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: Priyamvada Singh, M.B.B.S. [2]; Cafer Zorkun, M.D., Ph.D. [3]

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. (22)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
Zhiazolidinedione (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 c Nonsystemic	Generally modest A1C efficacy Gastrointestinal side effects (flatulence, diarrhea) Frequent dosing schedule	Low to moderate
DPP-4 inhibitors	Sitagliptin c Saxagliptin c Linagliptin c Alogliptin	Inhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentrations	↑ Insulin secretion (glucose dependent) c ↓ Glucagon secretion (glucose dependent)	Rare hypoglycemia c Well tolerated	Angioedema/urticaria and other immune-mediated dermatological effects c ? Acute pancreatitis c ↑ Heart failure hospitalizations (saxagliptin; ? alogliptin)	High
Bile acid sequestrants	Colesevelam	Binds bile acids in intestinal tract, increasing hepatic bile acid production	↓ Hepatic glucose production c ? ↑ Incretin levels	Rare hypoglycemia c ↓ LDL-C	Modest A1C efficacy c Constipation c ↑ Triglycerides c May ↓ absorption of other medications	High
Dopamine-2 agonists	Bromocriptine (quick release)§	Activates dopaminergic receptors	Modulates hypothalamic regulation of metabolism c ↑ Insulin sensitivity	Rare hypoglycemia c ? ↓ CVD events (Cycloset Safety Trial)	Modest A1C efficacy c Dizziness/syncope c Nausea c Fatigue c Rhinitis	High
SGLT2 inhibitors	Canagliflozin c Dapagliflozin‡ c Empagliflozin	Inhibits SGLT2 in the proximal nephron	Blocks glucose reabsorption by the kidney, increasing glucosuria	Rare hypoglycemia c ↓ Weight c ↓ Blood pressure c Associated with lower CVD event rate and mortality in patients with CVD (empagliflozin EMPA-REG OUTCOME)	Genitourinary infections c Polyuria c Volume depletion/hypotension/dizziness c ↑ LDL-C c ↑ Creatinine (transient) c DKA, urinary tract infections leading to urosepsis, pyelonephritis	High
GLP-1 receptor agonists	Exenatide c Exenatide extended release c Liraglutide c Albiglutide c Lixisenatide c Dulaglutide	Activates GLP-1 receptors	↑ Insulin secretion (glucose dependent) c ↓ Glucagon secretion (glucose dependent) c Slows gastric emptying c ↑ Satiety	Rare hypoglycemia c ↓ Weight c ↓ Postprandial glucose excursions c ↓ Some cardiovascular risk factors c Associated with lower CVD event rate and mortality in patients with CVD (liraglutide LEADER) (30)	Gastrointestinal side effects (nausea/vomiting/diarrhea) c ↑ Heart rate c ? Acute pancreatitis c C-cell hyperplasia/medullary thyroid tumors in animals c Injectable c Training requirements	High
Amylin mimetics	Pramlintide§	Activates amylin receptors	↓ Glucagon secretion c Slows gastric emptying c ↑ Satiety	Postprandial glucose excursions c ↓ Weight	Modest A1C efficacy c Gastrointestinal side effects (nausea/vomiting) c Hypoglycemia unless insulin dose is simultaneously reduced c Injectable c Frequent dosing schedule c Training requirements
Insulins	Rapid-acting analogs - Lispro - Aspart - Glulisine - Inhaled insulin c Short-acting - Human Regular c Intermediate-acting - Human NPH Basal insulin analogs - Glargine - Detemir - Degludec c Premixed insulin products - NPH/Regular 70/30 270/30 aspart mix 275/25 lispro mix 250/50 lispro mix	Activates insulin receptors	↑ Glucose disposal c ↓ Hepatic glucose production c Suppresses ketogenesis	Nearly universal response c Theoretically unlimited efficacy c ↓ Microvascular risk (UKPDS)	Hypoglycemia c Weight gain c Training requirements c Patient and provider reluctance c Injectable (except inhaled insulin) c Pulmonary toxicity (inhaled insulin)

Antidiabetic Drugs

Metformin 500mg tablets

Main article: anti-diabetic drug

The most important drug now used in Type 2 Diabetes is the Biguanide metformin which works primarily by reducing liver release of blood glucose from glycogen stores as well as some increase in uptake of glucose by the body's tissues. Both historically and currently commonly used are the Sulfonylurea group, of which several members (including glibenclamide and gliclazide) are widely used; these increase glucose stimulated insulin secretion by the pancreas.

