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Position Statement

7. Approaches to Glycemic Treatment

  1. American Diabetes Association
Diabetes Care 2016 Jan; 39(Supplement 1): S52-S59. https://doi.org/10.2337/dc16-S010
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  • Figure 7.1
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    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
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    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

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  • 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)

    ClassCompound(s)Cellular mechanism(s)Primary physiological action(s)AdvantagesDisadvantagesCost*
    Biguanides• MetforminActivates 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)
    Sulfonylureas2nd GenerationCloses KATP channels on β-cell plasma membranes• ↑ Insulin secretion• Extensive experience• HypoglycemiaLow
    • Glyburide/glibenclamide• ↓ Microvascular risk (UKPDS)• ↑ Weight
    • Glipizide
    • Gliclazide†
    • Glimepiride
    Meglitinides (glinides)• RepaglinideCloses KATP channels on β-cell plasma membranes• ↑ Insulin secretion• ↓ Postprandial glucose excursions• HypoglycemiaModerate
    • Nateglinide• Dosing flexibility• ↑ Weight
    • Frequent dosing schedule
    TZDs• Pioglitazone‡Activates the nuclear transcription factor PPAR-γ• ↑ Insulin sensitivity• No hypoglycemia• ↑ WeightLow
    • 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• AcarboseInhibits intestinal α-glucosidase• Slows intestinal carbohydrate digestion/absorption• No hypoglycemia• Generally modest A1C efficacyLow to moderate
    • Miglitol• ↓ Postprandial glucose excursions• Gastrointestinal side effects (flatulence, diarrhea)
    • ? ↓ CVD events (STOP-NIDDM)• Frequent dosing schedule
    • Nonsystemic
    DPP-4 inhibitors• SitagliptinInhibits DPP-4 activity, increasing postprandial active incretin (GLP-1, GIP) concentrations• ↑ Insulin secretion (glucose dependent)• No hypoglycemia• Angioedema/urticaria and other immune-mediated dermatological effectsHigh
    • Vildagliptin†• ↓ Glucagon secretion (glucose dependent)• Well tolerated• ? Acute pancreatitis
    • Saxagliptin• ? ↑ Heart failure hospitalizations
    • Linagliptin
    • Alogliptin
    Bile acid sequestrants• ColesevelamBinds bile acids in intestinal tract, increasing hepatic bile acid production• ? ↓ Hepatic glucose production• No hypoglycemia• Generally modest A1C efficacyHigh
    • ? ↑ 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 efficacyHigh
    • ↑ Insulin sensitivity• ? ↓ CVD events (Cycloset Safety Trial)• Dizziness/syncope
    • Nausea
    • Fatigue
    • Rhinitis
    SGLT2 inhibitors• CanagliflozinInhibits SGLT2 in the proximal nephron• Blocks glucose reabsorption by the kidney, increasing glucosuria• No hypoglycemia• Genitourinary infectionsHigh
    • 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• ExenatideActivates 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 efficacyHigh
    • 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 analogsActivates insulin receptors• ↑ Glucose disposal• Nearly universal response• HypoglycemiaModerate 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).

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7. Approaches to Glycemic Treatment
American Diabetes Association
Diabetes Care Jan 2016, 39 (Supplement 1) S52-S59; DOI: 10.2337/dc16-S010

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7. Approaches to Glycemic Treatment
American Diabetes Association
Diabetes Care Jan 2016, 39 (Supplement 1) S52-S59; DOI: 10.2337/dc16-S010
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  • Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association
  • Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association
  • Diabetes and Hypertension: A Position Statement by the American Diabetes Association
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