7. Approaches to Glycemic Treatment
Article Figures & Tables
Figures
- Figure 7.1
Antihyperglycemic therapy in type 2 diabetes: general recommendations (17). The order in the chart was determined by historical availability and the route of administration, with injectables to the right; it is not meant to denote any specific preference. Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. *See ref. 17 for description of efficacy categorization. †Consider starting at this stage when A1C is ≥9% (75 mmol/mol). ‡Consider starting at this stage when blood glucose is ≥300–350 mg/dL (16.7–19.4 mmol/L) and/or A1C is ≥10–12% (86–108 mmol/mol), especially if symptomatic or catabolic features are present, in which case basal insulin + mealtime insulin is the preferred initial regimen. §Usually a basal insulin (NPH, glargine, detemir, degludec). Adapted with permission from Inzucchi et al. (17).
- Figure 7.2
Approach to starting and adjusting insulin in type 2 diabetes (17). FBG, fasting blood glucose; GLP-1-RA, GLP-1 receptor agonist; hypo, hypoglycemia; mod., moderate; PPG, postprandial glucose; #, number. Adapted with permission from Inzucchi et al. (17).
Tables
- Table 7.1
Properties of available glucose-lowering agents in the U.S. and Europe that may guide individualized treatment choices in patients with type 2 diabetes (17)
Class Compound(s) Cellular mechanism(s) Primary physiological action(s) Advantages Disadvantages Cost* Biguanides • Metformin Activates AMP-kinase (? other) • ↓ Hepatic glucose production • Extensive experience • Gastrointestinal side effects (diarrhea, abdominal cramping) Low • No hypoglycemia • Vitamin B12 deficiency • ↓ CVD events (UKPDS) • Contraindications: CKD, acidosis, hypoxia, dehydration, etc. • Lactic acidosis risk (rare) Sulfonylureas 2nd Generation Closes KATP channels on β-cell plasma membranes • ↑ Insulin secretion • Extensive experience • Hypoglycemia Low • Glyburide/glibenclamide • ↓ Microvascular risk (UKPDS) • ↑ Weight • Glipizide • Gliclazide† • Glimepiride Meglitinides (glinides) • Repaglinide Closes KATP channels on β-cell plasma membranes • ↑ Insulin secretion • ↓ Postprandial glucose excursions • Hypoglycemia Moderate • Nateglinide • Dosing flexibility • ↑ Weight • Frequent dosing schedule TZDs • Pioglitazone‡ Activates the nuclear transcription factor PPAR-γ • ↑ Insulin sensitivity • No hypoglycemia • ↑ Weight Low • Rosiglitazone§ • Durability • Edema/heart failure • ↑ HDL-C • Bone fractures • ↓ Triglycerides (pioglitazone) • ↑ LDL-C (rosiglitazone) • ? ↓ CVD events (PROactive, pioglitazone) • ? ↑ MI (meta-analyses, rosiglitazone) α-Glucosidase inhibitors • Acarbose Inhibits intestinal α-glucosidase • Slows intestinal carbohydrate digestion/absorption • No hypoglycemia • Generally modest A1C efficacy Low to moderate • Miglitol • ↓ Postprandial glucose excursions • Gastrointestinal side effects (flatulence, diarrhea) • ? ↓ CVD events (STOP-NIDDM) • Frequent dosing schedule • Nonsystemic DPP-4 inhibitors • Sitagliptin Inhibits DPP-4 activity, increasing postprandial active incretin (GLP-1, GIP) concentrations • ↑ Insulin secretion (glucose dependent) • No hypoglycemia • Angioedema/urticaria and other immune-mediated dermatological effects High • Vildagliptin† • ↓ Glucagon secretion (glucose dependent) • Well tolerated • ? Acute pancreatitis • Saxagliptin • ? ↑ Heart failure hospitalizations • Linagliptin • Alogliptin Bile acid sequestrants • Colesevelam Binds bile acids in intestinal tract, increasing hepatic bile acid production • ? ↓ Hepatic glucose