Noninsulin Therapy of Type 2 Diabetes

Aka: Noninsulin Therapy of Type 2 Diabetes, Noninsulin Management of Type II Diabetes Mellitus, Oral Hypoglycemic, Oral Medications for Type 2 Diabetes, Type II Diabetes Medications, Type 2 Diabetes Preparations

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II. Background

  1. Lifestyle changes can lower A1C by 1-2%
  2. Efficacy Example: Weight loss, diet and Exercise
  3. Pre-intervention: HBA1C is 10%
    1. Post-intervention: HBA1C might drop to 8-9%
  4. New Type II Diabetes Mellitus available agents have exploded in number
    1. Some new novel agents have significant benefit beyond Glucose lowering
      1. SGLT2 Inhibitors and GLP-1 Agonists decrease Cardiovascular Risk and Chronic Kidney Disease progression
      2. SGLT2 Inhibitors and GLP-1 Agonists may assist with weight loss in Obesity
    2. Newer agents have some disadvantages compared with older agents (e.g. Metformin, Sulfonylureas, Glitazones)
      1. Most of these agents are expensive (>$300-400 per month)
      2. Glucose lowering effect is modest (typically 0.5 to 0.8%)
      3. Each have unique adverse effects of their own (e.g. Euglycemic Ketoacidosis, UTI, AKI with SLT2 Inhibitors)
    3. Several agent classes show little benefit (expensive, adverse effects, lack improved longterm outcomes)
      1. DPP-4 Inhibitors (e.g. Sitagliptin, Saxagliptin, Linagliptin)
      2. Amylin Analogue (e.g. Symlin)
  5. Insulin is very cost effective (consider early especially if Hemoglobin A1C>9-10%)
    1. Lowers HBA1C an unlimited amount
    2. Can be used with Insulin Resistance agents
      1. Thiazolidinediones (e.g. Rosiglitazone)
      2. Metformin (Glucophage)
    3. Start with Basal insulin (e.g. Insulin Glargine or Lantus)
      1. Basal insulin can be used with Oral Hypoglycemics
        1. Includes Sulfonylureas (cautiously)
      2. Add Bolus Insulin (e.g. InsulinLispro) if Hyperglycemia persists (especially if post-prandial)

III. Medications: Types

  1. Insulin Resistance Agents
    1. Biguanides (e.g. Metformin or Glucophage)
      1. Metformin is recommended as the initial Oral Hypoglycemic agent unless contraindicated
      2. Decreases hepatic Glucose release
      3. Lowers HBA1C by 1.5%
    2. Thiazolidinediones (e.g. Pioglitazone)
      1. Increases Muscle and fat Insulin sensitivity
      2. May also independently increase Cardiovascular Risk (especially Rosiglitazone)
      3. Lowers HBA1C by up to 1 to 1.5%
  2. Insulin Secretagogues (early Type II Diabetes)
    1. Second Generation Sulfonylurea (e.g. Glipizide, Glimepiride)
      1. Avoid Glyburide due to Hypoglycemia
      2. Lowers HBA1C by 1.5%
    2. Meglitinides (e.g. Nateglinide, Repaglinide)
      1. More expensive alternative to Sulfonylureas
      2. Lowers HBA1C by 0.5 to 1%
  3. Incretin Agents
    1. DPP-4 Inhibitors (e.g. Sitagliptin, Saxagliptin, Linagliptin)
      1. Inhibits Incretin degradation resulting in Insulin secretion
      2. No good longterm benefit evidence
      3. Risk of Pancreatitis
      4. Lowers HBA1C by 0.5 to 1%
    2. GLP-1 Agonists (e.g. Exenatide)
      1. Incretin Mimetic that binds GLP-1 receptors and stimulates Insulin release
      2. Decreases Cardiovascular Risk and Chronic Kidney Disease progression
      3. Facilitates weight loss in Obesity
      4. Lowers HBA1C by 1 to 1.5%
  4. Glucose Absorption Agents
    1. Alpha-Glucosidase Inhibitors (e.g. Acarbose)
      1. Decreases gastrointestinal Carbohydrate absorption
      2. Lowers HBA1C by 0.5 to 1%
    2. SGLT2 Inhibitors (e.g. Invokana)
      1. Decreases renal Glucose reabsorption (allows for greater urinary excretion of Glucose)
      2. Decreases Cardiovascular Risk and Chronic Kidney Disease progression
      3. Facilitates weight loss in Obesity
      4. Lowers HBA1C by 1%
  5. Combination agents
    1. Actoplus Met: Pioglitazone and Metformin
    2. Duetact: Pioglitazone and Glimepiride
    3. Janumet: Sitagliptin and Metformin
    4. Metaglip: Glipizide and Metformin
    5. Avoid agents with increased risk
      1. Glucovance contains Glyburide
      2. Avandamet and Avandaryl contain Rosiglitazone
  6. Other options
    1. Bromocriptine (Cycloset or Bromocriptine QR)
      1. Review Bromocriptine risks before using
      2. Consider in combination with Metformin (as part of dual or triple therapy)
      3. May lower Hemoglobin A1C 0.7 to 1.4%
      4. Joe Weidner, MD (2018) email communication, received 11/10/2018
      5. Gardner (2013) Endocr Pract 19(1):100-6 +PMID:23337160 [PubMed]
      6. Chamarthi (2017) Postgrad Med 129(4):446-455 +PMID:28374645 [PubMed]

