Table 2.

Glucose-lowering medications and therapies available in the U.S. or Europe and specific characteristics that may guide individualized treatment choices in nonpregnant adults with type 2 diabetes

Class	Medications/therapies in class	Primary physiological action(s)	Advantages	Disadvantages/adverse effects	Efficacy
Lifestyle
Diet quality	• Mediterranean type • DASH • Low carbohydrate • Vegetarian • Others	• Depends on diet	• Inexpensive • No side effects	• Requires instruction • Requires motivation • Requires lifelong behavioral change • Social barriers may exist	Intermediate
Physical activity	• Running, walking • Bicycling (including stationary) • Swimming • Resistance training • Yoga • Tai chi • Many others	• Energy expenditure • Weight management • ↑ Insulin sensitivity	• Inexpensive • ↓ Fall risk by increasing balance/strength • ? Improves mental health • ↑ Bone density • ↓ Blood pressure • ↓ Weight • Improves ASCVD risk factors	• Risk of musculoskeletal injury • Requires motivation • Risk of foot trauma in patients with neuropathy • Requires lifelong behavioral change	Intermediate
Energy restriction	• Individual energy restriction with or without energy tracking • Programs with counseling • Food substitution programs	• Energy restriction • Weight management • ↓ Hepatic and pancreatic fat • ↑ Insulin sensitivity	• Lowers glycemia • Reduces need for diabetes and other medications • No serious side effects • Improves ASCVD risk factors	• Requires motivation • Requires lifelong behavioral change	Variable, with potential for very high efficacy; often intermediate
Oral medications
Biguanides	• Metformin	• ↓ Hepatic glucose production • Multiple other non-insulin-mediated mechanisms	• Extensive experience • No hypoglycemia • Inexpensive	• GI symptoms • Vitamin B12 deficiency • Use with caution or dose adjustment for CKD stage 3B (eGFR 30–44 mL min−1 [1.73 m]−2) • Lactic acidosis (rare)	High
SGLT2 inhibitors	• Canagliflozin • Dapagliflozin • Empagliflozin • Ertugliflozin	• Blocks glucose reabsorption by the kidney, increasing glucosuria • ? Other tubulo-glomerular effects	• No hypoglycemia • ↓ Weight • ↓ Blood pressure • Effective at all stages of T2DM with preserved glomerular function • ↓ MACE, HF, CKD with some agents (see text)	• Genital infections • UTI • Polyuria • Volume depletion/hypotension/dizziness • ↑ LDL-C • ↑ Creatinine (transient) • Dose adjustment/avoidance for renal disease • ↑ Risk for amputation (canagliflozin) • ↑ Risk for fracture (canagliflozin) • ↑ Risk for DKA (rare) • Fournier’s gangrene (rare) • Expensive	Intermediate–high (dependent on GFR)
DPP-4 inhibitors	• Sitagliptin • Vildagliptina • Saxagliptin • Linagliptin • Alogliptin	• Glucose dependent: ↑ Insulin secretion ↓ Glucagon secretion	• No hypoglycemia • Weight neutral • Well tolerated	• Rare urticaria/angioedema • ↑ HF hospitalization (saxagliptin) • Dose adjustment/avoidance for renal disease depending on agent • ? Pancreatitis • ? Arthralgia • ? Bullous pemphigoid • Expensive (U.S.); variable in Europe	Intermediate
Sulfonylureas	• Glibenclamide/glyburide • Glipizide • Gliclazidea • Glimepiride	• ↑ Insulin secretion	• Extensive experience • ↓ Microvascular risk (UKPDS) • Inexpensive	• Hypoglycemia • ↑ Weight • Uncertain cardiovascular safety • Dose adjustment/avoidance for renal disease • High rate of secondary failure	High
TZDs	• Pioglitazone • Rosiglitazoneb	• ↑ Insulin sensitivity	• Low risk for hypoglycemia • Durability • ↑ HDL-C • ↓ Triacylglycerols (pioglitazone) • ↓ ASCVD events (pioglitazone: in a poststroke insulin-resistant population and as secondary end point in a high-risk-of-CVD diabetes population) • Lower cost	• ↑ Weight • Edema/heart failure • Bone loss • ↑ Bone fractures • ↑ LDL-C (rosiglitazone) • ? Bladder cancer • ? Macular edema	High
