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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.

The nonobese patient with type 2 diabetes

Nonobese patients with type 2 diabetes frequently have increased visceral adiposity - the so-called metabolically obese normal weight patient - and the treatment algorithm is much the same as in the obese patient except there is not as much emphasis on weight loss.

However, exercise remains an important aspect of treatment. Persons who do not have central obesity or insulin resistance should be evaluated for other types of diabetes such as latent autoimmune diabetes of adulthood (LADA) or maturity onset diabetes of the young (MODY). Patients with LADA can initially be treated with oral agents but require insulin within a few years, so experienced clinicians often prescribe insulin for these patients when the diagnosis is made.

Type 1 diabetes

Traditional once- or twice-daily insulin regimens are usually ineffective in type 1 patients without residual endogenous insulin. In these patients, information and counseling based on the findings of the DCCT should be provided about the advantages of taking multiple injections of insulin in conjunction with self-blood glucose monitoring. If near-normalization of blood glucose is attempted, at least three or four measurements of capillary blood glucose and three or four insulin injections are necessary.

A combination of rapid-acting insulin analogs and long-acting insulin analogs allows for more physiologic insulin replacement. The rapid-acting insulin analogs have been advocated as a safer and much more convenient alternative to regular human insulin for preprandial use. In a study comparing regular insulin with insulin lispro, daily insulin doses and hemoglobin A1c levels were similar, but insulin lispro improved postprandial control, reduced hypoglycemic episodes, and improved patient convenience compared with regular insulin. However, because of their relatively short duration (no more than 3-4 hours), the rapid-acting insulin analogs need to be combined with longer-acting insulins to provide basal coverage and avoid hyperglycemia prior to the next meal. In addition to carbohydrate content of the meal, the effect of simultaneous fat ingestion must also be considered a factor in determining the rapid-acting insulin analog dosage required to control the glycemic increment during and just after the meal. With low-carbohydrate content and high-fat intake, there is an increased risk of hypoglycemia from insulin lispro within 2 hours after the meal.

Multiple injections of NPH insulin can be mixed in the same syringe as the insulin lispro, insulin aspart, and insulin glulisine. Insulin glargine is usually given once in the evening to provide 24-hour coverage. This insulin cannot be mixed with any of the other insulins and must be given as a separate injection. There are occasional patients in whom insulin glargine does not seem to last for 24 hours, and in such cases it needs to be given twice a day. Insulin detemir may also need to be given twice a day to get adequate 24-hour basal coverage.

Continuous subcutaneous insulin infusion (CSII) by portable battery-operated "open loop" devices currently provides the most flexible approach, allowing the setting of different basal rates throughout the 24 hours and permitting patients to delay or skip meals and vary meal size and composition. The dosage is usually based on providing 50% of the estimated insulin dose as basal and the remainder as intermittent boluses prior to meals. For example, a 70-kg man requiring 35 units of insulin per day may require a basal rate of 0.7 units per hour throughout the 24 hours with the exception of 3 AM to 8 AM, when 0.8 units per hour might be appropriate (for the dawn phenomenon). The meal bolus would depend on the carbohydrate content of the meal and the premeal blood glucose value. One unit per 15 g of carbohydrate plus 1 unit for 50 mg/dL of blood glucose above a target value (eg, 120 mg/dL) is a common starting point. Further adjustments to basal and bolus dosages would depend on the results of blood glucose monitoring. The majority of patients use the rapid-acting insulin analogs in the pumps. One of the more difficult therapeutic problems in managing patients with type 1 diabetes is determining the proper adjustment of insulin dose when the prebreakfast blood glucose level is high. Occasionally, the prebreakfast hyperglycemia is due to the Somogyi effect, in which nocturnal hypoglycemia leads to a surge of counterregulatory hormones to produce high blood glucose levels by 7 AM. However, a more common cause for prebreakfast hyperglycemia is the waning of circulating insulin levels by the morning. Also, the "dawn phenomenon" - reduced tissue sensitivity to insulin between 5 AM and 8 AM - is present in as many as 75% of type 1 patients and can aggravate the hyperglycemia.

Table shows that diagnosis of the cause of prebreakfast hyperglycemia can be facilitated by self-monitoring of blood glucose at 3 AM in addition to the usual bedtime and 7 AM measurements. This is required for only a few nights, and when a particular pattern emerges from monitoring blood glucose levels overnight, appropriate therapeutic measures can be taken. The Somogyi effect can be treated by eliminating the dose of intermediate insulin at dinnertime and giving it at a lower dosage at bedtime or by supplying more food at bedtime. When a waning insulin level is the cause, then either increasing the evening dose or shifting it from dinnertime to bedtime (or both) can be effective. A bedtime dose either of insulin glargine or insulin detemir provides more sustained overnight insulin levels than human NPH and may be effective in managing refractory prebreakfast hyperglycemia. If this fails, insulin pump therapy may be required. When the dawn phenomenon alone is present, the dosage of intermediate insulin can be divided between dinnertime and bedtime; when insulin pumps are used, the basal infusion rate can be increased (eg, from 0.8 unit/h to 0.9 unit/h from 6 AM until breakfast).

Acceptable Levels of Glycemic Control

See above for a discussion of the DCCT and the UKPDS and their implications for diabetes therapy. A reasonable aim of therapy is to approach normal glycemic excursions without provoking severe or frequent hypoglycemia. What has been considered "acceptable" control includes blood glucose levels of 90-130 mg/dL before meals and after an overnight fast, and levels no higher than 180 mg/dL 1 hour after meals and 150 mg/dL 2 hours after meals. Glycohemoglobin levels should be no higher than 1% above the upper limit of the normal range for any particular laboratory. It should be emphasized that the value of blood pressure control was as great as or greater than glycemic control in type 2 patients as regards microvascular as well as macrovascular complications.