<sup>§</sup> Not licensed in Europe for type 2 diabetes.
<sup>§</sup> Not licensed in Europe for type 2 diabetes.
===Antidiabetic Drugs===
====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.<ref>Bolen S et al. Systematic Review: [http://www.annals.org/cgi/content/full/0000605-200709180-00178v1 Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus]. Ann Intern Med 2007;147:6
</ref> 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".<ref name="pmid17145742">
{{cite journal |author=Kahn SE, Haffner SM, Heise MA, ''et al'' |title=Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy |journal=N. Engl. J. Med. |volume=355 |issue=23 |pages=2427-43 |year=2006 |pmid=17145742 |doi=10.1056/NEJMoa066224}}
</ref> Of these, rosiglitazone had more weight gain and edema.<ref name="pmid17145742"/> Rosiglitazone may increase risk of death from cardiovascular causes.<ref name="nejm-rosiglitazone">
{{cite web |url=http://content.nejm.org/cgi/content/full/NEJMoa072761 |title=NEJM -- Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes}}
</ref> Pioglitazone and rosiglitazone may increase the risk of fractures.<ref name="fda-actos>
{{cite web |url=http://www.fda.gov/medwatch/safety/2007/safety07.htm#actos |title=MedWatch - 2007 Safety Information Alerts (Actos (pioglitazone))}}
</ref><ref name="fda-rosiglitazone">{{cite web |url=http://www.fda.gov/medwatch/safety/2007/safety07.htm#rosiglitazone |title=MedWatch - 2007 Safety Information Alerts (Rosiglitazone)}}
</ref>
For patients who also have heart failure, [[metformin]] may be the best drug.<ref name="pmid17761999">{{cite journal |author=Eurich DT, McAlister FA, Blackburn DF, ''et al'' |title=Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review |journal=BMJ |volume=335 |issue=7618 |pages=497 |year=2007 |pmid=17761999 |doi=10.1136/bmj.39314.620174.80}}</ref>
=====Insulin Preparations=====
=====Starting Insulin=====
If [[antidiabetic drug]]s 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.<ref name="pmid10068412"/> More complicated estimations to guide initial dosage of insulin are:<ref name="pmid2951066">{{cite journal |author=Holman RR, Turner RC |title=A practical guide to basal and prandial insulin therapy |journal=Diabet. Med. |volume=2 |issue=1 |pages=45–53 |year=1985 |pmid=2951066 |doi=}}</ref>
* 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.<ref name="pmid16847295">{{cite journal |author=Mooradian AD, Bernbaum M, Albert SG |title=Narrative review: a rational approach to starting insulin therapy |journal=Ann. Intern. Med. |volume=145 |issue=2 |pages=125-34 |year=2006 |pmid=16847295 |doi=|url=http://www.annals.org/cgi/content/full/145/2/125}}</ref> Initially, adding nightly insulin to patients failing oral medications may be best.<ref name="pmid1406860">{{cite journal |author=Yki-Järvinen H, Kauppila M, Kujansuu E, ''et al'' |title=Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus |journal=N. Engl. J. Med. |volume=327 |issue=20 |pages=1426-33 |year=1992 |pmid=1406860 |doi=}}</ref> Nightly insulin combines better with [[metformin]] that with [[sulfonylurea]]s.<ref name="pmid10068412">{{cite journal |author=Yki-Järvinen H, Ryysy L, Nikkilä K, Tulokas T, Vanamo R, Heikkilä M |title=Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial |journal=Ann. Intern. Med. |volume=130 |issue=5 |pages=389–96 |year=1999 |pmid=10068412 |doi=|url=http://www.annals.org/cgi/content/full/130/5/389}}</ref> 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.<ref name="pmid9761809">{{cite journal |author=Kratz A, Lewandrowski KB |title=Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Normal reference laboratory values |journal=N. Engl. J. Med. |volume=339 |issue=15 |pages=1063–72 |year=1998 |pmid=9761809 |doi=}}</ref>
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.<ref name="pmid17890232">{{cite journal |author=Holman RR, Thorne KI, Farmer AJ, ''et al'' |title=Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes |journal=N. Engl. J. Med. |volume=357 |issue= |pages= |year=2007 |pmid=17890232 |doi=10.1056/NEJMoa075392}}</ref><ref name="pmid15677776">{{cite journal |author=Raskin P, Allen E, Hollander P, ''et al'' |title=Initiating insulin therapy in type 2 Diabetes: a comparison of biphasic and basal insulin analogs |journal=Diabetes Care |volume=28 |issue=2 |pages=260-5 |year=2005 |pmid=15677776 |doi=|url=http://care.diabetesjournals.org/cgi/content/full/28/2/260}}</ref><ref name="pmid15823767">{{cite journal |author=Malone JK, Kerr LF, Campaigne BN, Sachson RA, Holcombe JH |title=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 |journal=Clinical therapeutics |volume=26 |issue=12 |pages=2034-44 |year=2004 |pmid=15823767 |doi=10.1016/j.clinthera.2004.12.015}}</ref>. 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".<ref name="pmid15677776"/> A guide to titrating fixed ratio insulin is available (http://www.annals.org/cgi/content/full/145/2/125/T4).<ref name="pmid16847295"/>
* 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".<ref name="pmid17443605">{{cite journal |author=Horvath K, Jeitler K, Berghold A, Ebrahim Sh, Gratzer T, Plank J, Kaiser T, Pieber T, Siebenhofer A |title=Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus |journal=Cochrane database of systematic reviews (Online) |volume= |issue=2 |pages=CD005613 |year=2007 |pmid=17443605}}</ref> More recently, a [[randomized controlled trial]] found that although long acting insulins were less effective, they were associated with less hypoglycemia.<ref name="pmid17890232"/>
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.
‡ lnitial concerns regarding bladder cancer risk are decreasing after subsequent study.
§ Not licensed in Europe for type 2 diabetes.
Alternative Medicines
Carnitine has been shown to increase insulin sensitivity and glucose storage in humans. [1]. 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.
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.
↑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.CS1 maint: Multiple names: authors list (link)
↑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. PMID12748199.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
↑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. PMID10639539.CS1 maint: Multiple names: authors list (link)
↑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. PMID15262665.CS1 maint: Multiple names: authors list (link)