IV. Medications: By A1C Lowering

  1. Most effective agents (1% or greater A1C lowering)
    1. Metformin (1.5%)
    2. GLP1 Agonists (1.5%)
    3. Sulfonylureas (1.5%)
    4. Thiazolidinediones (1%)
    5. Insulin (umlimited lowering of A1C)
  2. Less effective agents (<1% A1C lowering)
    1. DPP-4 Inhibitors (0.8%)
    2. Meglitinides (0.7%)
    3. Alpha-Glucosidase Inhibitors (0.6%)
    4. SGLT2 Inhibitors (0.6%)
    5. Colesevelam (0.4%)
  3. References
    1. Simha (2017) Novel Diabetes Medications Lectures, Mayo 91st Clinical Reviews, Rochester, MN
    2. Hirst (2013) Diabetologia

V. Medications: Comorbid Condition Benefits

  1. Chronic Kidney Disease
    1. SLGT2 Inhibitors (Canagliflozin, Dapagliflozin, Empagliflozin)
    2. GLP1 Agonists (Dulaglutide, Semaglutide, Liraglutide)
  2. Heart Failure
    1. SLGT2 Inhibitors (Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin)
  3. Arteriosclerotic Cardiovascular Disease
    1. SLGT2 Inhibitors (Canagliflozin, Empagliflozin)
    2. GLP1 Agonists (Dulaglutide, Semaglutide, Liraglutide, Tirzepatide)

VI. Medications: By Body Weight Effect

  1. Significant Weight Loss
    1. GLP-1 Agonists (Semaglutide, Tirzepatide, Dulaglutide, Liraglutide)
  2. Modest Weight loss (>2 kg weight loss)
    1. SGLT2 Inhibitors (primary weight loss is via diuresis)
  3. Weight neutral
    1. Alpha-Glucosidase Inhibitors
    2. DPP-4 Inhibitors
    3. Colesevelam
    4. Metformin (Glucophage)
  4. Weight gain (1-2 kg weight gain)
    1. Thiazolidinediones (1%)
    2. Sulfonylureas (1.5%)
    3. Insulin (1%)
    4. Meglitinides (0.7%)
  5. References
    1. Simha (2017) Novel Diabetes Medications Lectures, Mayo 91st Clinical Reviews, Rochester, MN

