Adlyxin): uptitration to 20 mcg SC qd; available in combination drug Soliqua (insulin glargine/lixisenatide)—15 to 60 units SC

SGLT2 inhibitors

–Inhibit glucose reabsorption by sodium glucose cotransporter-2 inhibition and cause modest weight loss, but might increase risk of lower extremity amputation. Avoid in patients with peripheral vascular disease and foot ulcers.

–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 cardiovascular morbidity and death (5)[B]

–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 longacting (degludec), concentrated (Humulin U200, U500 Kwikpen, and solution with U500-specific syringes)

–May be used in combination with some oral agents

–Long-acting and ultra long-acting insulins have lower risk of hypoglycemia than short-acting.

–Insulin detemir (Levemir) or insulin glargine (Lantus, Basaglar): 10 units (or 0.1 to 0.2 U/kg) once daily in the evening or 2 divided doses; added to oral agents and then titrated. Onset of action 1 hour. No peak; duration of action 16 to 23 hours

–Avariety of concentrations available U-100, U-200, and U-300

–Insulin degludec (Tresiba): 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 2.0 U/kg/day) after failure or oral agents.

–Degludec/aspart 70/30 (Ryzodeg) available

–Human insulin inhalation powder (Afrezza). Given as a single inhalation

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before a meal, in combination with long-acting insulin; contraindicated in chronic lung disease; can cause edema when given with TZDs

– Consider sensor-augmented insulin pump and CGM 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.

Meglitinide: repaglinide (Prandin): 0.5 to 4.0 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

– Colesevelam: 3.75 g/day or 1.875 g BID Sulfonylureas

–Caution with renal or liver disease, sulfa allergy, creatinine clearance <50 mL/min, pregnancy; may cause weight gain

–Glipizide (Glucotrol): 2.5 to 40.0 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 20.0 mg/day, Glynase: 0.75 to 12.00 mg/day

–Glimepiride (Amaryl): 1 to 8 mg/day

TZDs

–Obtain baseline liver function tests (LFTs). Use w/caution if history of heart failure.

–Increased risk of fractures and low bone mass

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

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

Bromocriptine (Cycloset): 1.6 to 4.8 mg PO q AM; a dopamine agonist, mechanism of action uncertain

Combination therapy

–Ertugliflozin/metformin hydrochloride (Segluromet): SGLT2 inhibitor and biguanide: 2.5 to 7.5 mg/500 to 1,000 mg

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–Canagliflozin/metformin (Invokamet): 50 to 150/500 to 1,000 mg, max dose 300/2,000 mg, XR form available

–Dapagliflozin/metformin (Xigduo): 5 to 10/500 to 1,000 mg, max dose 10/2,000 mg; XR form available

–Empagliflozin/metformin (Synjardy): 5.0 to 12.5/500 to 1,000 mg, max dose 25/2,000 mg; XR form available

–Glipizide/metformin (Metaglip): 2.5/250 mg, 2.5/500 mg, 5/500 mg; 1 to 2 tabs PO qd BID

–Glyburide/metformin (Glucovance): 1.25/250 mg, 2.5/5000 mg, 5/500 mg; 1 TO 2 tabs PO BID

–Pioglitazone/metformin (ACTOplus met) available in IR and XR forms

–Rosiglitazone/metformin (Avandamet): 2/500 mg, 2/1,000 mg, 4/500 mg, 4/1,000 mg initial therapy; 1 to 2 tabs PO BID, max 8 mg/2,000 mg/day

–Repaglinide/metformin (Prandimet): 1/500 mg, 2/500 mg, individualize dose PO BID to TID

–Alogliptin/metformin (Kazano): 12.5/500 to 1000 mg, 1 tab PO BID, max dose 25/2,000 mg

–Linagliptin/metformin (Jentadueto): 2.5/500 to 1,000 mg, 1 tab PO BID, max dose 5/2,000 mg

–Kombiglyze XR—2.5 to 5.0/500 to 1,000 mg; 1 to 2 tabs PO qd, max dose 5/2,000 mg PO daily

–Sitagliptin/metformin (Janumet): available in XR

–Empagliflozin/linagliptin (Glyxambi): 10 to 25 mg/5 mg, 1 tab q AM

–Alogliptin/pioglitazone (Oseni): 12.5 to 25/15 to 45 mg, max dose 25/45 mg daily

–Combination Duetact pioglitazone with glimepiride (Duetact): 30/2 to 4 mg, 1 tab q AM

–Insulin glargine/lixisenatide (Soliqua 100/33): 15 to 60 units SC qd

–Insulin degludec/liraglutide (Xultophy 100/3.6): 16 to 50 units SC qd

SURGERY/OTHER PROCEDURES

For patients with BMI >35 kg/m2, consider bariatric surgery (1)[A].

ONGOING CARE

FOLLOW-UPRECOMMENDATIONS

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Patient Monitoring

Monitor glucose, HbA1c, BP, body weight, lipid profile, and renal and liver function q 3mo at first.

A1c twice a year for patients with well-controlled blood glucose and quarterly for patients with hyperglycemia or recent changes in therapy

PROGNOSIS

Normal lifespan with attention and prevention of comorbid complications

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

REFERENCES

1.American Diabetes Association. Standards of medical care in diabetes— 2017. Diabetes Care. 2017;40(Suppl 1):S1–S135.

2.Shaughnessy AF, Erlich DR, Slawson DC, et al. Type 2 diabetes: updated evidence requires updated decision making. Am Fam Physician. 2015;92(1):22.

3.Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ. 2011;343:d4169.

4.Inzucchi SE, Lipska KJ, Mayo H, et al. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312(24):2668– 2775.

5.Zinman B, Wanner C, Lachin JM, et al; for EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2228.

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