Table 2.

Glucose-lowering therapy: Key clinical considerations

Lifestyle: Medical Nutritional Therapy consisting of healthy food choices and portion control Exercise as tolerated at least 30 minutes five times weekly
		Non-insulin add-on therapies to metformin*, or Monotherapy when metformin is contraindicated Optimal selection of diabetes medications should be made on an individual basis after consideration of multiple factors such as HbA1c lowering, risk for hypoglycemia, effect on weight and comorbidities, side effects, complexity of regimen, cost, and/or preference such as willingness to use injectable therapies.
Class	Biguanide *Metformin is first choice unless contraindicated	Glucagon-like peptide (GLP)-1 Receptor Agonist	Sodium-glucose cotransporter (SGLT) 2 Inhibitor	Dipeptidyl Peptidase (DPP) 4 Inhibitor	Insulin Secretagogue (sulfonylurea, meglitinide, or D-phenylalanine derivative)	Thiazolidinedione (TZD)	α-Glucosidase Inhibitor	Bile Acid Sequestrant	Centrally Acting Agent	Amylin Analog *Only for use with Insulin*
Estimated HbA1c reduction	1%	0.8–1.5%	0.5–0.6%	0.75%	0.75–1.25%	1.0–1.25%	0.5–1.0%	0.3–0.9%	0.4–0.8%	0.5–0.6%
Agents	metformin	exenatide liraglutide albiglutide dulaglutide	canagliflozin dapagliflozin empaglifozin	alogliptin linagliptin saxagliptin sitagliptin	glipizide glyburide glimepiride repaglinide nateglinide	pioglitazone rosiglitazone	acarbose miglitol	colesevelam	Bromocriptine mesylate	Pramlintide
Route	oral	Injectable	oral	oral	oral	oral	oral	oral	oral	injectable
Actions	Decreases hepatic glucose production and intestinal absorption of glucose; improves insulin sensitivity by increasing peripheral glucose uptake and utilization	Increases glucose-dependent insulin secretion, lowers glucagon secretion, slows gastric emptying, and promotes satiety	Lowers the renal threshold for glucose reabsorption to increase urinary glucose excretion	Blocks inactivation of incretin hormones to increase insulin release and decrease glucagon in a glucose-dependent manner	Stimulates insulin release from pancreatic β cells.	Activates PPARγ, increases peripheral glucose utilization, and decreases hepatic glucose production	Reduces absorption of dietary carbohydrate	Uncertain mechanism of glucose lowering; binds bile acids in intestine, impeding their reabsorption and increasing LDL-C clearance	Uncertain mechanism of glucose lowering with increased insulin sensitivity and glucose disposal	Slows gastric emptying, reduces glucagon secretion, and increases satiety
Side Effects	Diarrhea, nausea/vomiting, flatulence, vitamin B12 deficiency, lactic acidosis	Nausea, diarrhea, possible pancreatitis	Polyuria, urinary frequency, hypovolemia, genital and urinary tract infections, hyperkalemia. Reported diabetic ketoacidosis with serum glucose as low as 200 mg/dl	Occasional gastrointestinal discomfort, upper respiratory tract complaints	Hypoglycemia	Weight gain, edema, congestive heart failure in patients with underlying disease	Gastrointestinal discomfort, flatulence, diarrhea, elevated transaminases	Gastrointestinal discomfort, Reduces gastric absorption of some drugs	Gastrointestinal discomfort, headache	Gastrointestinal discomfort, headache
Contraindications	Chronic kidney disease with eGFR<30 mL/min; Acidosis; Alcohol excess; severe congestive heart failure; hypovolemia. If IV contrast to be used, hold on day of study and restart 48 hours after IV contrast if eGFR>45 mL/min	History of pancreatitis. personal or family history of medullary thyroid cancer or MEN2. Do not use with DPP4 inhibitors.	Severe renal disease with eGFR<30 mL/min, use with caution in patients with bladder cancer	History of pancreatitis. Do not use with GLP-1 receptor agonists.	Severe liver or renal disease	Severe heart disease at risk for CHF, NYHA Class III or IV heart failure, liver disease. Caution in patients with macular edema	Chronic intestinal disorders, moderate to severe renal impairment (creatinine >2 mg/dl), caution in cirrhosis	Serum triglyceride >500 mg/dl; History of hypertriglyceridemia-related pancreatitis, Bowel obstruction	Lactating women, syncopal migraines or use of ergot class of medications	Gastroparesis. Do not use with α-glucosidase inhibitors, may delay absorption of concomitant medications
Comments	Modest weight loss. Reduced cardiovascular event rates (UKPDS).	Weight loss. Decrease in MACE seen with liraglutide (LEADER). No increase in cardiovascular risk or hospitalizations for heart failure in high risk patients with lixisenatide (ELIXA). Others under evaluation.	Reduced blood pressure, weight loss. Improved cardiovascular and total mortality, and decreased hospitalization for heart failure in high risk patients seen with empagliflozin (EMPA-REG). Others under evaluation.	Weight neutral. No increase in cardiovascular risk compared to other diabetes agents in high risk patients (SAVOR-TIMI53, EXAMINE, TECOS). May increase hospitalization for heart failure, but not seen with sitagliptin (TECOS).	Long duration follow-up of glycemic lowering using SFU is associated with reductions in cardiovascular risk (UKPDS).	Increased risk for bone fractures. Increased fluid retention. Rosiglitazone is not inferior for cardiovascular outcomes (RECORD). Pioglitazone is neutral to beneficial for composite cardiovascular outcomes (PROACTIVE)	May reduce cardiovascular risk in patients with impaired glucose tolerance (STOP-NIDDM).	Lowers LDL-C.	Reduced cardiovascular events in FDA enabling trials Cycloset™ Safety Trials.

eGFR, estimated glomerular filtration rate; FDA, Food and Drug Administration; IV, intravenous; LDL-C, low density lipoprotein cholesterol; MEN2, Multiple endocrine neoplasia type 2; NYHA, New York Heart Association; PPARγ, Peroxisome proliferator-activated receptor gamma; SFU, sulfonylurea.

Studies: Cycloset Safety trials;³⁸¹ ELIXA, Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide;³⁸² EMPA-REG, (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients;³⁷³ EXAMINE trial, EXamination of cArdiovascular outcoMes with alogliptIN versus standard of care;³⁸³ LEADER trial, Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results.³⁸⁴ PROACTIVE, PROspective pioglitAzone Clinical Trial In macroVascular Events;³⁸⁰ RECORD, Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes;³⁷⁰ SAVOR-TIMI53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53;³⁷⁵ STOP-NIDDM, Stop Non-Insulin Dependent Diabetes Mellitus;³⁸⁵ TECOS, Trial Evaluating Cardiovascular Outcomes With Sitagliptin;³⁸⁶ UKPDS, United Kingdom Prospective Diabetes Study.^41,103