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

ClassMedications/therapies in classPrimary physiological action(s)AdvantagesDisadvantages/adverse effectsEfficacy
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 HbA1c: >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.

  • a Not licensed in the U.S. for type 2 diabetes.

  • b Not 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.