Meglitinides (Glinides)	• Repaglinide • Nateglinide	• ↑ Insulin secretion	• ↓ Postprandial glucose excursions • Dosing flexibility • Safe in advanced renal disease with cautious dosing (especially repaglinide) • Lower cost	• Hypoglycemia • ↑ Weight • Uncertain cardiovascular safety • Frequent dosing schedule	Intermediate–high
α-Glucosidase inhibitors	• Acarbose • Miglitol	• Slows carbohydrate digestion/absorption	• Low risk for hypoglycemia • ↓ Postprandial glucose excursions • Nonsystemic mechanism of action • Cardiovascular safety • Lower cost	• Frequent GI side effects • Frequent dosing schedule • Dose adjustment/avoidance for renal disease	Low–intermediate
Bile acid sequestrants	• Colesevelamb	• ? ↓ Hepatic glucose production • ? ↑ Incretin levels	• No hypoglycemia • ↓ LDL-C	• Constipation • ↑ Triacylglycerols • May ↓ absorption of other medications • Intermediate expense	Low–intermediate
Dopamine-2 agonists	• Quick-release bromocriptineb	• Modulates hypothalamic regulation of metabolism • ↑ Insulin sensitivity	• No hypoglycemia • ? ↓ ASCVD events	• Headache/dizziness/syncope • Nausea • Fatigue • Rhinitis • High cost	Low–intermediate
Injectable medications
Insulins
Long acting (basal)	• Degludec (U100, U200) • Detemir • Glargine (U100, U300)	• Activates insulin receptor • ↑ Glucose disposal • ↓ Glucose production	• Nearly universal response • Theoretically unlimited efficacy • Once-daily injection	• Hypoglycemia • Weight gain • Training requirements • Frequent dose adjustment for optimal efficacy • High cost	Very high
Intermediate acting (basal)	• Human NPH	• Activates insulin receptor • ↑ Glucose disposal • ↓ Glucose production	• Nearly universal response • Theoretically unlimited efficacy • Less expensive than analogs	• Hypoglycemia • Weight gain • Training requirements • Often given twice daily • Frequent dose adjustment for optimal efficacy	Very high
Rapid acting	• Aspart (conventional and fast acting) • Lispro (U100, U200) • Glulisine	• Activates insulin receptor • ↑ Glucose disposal • ↓ Glucose production	• Nearly universal response • Theoretically unlimited efficacy • ↓ Postprandial glucose	• Hypoglycemia • Weight gain • Training requirements • May require multiple daily injections • Frequent dose adjustment for optimal efficacy • High cost	Very high
Inhaled rapid acting	• Human insulin inhalation powderb	• Activates insulin receptor • ↑ Glucose disposal • ↓ Glucose production	• Nearly universal response • ↓ Postprandial glucose • More rapid onset and shorter duration than rapid-acting analogs	• Spirometry (FEV1) required before initiating, after 6 months, and annually • Contraindicated in chronic lung disease • Not recommended in smokers • Hypoglycemia • Weight gain • Training requirements • May require multiple inhalations daily • Frequent dose adjustment for optimal efficacy; limited options in dosing interval • High cost • Respiratory side effects (e.g., bronchospasm, cough, decline in FEV1)	High
Short acting	• Human regular (U100, U500)	• Activates insulin receptor • ↑ Glucose disposal • ↓ Glucose production	• Nearly universal response • Theoretically unlimited efficacy • ↓ Postprandial glucose • Less expensive than analogs	• Hypoglycemia • Weight gain • Training requirements • Frequent dose adjustment for optimal efficacy • May require multiple daily injections	Very high
Premixed	• Many	• Activates insulin receptor • ↑ Glucose disposal • ↓ Glucose production	• Nearly universal response • Theoretically unlimited efficacy • Fewer injections than basal/bolus before every meal • Recombinant human analogs are less expensive	• Hypoglycemia • Weight gain • Training requirements • Frequent dose adjustment for optimal efficacy • High cost (except human insulin premix) • Can lead to obligate eating	Very high