production • No hypoglycemia • Generally modest A1C efficacy High • ? ↑ Incretin levels • ↓ LDL-C • Constipation • ↑ Triglycerides • May ↓ absorption of other medications Dopamine-2 agonists • Bromocriptine (quick release)§ Activates dopaminergic receptors • Modulates hypothalamic regulation of metabolism • No hypoglycemia • Generally modest A1C efficacy High • ↑ Insulin sensitivity • ? ↓ CVD events (Cycloset Safety Trial) • Dizziness/syncope • Nausea • Fatigue • Rhinitis SGLT2 inhibitors • Canagliflozin Inhibits SGLT2 in the proximal nephron • Blocks glucose reabsorption by the kidney, increasing glucosuria • No hypoglycemia • Genitourinary infections High • Dapagliflozin‡ • ↓ Weight • Polyuria • Empagliflozin • ↓ Blood pressure • Volume depletion/hypotension/ dizziness • Effective at all stages of type 2 diabetes • ↑ LDL-C • Associated with lower CVD event rate and mortality in patients with CVD (EMPA-REG OUTCOME) • ↑ Creatinine (transient) • DKA, urinary tract infections leading to urosepsis, pyelonephritis GLP-1 receptor agonists • Exenatide Activates GLP-1 receptors • ↑ Insulin secretion (glucose dependent) • No hypoglycemia • Gastrointestinal side effects (nausea/vomiting/diarrhea) High • Exenatide extended release • ↓ Glucagon secretion (glucose dependent) • ↓ Weight • ↑ Heart rate • Liraglutide • Slows gastric emptying • ↓ Postprandial glucose excursions • ? Acute pancreatitis • Albiglutide • ↑ Satiety • ↓ Some cardiovascular risk factors • C-cell hyperplasia/medullary thyroid tumors in animals • Lixisenatide† • Injectable • Dulaglutide • Training requirements Amylin mimetics • Pramlintide§ Activates amylin receptors • ↓ Glucagon secretion • ↓ Postprandial glucose excursions • Generally modest A1C efficacy High • Slows gastric emptying • ↓ Weight • Gastrointestinal side effects (nausea/vomiting) • ↑ Satiety • Hypoglycemia unless insulin dose is simultaneously reduced • Injectable • Frequent dosing schedule • Training requirements Insulins • Rapid-acting analogs Activates insulin receptors • ↑ Glucose disposal • Nearly universal response • Hypoglycemia Moderate to high# - Lispro - Aspart - Glulisine - Inhaled insulin • Short-acting • ↓ Hepatic glucose production • Theoretically unlimited efficacy • Weight gain - Human Regular • Intermediate-acting • Suppresses ketogenesis • ↓ Microvascular risk (UKPDS) • ? Mitogenic effects - Human NPH • Basal insulin analogs • Training requirements - Glargine - Detemir - Degludec† • Premixed (several types) • Patient reluctance • Injectable (except inhaled insulin) • Pulmonary toxicity (inhaled insulin) CKD, chronic kidney disease; CVD, cardiovascular disease; DKA, diabetic ketoacidosis; EMPA-REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (31); GIP, glucose-dependent insulinotropic peptide; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; MI, myocardial infarction; PPAR-γ, peroxisome proliferator–activated receptor γ; PROactive, Prospective Pioglitazone Clinical Trial in Macrovascular Events (32); STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (33); TZD, thiazolidinedione; UKPDS, UK Prospective Diabetes Study (34,35). Cycloset trial of quick-release bromocriptine (36).
↵* Cost is based on lowest-priced member of the class (see ref. 17).
↵† Not licensed in the U.S.
↵‡ Initial concerns regarding bladder cancer risk are decreasing after subsequent study.
↵§ Not licensed in Europe for type 2 diabetes.
↵# Cost is highly dependent on type/brand (analogs > human insulins) and dosage. Adapted with permission from Inzucchi et al. (17).