Newer drug classes include:

• Thiazolidinediones (TZDs) (rosiglitazone, pioglitazone, and troglitazone) (withdrawn from the US market)
• α-glucosidase inhibitors (acarbose and miglitol)
• Meglitinides which stimulate insulin release (nateglinide, repaglinide, and their analogs)
• Peptide analogs which work in a variety of ways:
  • Incretin mimetics act as insulin secretagogue among other effects. These includes the Glucagon-like peptide (GLP) analog exenatide
  • Dipeptidyl peptidase-4 (DPP-4) inhibitors increase Incretin levels ( sitagliptin)
  • Amylin agonist analog, which slows gastric emptying and suppresses glucagon (pramlintide)

Selecting an Antidiabetic Drug

Oral Drugs

A systematic review of randomized controlled trials found that metformin and second-generation sulfonylureas are the preferred choices for most. Failure of response after a time is not unknown with most of these agents: the initial choice of anti-diabetic drug has been compared in a randomized controlled trial which found "cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide". Of these, rosiglitazone had more weight gain and edema. Rosiglitazone may increase risk of death from cardiovascular causes. Pioglitazone and rosiglitazone may increase the risk of fractures.

For patients who also have heart failure, metformin may be the best drug.

Starting Insulin

If antidiabetic drugs fail (or stop helping), insulin therapy may be necessary -- usually in addition to oral medication therapy -- to maintain normal glucose levels.

Typical total daily dosage of insulin is 0.6 U/kg. More complicated estimations to guide initial dosage of insulin are:

• For men, [(fasting plasma glucose [mmol/liter]–5)x2] x (weight [kg]÷(14.3xheight [m])–height [m])
• For women, [(fasting plasma glucose [mmol/liter]–5)x2] x (weight [kg]÷(13.2xheight [m])–height [m])

The initial insulin regimen can be chosen based on the patient's blood glucose profile. Initially, adding nightly insulin to patients failing oral medications may be best. Nightly insulin combines better with metformin that with sulfonylureas. The initial dose of nightly insulin (measured in IU/d) should be equal to the fasting blood glucose level (measured in mmol/L). If the fasting glucose is reported in mg/dl, multiple by 0.05551 to convert to mmol/L.

When nightly insulin is insufficient, choices include:

• Premixed insulin with a fixed ratio of short and intermediate acting insulin; this tends to be more effective than long acting insulin, but is associated with more hypoglycemia.. Initial total daily dosage of biphasic insulin can be 10 units if the fasting plasma glucose values are less than 180 mg/dl or 12 units when the fasting plasma glucose is above 180 mg/dl". A guide to titrating fixed ratio insulin is available (http://www.annals.org/cgi/content/full/145/2/125/T4).

• Long acting insulins such as insulin glargine and insulin detemir. A meta-analysis of randomized controlled trials by the Cochrane Collaboration found "only a minor clinical benefit of treatment with long-acting insulin analogues for patients with diabetes mellitus type 2". More recently, a randomized controlled trial found that although long acting insulins were less effective, they were associated with less hypoglycemia.

Alternative Medicines

Carnitine has been shown to increase insulin sensitivity and glucose storage in humans. . It is important to note that this was with a constant blood infusion, not an oral dose, and that the clinical significance of this result is unclear.

Taurine has also shown significant improvement in insulin sensitivity and hyperlipidemia in rats.

Neither of these have shown permanent positive effects, nor a complete restoration to pre-diabetes conditions, only improvement. Their clinical importance in humans remains unclear.

Antihypertensive Agents

Main article: Antihypertensive

The goal blood pressure is 130/80 which is lower than in non-diabetic patients.

ACE Inhibitors

The HOPE study suggests that diabetics should be treated with ACE inhibitors (specifically ramipril 10 mg/d) if they have one of the following :

• Hypertension
• Hypercholesterolemia or reduced low high-density lipoprotein cholesterol levels
• Cigarette smoking
• Microalbuminuria

After treatment with ramipril for 5 years the number needed to treat was 50 patients to prevent one cardiovascular death. Other ACE inhibitors may not be as effective.

Hypolipidemic Agents

Main article: Hypercholesterolemia § Diabetic_patients

Contraindicated medications

Type 2 Diebetes is considered an absolute contraindication to the use of the following medications:

• Eplerenone