Type 2 diabetes Mellitus Treatment

Treatment must be individualized on the basis of the type of diabetes and specific needs of each patient. However, certain general principles of management can be outlined for hyperglycemic states of different types. 

1. Type 2 diabetes

The most common type of diabetic patient is obese, is non-insulin-dependent, and has hyperglycemia because of insensitivity to normal or elevated circulating levels of insulin. 

(1) Weight reduction

Treatment is directed toward achieving weight reduction, and prescribing a diet is only one means to this end. Behavior modification to achieve adherence to the diet - as well as increased physical activity to expend energy - is also required. Cure can be achieved by reducing adipose stores, with consequent restoration of tissue sensitivity to insulin, but weight reduction is hard to achieve and even more difficult to maintain with our current therapies. The presence of diabetes with its added risk factors may motivate the obese diabetic to greater efforts to lose weight. 

(2) Hypoglycemic agents

If the patient is not able to achieve target glycemic control with weight management and exercise, then pharmacologic therapy is indicated. The choice of initial agent depends on a number of factors, including comorbid conditions, adverse reactions to the medications, ability of the patient to monitor for hypoglycemia, drug cost, and patient and physician preferences. Metformin is advantageous because apart from lowering glucose without the risk of hypoglycemia, it also lowers triglycerides and promotes some modest weight loss. The drug, however, cannot be used in patients with renal failure, and gastrointestinal side effects develop in some patients at even the lowest doses. Thiazolidinediones improve peripheral insulin resistance and lower glucose without causing hypoglycemia. They also have been reported to improve nonalcoholic fatty liver disease, have beneficial effects on the lipid profile and some other cardiovascular risk factors, decrease microalbuminuria, and reduce neointimal tissue hyperplasia after coronary artery stent placement. These drugs, however, can cause fluid retention and are contraindicated in patients with heart failure. 

They also very commonly increase weight, which patients find distressing, affecting adherence. The drugs are also contraindicated in patients with active liver disease and in patients with liver enzymes ≥ 2.5 times the upper limit of normal. Sulfonylureas have been available for many years and their use in combination with metformin is well established. They do, however, have the propensity of causing hypoglycemia and weight gain. The α-glucosidase inhibitors have modest glucose lowering effects and have gastrointestinal side effects. Exenatide has a lower risk of hypoglycemia than the sulfonylureas and promotes weight loss. However, it needs to be given by injection, causes nausea, and is contraindicated in patients with gastroparesis. Exenatide is also expensive and lacks long-term safety data.

For most obese patients with mild type 2 diabetes, metformin is the first-line agent. If it proves to be inadequate, then a second agent should be added. In those patients where the problem is hyperglycemia after a carbohydrate rich meal (such as dinner), then a short-acting secretagogue before meals may suffice to get the glucose levels into the target range. Patients with nonalcoholic fatty liver disease or microalbuminuria may be candidates for one of the thiazolidinediones. Subjects who are very concerned about weight gain may benefit from a trial of exenatide. If two agents are inadequate, then a third agent is added, although data regarding efficacy of such combined therapy are limited. Experienced clinicians have found that instead of maximizing the dose of each agent before adding another agent, some patients are more tolerant of submaximal combinations of drugs. Insulin therapy should be instituted if combination of oral agents (and exenatide) fail to restore euglycemia. Weight-reducing interventions should continue and may allow for simplification of this regimen in the future. 

When the combination of oral agents (and exenatide) fail to achieve euglycemia in patients with type 2 diabetes, various insulin regimens may be effective. There is no consensus about how insulin therapy should be instituted. One proposed regimen is to continue the oral combination therapy and then simply add a bedtime dose of NPH or long-acting insulin analog (insulin glargine or insulin detemir) to reduce excessive nocturnal hepatic glucose output and improve fasting glucose levels. If the patient does not achieve target glucose levels during the day, then daytime insulin treatment can be initiated. A convenient insulin regimen under these circumstances is a split dose of 70/30 NPH/regular mixture (or Humalog Mix 75/25 or NovoLogMix 70/30) before breakfast and before dinner. If this regimen fails to achieve satisfactory glycemic goals or is associated with unacceptable frequency of hypoglycemic episodes, then a more intensive regimen of multiple insulin injections can be instituted as in patients with type 1 diabetes. Metformin principally reduces hepatic glucose output and the thiazolidinediones improve peripheral insulin resistance, so it is a reasonable option to continue these drugs when insulin therapy is instituted. The sulfonylureas also have been shown to be of continued benefit. Thus, the continued use of the oral drugs may permit the use of lower doses of insulin and simpler regimens. There is no data on the continued administration of exenatide under these circumstances.