The treatment of type 2 DM continues to be a major therapeutic challenge. Our knowledge of the efficacy of treatment strategies was informed by the landmark intervention study, the United Kingdom Prospective Diabetes Study (UKPDS). In this study, an intensive glucose control policy, which was able to maintain a HbA1c value 0.9% lower than conventional treatment, was associated with significant reductions in the risk of microvascular endpoints. The UKPDS has demonstrated the progressive nature of type 2 diabetes and the need to employ combination treatments and insulin to achieve target goals. Redefining of such goals has also occurred, and the American Diabetes Association has proposed a target value for HbA1c of 7.0%, while the European Diabetes Project Group has proposed a HbA1c value of < 6.5%.
Dietary modification and physical activity are the mainstay of treatment of type 2 diabetes. However, it is well recognized that only a minority of type 2 diabetes patients are able to achieve long-term glycemic control by such measures alone. Failure of dietary treatment is due to either (or both) an inability to sustain the necessary diet modifications or worsening of the diabetic state. Drug treatment should not be instituted until an adequate trial of diet has been shown to have failed. However, there is now an increasing tendency to advocate an intensive aggressive therapeutic strategy from the outset to reduce fasting blood glucose and HbA1c levels to those defined above in an effort to minimize the risk of future complications. When diet fails, treatment with oral hypoglycemic agents is indicated, initially as monotherapy, and if and when that fails as combination therapy. Five classes of oral antidiabetic agents are currently available. In the past sulfonylureas have been widely prescribed as firstline agents after dietary failure (in some countries a-glucosidase inhibitors have had this role). However, the UKPDS has shown significant benefits for metformin as a first-line agent especially in obese patients. The place of agents such as meglitinides and thiazo-lidinediones (glitazones) as initial monotherapy is still subject to assessment and review.
Sulfonylureas stimulate insulin secretion from the P-cell. They also appear to sensitize the p-cell to various other insulin secretagogs, such as glucose. An improvement in insulin resistance may also be observed with the sulfonylureas, but this is thought to be secondary to their primary mode of action and not a direct effect of the drug.
Among sulfonylureas, there is a wide variation in half-life, ranging from 3-8h (tolbutamide) to 35 h (chlorpropamide). Side-effects, such as skin rashes, are relatively uncommon with the exception of hypo-glycemia. Particular caution should be taken in type 2 diabetic patients with renal failure. Sulfonylureas have a tendency to produce weight gain, although any intervention that improves diabetic control in a patient following an isocaloric diet would be expected to result in such an effect.
Metformin lowers plasma glucose by inhibiting hepatic glucose production and increasing the sensitivity of peripheral tissue to insulin. It does not usually cause hypoglycemia but, as it is renally excreted, it should not be used in patients with renal impairment.
Gastrointestinal side-effects are common and include diarrhea, anorexia, dyspepsia and a metallic taste in the mouth. To minimize the occurrence of side-effects, patients should be started on a low dose. Weight gain is usually not a problem with metformin, possibly because it has a slight anorectic effect. Lactic acidosis (which led to the withdrawal of phenformin) is a potentially serious side-effect of metformin therapy, but is rare and unlikely to occur if the drug is not used in patients with hepatic disease, renal impairment or severe cardiac problems.
These drugs, which include acarbose (Glucobay®, Bayer) and miglitol (Glyset®, Bayer), are widely used first-line agents in Japan. They delay the absorption of complex carbohydrates from the gastrointestinal tract and are of value in controlling postprandial hyper-glycemia; however, their blood glucose lowering effect is lower than those of metformin or the sulfonylureas, and the side-effects of flatulence and diarrhea often limit their tolerability.
Meglitinides (or prandial glucose regulators)
These newer agents, like the sulfonylureas, act via closure of K-ATP channels in the p-cells, although their receptor binding characteristics are different. They include repaglinide (NovoNorm®, Novo Nordisk) and nateglinide (Starlix®, Novartis) and they rapidly produce a short-lived insulin release that is dependent on the concentration of glucose. Thus, taken before meals they restore towards normal the delayed and impaired insulin response to meals seen in type 2 diabetes, without causing hypoglycemia. Evidence suggests that prandial glucose spikes may have a role in the development of diabetic macrovascular complications but, as yet, there is no consensus as to the place of prandial glucose regulation in the management of type 2 diabetes. Meglitinides may safely be used in combination with metformin. In some countries, the enthusiasm for use of these drugs appears to be declining and they have not established themselves as first-line agents. The cost of meglitinides is high compared with that of generic sulfonylureas.
