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 benefit beyond Glucose lowering
      1. Jardiance may lower cardiovascular risk (albeit with a NNT 45 for 3 years)
      2. Byetta may assist with weight loss in Obesity
    2. Newer agents have significant disadvantages compared with 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 (no respite from Sulfonylurea or Glitazone risks)
    3. Several agent classes show little benefit (expensive, adverse effects, no good longterm benefit)
      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. Preparations

  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. 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. Facilitates weight loss
      3. 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. 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. Consider in combination with Metformin (as part of dual or triple therapy)
      2. May lower Hemoglobin A1C 0.7 to 1.4%
      3. Joe Weidner, MD (2018) email communication, received 11/10/2018
      4. Gardner (2013) Endocr Pract 19(1):100-6 +PMID:23337160 [PubMed]
      5. Chamarthi (2017) Postgrad Med 129(4):446-455 +PMID:28374645 [PubMed]

IV. Preparations: By A1C Lowering

  1. Most effective agents (1% or greater A1C lowering)
    1. Sulfonylureas (1.5%)
    2. Thiazolidinediones (1%)
    3. Insulin (1%)
  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. Preparations: Other Benefits

  1. Reduced Cardiovascular risk AND death
    1. Jardiance (Empagliflozin)
    2. Victoza (Liraglutide)
  2. Reduced cardiovascular risk
    1. Invokana (Canagliflozin)
    2. Ozempic (Semaglutide)

VI. Preparations: By body weight effect

  1. Weight loss (2 kg weight loss)
    1. Alpha-glucosidase Inhibitors
    2. SGLT2 Inhibitors
    3. GLP-1 Agonists
  2. Weight neutral
    1. DPP-4 Inhibitors
    2. Colesevelam
  3. Weight gain (1-2 kg weight gain)
    1. Thiazolidinediones (1%)
    2. Sulfonylureas (1.5%)
    3. Insulin (1%)
    4. Meglitinides (0.7%)
  4. References
    1. Simha (2017) Novel Diabetes Medications Lectures, Mayo 91st Clinical Reviews, Rochester, MN

VII. Preparations: 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. Protocol: 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. Sulfonylurea (e.g. Glipizide, Glimepiride)
      1. Most cost effective second agent
      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. Thiazolidinediones or Glitazones (e.g. Pioglitazone)
      1. Avoid in Class III or Class IV Heart Failure
    2. Gliptin or DPP-4 Inhibitor (e.g.Sitagliptin or Januvia)
      1. Other agents may have greater benefit
    3. Incretin Mimetic or GLP-1 Agonist (e.g. Exenatide or Byetta)
      1. Injection, but more effective and facilitates weight loss
    4. SGLT2 Inhibitors or Flozins (e.g. Invokana)
    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. 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
  7. Agents with greatest effect based on body habitus
    1. Obese patients
      1. Metformin (Glucophage)
      2. Thiazolidinediones (e.g. Rosiglitazone)
      3. Exenatide (Byetta) or other GLP-1 Agonists
    2. Lean patients
      1. Sulfonylurea (e.g. Glipizide) or Meglitinide (e.g. Repaglinide)
      2. Sitagliptin (Januvia)
      3. Insulin
  8. 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: Oral Agents (injectables included for comparison)

  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)

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Related Studies

Ontology: Hypoglycemic Agents (C0020616)

Definition (MSH) Substances which lower blood glucose levels.
Definition (MEDLINEPLUS)

Diabetes means your blood glucose, or blood sugar, levels are too high. If you can't control your diabetes with wise food choices and physical activity, you may need diabetes medicines. The kind of medicine you take depends on your type of diabetes, your schedule, and your other health conditions.

With type 1 diabetes, your pancreas does not make insulin. Insulin is a hormone that helps glucose get into your cells to give them energy. Without insulin, too much glucose stays in your blood. If you have type 1 diabetes, you will need to take insulin.

Type 2 diabetes, the most common type, can start when the body doesn't use insulin as it should. If your body can't keep up with the need for insulin, you may need to take pills. Along with meal planning and physical activity, diabetes pills help people with type 2 diabetes or gestational diabetes keep their blood glucose levels on target. Several kinds of pills are available. Each works in a different way. Many people take two or three kinds of pills. Some people take combination pills. Combination pills contain two kinds of diabetes medicine in one tablet. Some people take pills and insulin.

NIH: National Institute of Diabetes and Digestive and Kidney Diseases

Definition (CSP) class of agents which lower blood glucose levels.
Concepts Pharmacologic Substance (T121)
MSH D007004
SnomedCT 373299009, 9356005, 325290009, 312064005
LNC LP33333-3, MTHU016642
English Agents, Hypoglycemic, Hypoglycemic Agents, hypoglycemic agent, Drugs, Hypoglycemic, Hypoglycemic Drugs, Hypoglycemics, Drugs for hypoglycaemia, Drugs for hypoglycemia, antihyperglycemic, Hypoglycaemic drug, Hypoglycemic drug, hypoglycemic drugs, hypoglycemic agents, hypoglycaemic, hypoglycemic, hypoglycemic drug, Agents, Antihyperglycemic, Antihyperglycemic Agents, Antihyperglycemics, Hypoglycemic Medicines, Diabetes Medicines, Hypoglycemic product (product), Drugs for hypoglycemia (product), Anti-hyperglycemics, Hypoglycemic agents, Hypoglycaemic, Hypoglycemic agent (substance), Hypoglycemic, Hypoglycaemic agent, Hypoglycemic agent, Hypoglycaemic product, Hypoglycemic agent (product), Hypoglycemic product, Hypoglycemic drug, NOS, Hypoglycaemic drug, NOS, Drugs for hypoglycemia (substance), Hypoglycemic drug (substance)
French Agents hypoglycémiques, Agents hypoglycémiants, Médicaments hypoglycémiants, Médicaments hypoglycémiques, Hypoglycémiants
Swedish Hypoglykemiska medel
Czech hypoglykemika
Finnish Verensokeria alentavat aineet
Italian Ipoglicemici, Farmaci ipoglicemici, Sostanze ipoglicemiche
Japanese 血糖降下薬, 経口抗糖尿病薬, 抗糖尿病薬, 糖尿病薬, 糖尿病治療剤, 抗糖尿病剤, 血糖降下剤, 経口血糖降下薬
Polish Leki hipoglikemizujące, Czynniki hipoglikemizujące, Środki przeciwcukrzycowe, Środki hipoglikemiczne
Portuguese Hipoglicemiantes, Medicamentos Hipoglicemiantes, Agentes Hipoglicemiantes, Fármacos Hipoglucemiantes, Medicamentos Hipoglucemiantes, Hipoglicêmicos, Hipoglucemiantes, Efeito Hipoglicemiante, Fármacos Hipoglicemiantes
Spanish Hipoglucemiantes, fármaco hipoglucemiante (producto), fármacos para el tratamiento de la hipoglucemia, fármaco hipoglucemiante, fármacos para el tratamiento de la hipoglucemia (producto), Medicamentos Hipoglucemiantes, Medicamentos Hipoglicemiantes, Efecto Hipoglucemiante, Hipoglicemiantes, Agentes Hipoglucemiantes, Fármacos Hipoglicemiantes, Fármacos Hipoglucemiantes, agente hipoglucemiante (sustancia), agente hipoglucemiante, droga hipoglucemiante (producto), droga hipoglucemiante (sustancia), droga hipoglucemiante, hipoglucemiante (producto), hipoglucemiante
German Blutzuckersenkende Mittel