Diabetes mellitus type 2 medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Overview

The main goals of treatment are, eliminate hyperglycemic symptoms, control the long term complications and improve the patient's quality of life.

Diabetes mellitus type 2 is initially treated by life style modification and weight loss, especially in obese patients. Metformin is the first line pharmacologic therapy that usually starts once the diagnosis is confirmed unless contraindications exist. If glycemic goals does not achieved, the second agent must be add to metformin. A wide range of options are available to add as combination therapy based on patient condition and comorbidities.

Pharmacologic therapy

Medical therapy starts with metformin monotherapy unless there is a contraindication for it. In following conditions, treatment starts with dual therapy:

• If HbA1C is greater than 9, start with dual oral blood glucose lowering agent.
• If HbA1C is greater than 10 or blood glucose is more than 300 mg/dl or patient is markedly symptomatic, consider combination therapy with insulin.

Metformin

Metformin is effective and safe, is inexpensive, and may reduce risk of cardiovascular events and death. Patients should be advised to stop the medication in cases of nausea, vomiting or dehydration. It's contraindications include, heart failure, liver failure, GFR ≤30 and metabolic acidosis.

Combination therapy

Any agent can be added as second drug based on patient condition but American Association of Clinical Endocrinologists recommends either incretin based therapy or sodium glucose transporter 2 (SGLT2) inhibition agents.

The following table summarize the available FDA approved glucose lowering agents that may help to individualize treatment for each patient.

Class	Drug	Mechanism of action	Primary physiologic action	Advantages	Disadvantages	Cost
Biguanids	Metformin	Activates AMP-kinase	↓ Hepatic glucose production	Extensive experience Rare hypoglycemia ↓ CVD events Relatively higher A1C efficacy	Gastrointestinal side effects (diarrhea, abdominal cramping, nausea) Vitamin B12 deficiency Contraindications: eGFR ≤30 mL/min/1.73 m2, acidosis, hypoxia, dehydration. Lactic acidosis risk (rare)	Low
Sulfonylureas	2nd generation Glyburide Glipizide Glimepiride	Closes K-ATP channels on beta cell plasma membranes	↑ Insulin secretion	Extensive experience ↓ Microvascular risk Relatively higher A1C efficacy	Hypoglycemia ↑ Weight	Low
Meglitinides	Repaglinide Nateglinide	Closes K-ATP channels on beta cell plasma membranes	↑ Insulin secretion	↓ Postprandial glucose excursions Dosing flexibility	Hypoglycemia ↑ Weight Frequent dosing schedule	Moderate
Thiazolidinedione (TZDs)	Pioglitazone‡ Rosiglitazone§	Activates the nuclear transcription factor PPAR-gama	↑ Insulin sensitivity	Rare hypoglycemia Relatively higher A1C efficacy Durability ↓ Triglycerides (pioglitazone) ↓ CVD events (PROactive, pioglitazone) ↓ Risk of stroke and MI in patients without diabetes and with insulin resistance and history of recent stroke or TIA	↑ Weight Edema/heart failure Bone fractures ↑ LDL-C (rosiglitazone)	Low
α-Glucosidase inhibitors	Acarbose Miglitol	Inhibits intestinal α-glucosidase	Slows intestinal carbohydrate digestion/absorption	Rare hypoglycemia ↓ Postprandial glucose excursions ↓ CVD events in prediabetes Nonsystemic	Generally modest A1C efficacy Gastrointestinal side effects (flatulence, diarrhea) Frequent dosing schedule	Low to moderate
DPP-4 inhibitors	Sitagliptin Saxagliptin Linagliptin Alogliptin	Inhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentrations	↑ Insulin secretion (glucose dependent) ↓ Glucagon secretion (glucose dependent)	Rare hypoglycemia Well tolerated	Angioedema/urticaria and other immune-mediated dermatological effects Acute pancreatitis ↑ Heart failure hospitalizations (saxagliptin, alogliptin)	High
Bile acid sequestrants	Colesevelam	Binds bile acids in intestinal tract, increasing hepatic bile acid production	↓ Hepatic glucose production ↑ Incretin levels	Rare hypoglycemia ↓ LDL-C	Modest A1C efficacy Constipation ↑ Triglycerides May ↓ absorption of other medications	High
Dopamine-2 agonists	Bromocriptine (quick release)§	Activates dopaminergic receptors	Modulates hypothalamic regulation of metabolism ↑ Insulin sensitivity	Rare hypoglycemia ↓ CVD events	Modest A1C efficacy Dizziness/syncope Nausea Fatigue Rhinitis	High
SGLT2 inhibitors	Canagliflozin Dapagliflozin‡ Empagliflozin	Inhibits SGLT2 in the proximal nephron	Blocks glucose reabsorption by the kidney,increasing glucosuria	Rare hypoglycemia ↓ Weight ↓ Blood pressure Associated with lower CVD event rate and mortality in patients with CVD	Genitourinary infections Polyuria Volume depletion, hypotension, dizziness ↑ LDL-C ↑ Creatinine (transient) DKA, urinary tract infections leading to urosepsis, pyelonephritis	High
GLP-1 receptor agonists	Exenatide Exenatide extended release Liraglutide Albiglutide Lixisenatide Dulaglutide	Activates GLP-1 receptors	↑ Insulin secretion (glucose dependent) ↓ Glucagon secretion (glucose dependent) Slows gastric emptying ↑ Satiety	Rare hypoglycemia ↓ Weight ↓ Postprandial glucose excursions ↓ Some cardiovascular risk factors Associated with lower CVD event rate and mortality in patients with CVD	Gastrointestinal side effects (nausea/vomiting/diarrhea) ↑ Heart rate Acute pancreatitis C-cell hyperplasia/medullary thyroid tumors in animals Injectable Training requirements	High
Amylin mimetics	Pramlintide§	Activates amylin receptors	↓ Glucagon secretion Slows gastric emptying ↑ Satiety	Postprandial glucose excursions ↓ Weight	Modest A1C efficacy Gastrointestinal side effects (nausea/vomiting) Hypoglycemia unless insulin dose is simultaneously reduced Injectable Frequent dosing schedule Training requirements	High
Insulins	Rapid-acting analogs Lispro Aspart Glulisine Inhaled insulin	Activates insulin receptors	↑ Glucose disposal ↓ Hepatic glucose production Suppresses ketogenesis	Nearly universal response Theoretically unlimited efficacy ↓ Microvascular risk	Hypoglycemia Weight gain Training requirements Patient and provider reluctance Injectable (except inhaled insulin) Pulmonary toxicity (inhaled insulin)	High
	Short-acting Human Regular
	Intermediate-acting Human NPH
	Basal insulin analogs Glargine Detemir Degludec
	Premixed insulin products NPH/Regular 70/30 70/30 aspart mix 75/25 lispro mix 50/50 lispro mix

^‡ lnitial concerns regarding bladder cancer risk are decreasing after subsequent study.

^§ Not licensed in Europe for type 2 diabetes.