The initial enthusiasm for the thiazolidinediones (or glitazones) was tempered by the severe hepatotoxicity associated with troglitazone, which has now been withdrawn. The newer glitazones, rosiglitazone (Avan-dia®, GlaxoSmithKline) and pioglitazone (Actos®, Takeda) show no significant association with hepato-toxicity. Their mode of action is mediated by activation of the nuclear receptor peroxisome proliferator-
activated receptor-gamma (PPARy), which is found predominantly in adipose tissue but also in skeletal muscle and liver. This leads to stimulation of insulinsensitive proteins with a reduction of hepatic glucose production and an increase in peripheral glucose uptake. Thiazolidinediones act to increase fatty acid uptake into adipocytes thus lowering triglyceride and non-esterified fatty acid levels which contribute to the favorable effect on glucose metabolism outlined above. They also induce adipocyte differentiation. As monotherapy these agents are comparable with sul-fonylureas and metformin but, because of the effects outlined above, they may prove to have a particularly beneficial role in ameliorating insulin resistance. They reduce intra-abdominal fat deposition but also promote peripheral fat deposition. This latter effect and their tendency to produce edema is associated with weight gain. They should not be used in patients with cardiac failure or who are at risk of developing heart failure.
In a prospective randomized controlled trial (the PROACTIVE study), 5238 patients with type 2 DM who had evidence of macrovascular disease were assigned to pioglitazone or placebo and studied for nearly 36 months. Although there was no statistically significant reduction in the study composite primary endpoint, the use of pioglitazone was associated with a significant reduction in the secondary composite endpoint of all-cause mortality, non-fatal myocardial infarction and stroke, suggesting that glitazones may have a role in secondary prevention of macrovascular events in patients with type 2 diabetes.
If diabetic control remains unacceptable despite dietary improvements with oral drug treatment, insulin therapy may be indicated. Insulin is the only efficacious therapy in type 2 DM once significant P-cell failure has supervened. Oral agents fail to lower blood glucose levels adequately once P-cell reserve falls below about 15% of normal. Approximately half of all patients with type 2 DM will need insulin therapy within 6 years of diagnosis because of a progressive decline in P-cell function. It seems sensible to outline this potential future therapeutic direction to patients at the time of diagnosis. In patients with type 2 DM, insulin therapy may be associated with an increase in weight, especially in those who are over eating in the first place. This is unavoidable as the patients are unlikely, at this stage, to reduce their caloric intake. If substantially improved glycemic control is obtained, this will probably override the detrimental effects of any weight gained by the patient. However, the majority of normal-weight or moderately overweight type 2 DM patients transferring to insulin gain only a modest amount of weight (around 2-4 kg).
There are many ways of giving insulin to patients with type 2 DM and each regimen has its own advocates. No universal consensus exists, although studies examining this issue are in progress. One simple and popular approach is to give a subcutaneous injection of an intermediate or long-acting insulin (NPH, insulin glargine or insulin detemir) before bed with the object of normalizing the pre-breakfast blood glucose. Possible alternative regimens, or when the above approach fails to deliver adequate glycemic control, include twice-daily injections of fixed mixtures of soluble and intermediate-acting insulins (e.g. Human Mixtard 30, NovoMix 30 (Novo Nordisk) or Humalog Mix 25 (Eli Lilly)) given before or at breakfast and the evening meal according to insulin type. Finally, and especially in the context of severe insulin deficiency, insulin may be administered in a basal bolus regimen, as for type 1 DM patients, with short-acting insulin given with each meal accompanied by an injection of a longer-acting insulin before bed. Metformin treatment can be continued in those who are overweight to lower insulin resistance. In the USA, thiazolidinediones (glitazones) are licensed for use in combination with insulin except in those who show any evidence of heart failure. Such a combination is not yet licensed in Europe. Insulin therapy dictates the need to practice self blood glucose monitoring.
Logically, drugs used for the treatment of obesity might have a beneficial effect in type 2 DM by improving insulin sensitivity as a result of weight loss. Studies have demonstrated such benefit for the lipase inhibitor orlistat (Xenical) and for the serotonin-norepinephrine reuptake inhibitor sibutramine (Knoll Pharmaceuticals), but the exact role of these drugs in the management of type 2 DM is not clear.
Metformin is the drug of choice in overweight patients who are not intolerant of this agent. In those overweight patients who are intolerant of metformin, gli-tazone monotherapy is a possible alternative. In patients who are not overweight (BMI 19-25 or 19-23 in South Asian people), metformin or a sulfonylurea can be used. When monotherapy fails, a second drug is added, e.g. a sulfonylurea or glitazone for those on metformin alone or metformin or a glitazone for those on a sulfonylurea alone. When treatment with two oral hypoglycemic agents fails then consideration should be given to the addition of insulin or the use of 'triple therapy' (sulfonylurea, metformin and a glitazone). In the regimens described a prandial glucose regulator may be substituted for a sulfonylurea, although a generic sulfonylurea would be preferred. As mentioned previously, some specialists use a glitazone in combination with insulin in special circumstances. If patients have a BMI of less than 19 at presentation they should be treated with a sulfonylurea but very frequently monitored as they may need to proceed to insulin therapy on an early basis.
No treatment of type 2 DM should focus solely on glycemic control. As the cause of death in type 2 DM is major vascular disease, rigorous attention must be paid to the treatment of hypertension, lowering of blood lipids, the cessation of smoking and an active program of exercise.
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