Diabetes mellitus type 2 medical therapy


 * Associate Editor(s)-In-Chief: Priyamvada Singh, M.B.B.S. [mailto:psingh@perfuse.org];

Treatment
Diabetes mellitus type 2 is a chronic, progressive disease that has no medically proven cure. There are two main goals of treatment of the disease: The first goal can be achieved through close glycemic control (i.e., blood glucose levels); the reduction effect in diabetic complications has been well demonstrated in several extensive clinical trials and is thus well established. The second goal is often addressed (in developed countries) by support and care from teams of diabetic health workers (physician, PA, nurse, dietitian or a certified diabetic educator). Endocrinologists, family practitioners, and general internists are the types of physicians most likely to treat people with diabetes. Knowledgeable patient participation is vital and so patient education is a crucial aspect of this effort.
 * 1) reduction of mortality and concomitant morbidity (from assorted diabetic complications)
 * 2) preservation of quality of life

Type 2 is initially treated by adjustment in diet and exercise, and by weight loss, especially in obese patients. The amount of weight loss which improves the clinical picture is sometimes modest (2-5 kg or 4.4-11 lb); this is almost certainly due to currently poorly understood aspects of fat tissue chemical signaling (especially in visceral fat tissue in and around abdominal organs). In many cases, such initial efforts can substantially restore insulin sensitivity.

Treatment goals
For most patients, clinical practice guidelines recommend a goal Hba1c of 6.0% to 7.0%.

In older patients, clinical practice guidelines by the American Geriatrics Society states "for frail older adults, persons with life expectancy of less than 5 years, and others in whom the risks of intensive glycemic control appear to outweigh the benefits, a less stringent target such as 8% is appropriate".

Self monitoring of blood glucose
It is unclear if self-monitoring of blood glucose improves outcomes among "reasonably well controlled non-insulin treated patients with type 2 diabetes".

Dietary management
Modifying the diet is known to help control glucose intake, and in response, blood glucose levels.

One 2007 study will report that in a Paleolithic diet, all 14 patients returned blood glucose levels to normal after the trial period of 12 weeks, and improved glucose tolerance (26% less blood glucose rise following a carbohydrate intake compared to 7% reduction for control group on a Mediterranean diet). This was the first Paleolithic diet study, and suggested that "it may be more efficient to avoid some of our modern foods than to count calories or carbohydrate".

Other evidence for modified diets treating and being beneficial include:
 * A vegan diet.
 * Caloric restriction.
 * Cinnamon and Nutmeg (spices commonly found in apple pie).

Exercise
In September 2007, a joint randomized controlled trial by the University of Calgary and the University of Ottawa found that "Either aerobic or resistance training alone improves glycemic control in type 2 diabetes, but the improvements are greatest with combined aerobic and resistance training than either alone." The combined program reduced the HbA1c by 0.5 percentage point.

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)

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
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 : 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.
 * hypertension
 * hypercholesterolemia or reduced low high-density lipoprotein cholesterol levels
 * cigarette smoking
 * microalbuminuria