VII. Medications: Children with Type II Diabetes

  1. First-line agents
    1. Metformin
    2. Insulin
      1. Start with Basal insulin
      2. Consider pre-mixed Insulin (e.g. 70/30) for postprandial Hyperglycemia
  2. Second-line agents
    1. Sulfonylureas (risk of Hypoglycemia)
    2. Acarbose or Colesevelam
  3. Agents with unknown safety in children
    1. Actos
    2. Januvia
    3. Byetta
  4. References
    1. (2012) Presc Lett 19(7): 40

VIII. Approach: Sample Template for Prescribing Combination Oral Agents

  1. General
    1. Use a combination of agents (consider from onset)
    2. Treat Insulin Resistance and Insulin shortage
    3. Lifestyle changes form the base of treatment
      1. Weight loss with calorie restriction and daily activity
      2. Carbohydrate Counting and awareness of its impact on Glucose control
  2. Step 1: Metformin (Glucophage)
    1. Most effective single agent in all patients
    2. Previously a Sulfonylurea was considered first-line in lean patients (no longer the case)
    3. Contraindicated in GFR <30 due to Lactic Acidosis risk
      1. Exercise caution in GFR <45-60 ml/min or Serum Creatinine >1.5 mg/dl
      2. However, there is some controversy as to what GFR level should contraindicate Metformin
    4. Consider starting with a combination agent that includes Metformin
      1. Example: Metaglip (Metformin with Glipizide)
  3. Step 2: Add second agent to Metformin
    1. See Step 3 for other agents to consider instead of Sulfonylureas
    2. Strongly consider SGLT2 Inhibitor or GLP-1 Receptor Agonist for CKD or CV risk or disease (see below)
    3. Sulfonylurea (e.g. Glipizide, Glimepiride)
      1. Most cost effective second agent, but mortality or comorbid condition benefit
      2. Avoid if Hypoglycemia risk
      3. Meglitinides (e.g. Repaglinide) may be used as alternative (but more expensive)
        1. Consider for as needed pre-meal dosing in post-prandial Hyperglycemia
  4. Step 3: Add third agent
    1. SGLT2 Inhibitors or Flozins (e.g. Invokana)
      1. Strongly consider for CKD or CV risk/disease (see below)
    2. Incretin Mimetic or GLP-1 Agonist (e.g. Exenatide or Byetta)
      1. SQ Injection (with a few oral options) but more effective and significantly facilitates weight loss
    3. Thiazolidinediones or Glitazones (e.g. Pioglitazone)
      1. Avoid in Class III or Class IV Heart Failure
    4. Gliptin or DPP-4 Inhibitor (e.g.Sitagliptin or Januvia)
      1. Other agents may have greater benefit
    5. Basal insulin (e.g. Insulin Glargine or Lantus)
      1. Consider for longer history of Type II Diabetes or if persistent HBA1C >9-10%
      2. Start at a lower Basal insulin dose if concurrent Sulfonylurea, Meglitinide or GLP-1 Agonist
  5. Step 4: Insulin for refractory Hyperglycemia
    1. Basal insulin (e.g. Insulin Glargine or Lantus)
    2. Bolus Insulin or pre-meal Insulin (e.g. Lispro)
      1. Stop Sulfonylurea or Meglitinide
  6. Indications to add SGLT2 Inhibitor or GLP-1 Receptor Agonist (Associated with lower mortality)
    1. Established cardiovascular disease or Chronic Kidney Disease (esp. SGLT Inhibitor)
    2. Four or more Cardiovascular Risk Factors
    3. Li (2021) BMJ 373: n1091 [PubMed]
  7. Agents with greatest effect based on timing of Hyperglycemia
    1. Pre-meal Fasting Hyperglycemia
      1. Sulfonylurea (most of effect is on pre-meal Glucose)
      2. Insulin Resistance agents
        1. Glucophage (Metformin)
        2. Thiazolidinediones (e.g. Rosiglitazone)
    2. Postprandial Hyperglycemia (Insulin deficiency)
      1. Meglitinides (e.g. Repaglinide)
      2. Alpha-Glucosidase Inhibitors
  8. Agents with greatest effect based on body habitus
    1. Obese patients (agents that promote weight loss)
      1. GLP-1 Agonists (Semaglutide, Tirzepatide, Dulaglutide, Liraglutide)
      2. SGLT2 Inhibitors (primary weight loss is via diuresis)
    2. Lean patients (agents that may cause weight gain)
      1. Sulfonylurea (e.g. Glipizide) or Meglitinide (e.g. Repaglinide)
      2. Insulin
      3. Thiazolidinediones
    3. Weight neutral agents
      1. DPP-4 Inhibitor (Gliptin)
      2. Metformin (Glucophage)
  9. Avoid agents with lower efficacy, higher cost, and less tolerability
    1. Alpha-Glucosidase Inhibitors (e.g. Acarbose)
    2. Meglitinides (e.g. Nateglinide, Repaglinide)

