Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

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 

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