GLP-1 RA
Shorter acting	• Exenatide • Lixisenatide	• Glucose dependent: ↑ Insulin secretion ↓ Glucagon secretion • Slows gastric emptying • ↑ Satiety	• No hypoglycemia as monotherapy • ↓ Weight • Excellent postprandial glucose efficacy for meals after injections • Improves cardiovascular risk factors	• Frequent GI side effects that may be transient • Modestly ↑ heart rate • Training requirements • Dose adjustment/avoidance in renal disease • Acute pancreatitis (rare/uncertain) • Very high cost	Intermediate–high
Longer acting	• Dulaglutide • Exenatide extended-release • Liraglutide • Semaglutide	• Glucose dependent: ↑ Insulin secretion ↓ Glucagon secretion • ↑ Satiety	• No hypoglycemia as monotherapy • ↓ Weight • ↓ Postprandial glucose excursions • Improves cardiovascular risk factors • ↓ MACE with some agents (see text) • ↓ Albuminuria with some agents (see text) • Greater lowering of fasting glucose vs. short-acting preparations • Once-weekly dosing (except liraglutide, which is daily)	• GI side effects, including gallbladder disease • Greater ↑ heart rate • Training requirements • Dose adjustment/avoidance for some agents in renal disease • Acute pancreatitis (rare/uncertain) • C-cell hyperplasia/medullary thyroid tumors (rare/uncertain; observed in animals only) • Very high cost	High–very high
Other injectables
Amylin mimetics	• Pramlintideb	• ↓ Glucagon secretion • Slows gastric emptying • ↑ Satiety	• ↓ Postprandial glucose excursions • ↓ Weight	• Hypoglycemia • Frequent dosing schedule • Training requirements • Frequent GI side effects • Very high cost	Intermediate
Fixed-dose combination of GLP-1 RA and basal insulin analogs	• Liraglutide/degludec • Lixisenatide/glargine	• Combined activities of components	• Enhanced glycemic efficacy vs. components • Reduced adverse effects (e.g., GI, hypoglycemia) vs. components	• Less weight loss than GLP-1 receptor agonist alone • Very high cost	Very high
Weight loss medications	• Lorcaserinb • Naltrexone/bupropion • Orlistat • Phentermine/topiramateb • Liraglutide 3 mg	• Reduced appetite • Fat malabsorption (orlistat)	• Mean 3–9 kg weight loss vs. placebo	• High discontinuation rates from side effects • <50% achieve ≥5% weight loss • Drug-specific side effects • Limited durability • High cost	Intermediate
Metabolic surgery	• VSG • RYGB • Adjustable gastric band • BPD	• Restriction of food intake (all) • Malabsorption (RYGB, BPD) • Changes in hormonal and possibly neuronal signaling (VSG, RYGB, BPD)	• Sustained weight reduction • ↑ Rate of remission of diabetes • ↓ Number of diabetes drugs • ↓ Blood pressure • Improved lipid metabolism	• High initial cost • ↑ Risk for early and late surgical complications • ↑ Risk for reoperation • ↑ Risk for dumping syndrome • ↑ Nutrient and vitamin malabsorption • ↑ Risk for new-onset depression • ↑ Risk for new-onset opioid use • ↑ Risk for gastroduodenal ulcer • ↑ Risk for hypoglycemia • ↑ Risk for alcohol use disorder	Very high

More details available in ADA’s Standards of Medical Care in Diabetes—2018 (3). Glucose-lowering efficacy of drugs by change in HbA_1c: >22 mmol/mol (2%) very high, 11–22 mmol/mol (1–2%) high, 6–11 mmol/mol (0.5–1.5%) intermediate, <6 mmol/mol (0.5%) low.

^aNot licensed in the U.S. for type 2 diabetes.

^bNot licensed in Europe for type 2 diabetes. BPD, biliopancreatic diversion; DKA, diabetic ketoacidosis; FEV₁, forced expiratory volume in 1 s on pulmonary function testing; GI, gastrointestinal; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; RYGB, Roux-en-Y gastric bypass; VSG, vertical sleeve gastroplasty; T2DM, type 2 diabetes mellitus; UTI, urinary tract infection.