IX. Adverse Effects

  1. Hypoglycemia
    1. May account for 14% DM admissions for Hypoglycemia
    2. Highest risk with Bolus Insulin (e.g. Lispro) and should not be combined with Sulfonylureas
    3. Higher risk with Sulfonylureas (especially Glyburide) and to a lesser extent Meglitinides (e.g. Prandin)
    4. Increased risk when combined with ACE Inhibitors (especially Captopril)
    5. Amylins (Symlin) have been associated with severe Hypoglycemia (FDA black box warning)
  2. Weight gain
    1. Sulfonylureas
    2. Insulin
    3. Thiazolidinediones (e.g. Actos)
  3. Gastrointestinal side effects (e.g. Nausea, gas, bloating, Diarrhea)
    1. Metformin (Glucophage)
    2. Alpha-Glucosidase Inhibitors (Acarbose, Miglitol)
      1. GI effects may be severe, in >50% of patients
    3. GLP-1 Agonist (Byetta)
    4. Meglitinides (<10% of patients)
  4. Pancreatitis
    1. GLP-1 Agonist (Byetta)
    2. DPP-4 Inhibitors (e.g. Januvia)
  5. Liver toxicity
    1. Thiazolidinediones (e.g. Actos)
  6. Metabolic Acidosis
    1. Metformin (Glucophage)
      1. Theoretical Lactic Acidosis
      2. Use with caution in reduced GFR (and avoid following IV contrast)
    2. SGLT2 Inhibitors (Flozins, e.g. Invokana)
      1. Euglycemic Ketoacidosis risk (esp. in impaired Renal Function)
  7. Edema (avoid in Congestive Heart Failure)
    1. Thiazolidinediones (e.g. Actos)
    2. DPP-4 Inhibitors (esp. Saxagliptin and Alogliptin, while other Gliptins do not appear to carry this risk)
  8. Fracture risk
    1. Thiazolidinediones (e.g. Actos)
  9. Infection risk
    1. SGLT2 Inhibitors (e.g. Invokana)
      1. Adverse effects include Vaginitis and Urinary Tract Infection
  10. Cancer
    1. Pioglitazone (Bladder Cancer)
    2. GLP-1 Agonist (Medullary Thyroid Carcinoma, Multiple Endocrine Neoplasia Type 2)

X. Resources

  1. http://care.diabetesjournals.org/content/35/Supplement_1

XI. References

  1. (2014) Presc Lett 21(4): 19
  2. (2012) Diabetes Care 35(suppl 1): s11-63
  3. George (2015) Am Fam Physician 92(1): 27-34 [PubMed]
  4. Luna (2001) Am Fam Physician 63(9):1747-56ces [PubMed]
  5. Steinberg (2019) Am Fam Physician 99(4): 237-43 [PubMed]
  6. Yki-Jarvinen (2001) 24:758-67 [PubMed]
  7. Vaughan (2024) Am Fam Physician 109(4): 333-42 [PubMed]

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