Diabetes mellitus type 2 medical therapy
Diabetes mellitus type 2 Microchapters |
Differentiating Diabetes Mellitus Type 2 from other Diseases |
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Treatment |
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 |
|
|
Low |
Sulfonylureas | 2nd generation | Closes K-ATP channels on beta cell plasma membranes | ↑ Insulin secretion |
|
|
Low |
Meglitinides | Closes K-ATP channels on beta cell plasma membranes | ↑ Insulin secretion |
|
|
Moderate | |
Zhiazolidinedione
(TZDs) |
Activates the nuclear transcription factor PPAR-gama | ↑ Insulin sensitivity |
|
|
Low | |
α-Glucosidase
inhibitors |
Inhibits intestinal
α-glucosidase |
Slows intestinal carbohydrate
digestion/absorption |
|
|
Low to
moderate | |
DPP-4 | Inhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentrations |
|
|
|
High | |
Bile acid sequestrants | Colesevelam | Binds bile acids in intestinal tract,
increasing hepatic bile acid production |
|
|
|
High |
Dopamine-2 | Bromocriptine
(quick release)§ |
Activates dopaminergic receptors |
|
|
|
High |
SGLT2
inhibitors |
Inhibits SGLT2 in the proximal nephron |
|
|
|
High | |
GLP-1 receptor
agonists |
|
Activates GLP-1 receptors |
|
|
|
High |
Amylin mimetics | Pramlintide§ | Activates amylin receptors |
|
|
|
High |
Insulins |
|
Activates insulin receptors |
|
|
|
High |
| ||||||
| ||||||
| ||||||
|
‡ lnitial concerns regarding bladder cancer risk are decreasing after subsequent study.
§ Not licensed in Europe for type 2 diabetes.
Antidiabetic Drugs
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.[1] 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".[2] Of these, rosiglitazone had more weight gain and edema.[2] Rosiglitazone may increase risk of death from cardiovascular causes.[3] Pioglitazone and rosiglitazone may increase the risk of fractures.[4][5]
For patients who also have heart failure, metformin may be the best drug.[6]
Insulin Preparations
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.[7] More complicated estimations to guide initial dosage of insulin are:[8]
- 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.[9] Initially, adding nightly insulin to patients failing oral medications may be best.[10] Nightly insulin combines better with metformin that with sulfonylureas.[7] 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.[11]
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.[12][13][14]. 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".[13] A guide to titrating fixed ratio insulin is available (http://www.annals.org/cgi/content/full/145/2/125/T4).[9]
- 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".[15] More recently, a randomized controlled trial found that although long acting insulins were less effective, they were associated with less hypoglycemia.[12]
Alternative Medicines
Carnitine has been shown to increase insulin sensitivity and glucose storage in humans. [16]. 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.[17]
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
The goal blood pressure is 130/80 which is lower than in non-diabetic patients.[18]
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 [19]:
- 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.[20]
Hypolipidemic Agents
Contraindicated medications
Type 2 Diebetes is considered an absolute contraindication to the use of the following medications:
References
- ↑ Bolen S et al. Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus. Ann Intern Med 2007;147:6
- ↑ 2.0 2.1 Kahn SE, Haffner SM, Heise MA; et al. (2006). "Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy". N. Engl. J. Med. 355 (23): 2427–43. doi:10.1056/NEJMoa066224. PMID 17145742.
- ↑ "NEJM -- Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes".
- ↑ "MedWatch - 2007 Safety Information Alerts (Actos (pioglitazone))".
- ↑ "MedWatch - 2007 Safety Information Alerts (Rosiglitazone)".
- ↑ Eurich DT, McAlister FA, Blackburn DF; et al. (2007). "Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review". BMJ. 335 (7618): 497. doi:10.1136/bmj.39314.620174.80. PMID 17761999.
- ↑ 7.0 7.1 Yki-Järvinen H, Ryysy L, Nikkilä K, Tulokas T, Vanamo R, Heikkilä M (1999). "Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial". Ann. Intern. Med. 130 (5): 389–96. PMID 10068412.
- ↑ Holman RR, Turner RC (1985). "A practical guide to basal and prandial insulin therapy". Diabet. Med. 2 (1): 45–53. PMID 2951066.
- ↑ 9.0 9.1 Mooradian AD, Bernbaum M, Albert SG (2006). "Narrative review: a rational approach to starting insulin therapy". Ann. Intern. Med. 145 (2): 125–34. PMID 16847295.
- ↑ Yki-Järvinen H, Kauppila M, Kujansuu E; et al. (1992). "Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus". N. Engl. J. Med. 327 (20): 1426–33. PMID 1406860.
- ↑ Kratz A, Lewandrowski KB (1998). "Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Normal reference laboratory values". N. Engl. J. Med. 339 (15): 1063–72. PMID 9761809.
- ↑ 12.0 12.1 Holman RR, Thorne KI, Farmer AJ; et al. (2007). "Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes". N. Engl. J. Med. 357. doi:10.1056/NEJMoa075392. PMID 17890232.
- ↑ 13.0 13.1 Raskin P, Allen E, Hollander P; et al. (2005). "Initiating insulin therapy in type 2 Diabetes: a comparison of biphasic and basal insulin analogs". Diabetes Care. 28 (2): 260–5. PMID 15677776.
- ↑ Malone JK, Kerr LF, Campaigne BN, Sachson RA, Holcombe JH (2004). "Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy". Clinical therapeutics. 26 (12): 2034–44. doi:10.1016/j.clinthera.2004.12.015. PMID 15823767.
- ↑ Horvath K, Jeitler K, Berghold A, Ebrahim Sh, Gratzer T, Plank J, Kaiser T, Pieber T, Siebenhofer A (2007). "Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus". Cochrane database of systematic reviews (Online) (2): CD005613. PMID 17443605.
- ↑ Geltrude Mingrone, Aldo V. Greco, Esmeralda Capristo, Giuseppe Benedetti, Annalisa Giancaterini, Andrea De Gaetano, and Giovanni Gasbarrini (1999). "L-Carnitine Improves Glucose Disposal in Type 2 Diabetic Patients". Journal of the American College of Nutrition. 18 (1): 77–82.
- ↑ Yutaka Nakaya, Asako Minami, Nagakatsu Harada, Sadaichi Sakamoto, Yasuharu Niwa and Masaharu Ohnaka. "Taurine improves insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty rat, a model of spontaneous type 2 diabetes". American Journal of Clinical Nutrition. 71 (1): 54–58. Text "date January 2000 " ignored (help)
- ↑ Chobanian AV, Bakris GL, Black HR; et al. (2003). "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report". JAMA. 289 (19): 2560–72. doi:10.1001/jama.289.19.2560. PMID 12748199.
- ↑ Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G (2000). "Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators". N. Engl. J. Med. 342 (3): 145–53. PMID 10639539.
- ↑ Pilote L, Abrahamowicz M, Rodrigues E, Eisenberg MJ, Rahme E (2004). "Mortality rates in elderly patients who take different angiotensin-converting enzyme inhibitors after acute myocardial infarction: a class effect?". Ann. Intern. Med. 141 (2): 102–12. PMID 15262665.