A number of landmark randomized clinical trials established that insulin therapy reduces microvascular complications (1,2). In addition, recent follow-up data from the U.K. Prospective Diabetes Study (UKPDS) suggest that early insulin treatment also lowers macrovascular risk in type 2 diabetes (3). Whereas there is consensus on the need for insulin, controversy exists on how to initiate and intensify insulin therapy. The options for the practical implementation of insulin therapy are many. In this presentation, we will give an overview of the evidence on the various insulin regimens commonly used to treat type 2 diabetes. Secondary analyses of the aforementioned landmark trials endeavored to establish a glycemic threshold value below which no complications would occur. The UKPDS found no evidence for such a threshold for A1C, but instead showed that better glycemic control was associated with reduced risks of complications over the whole glycemic range (“the lower the better”) (4). For the management of type 2 diabetes, this resulted in the recommendation to “maintain glycemic levels as close to the nondiabetic range as possible” (5). However, in contrast to the UKPDS, the Kumamoto study observed a threshold, with no exacerbation of microvascular complications in patients with type 2 diabetes whose A1C was 8.5% at the start of insulin therapy), treatment with once-daily basal insulin alone would not attain glycemic goals (11,32,33). However, the LANMET study proved otherwise. In this clinical trial, A1C levels decreased from 9.1% at baseline to 7.1% with combination therapy of bedtime insulin glargine or NPH insulin and metformin (36). Finally, it seems likely that insulin initiation by means of one (basal) injection may also facilitate patients' acceptance of insulin initiation. Combined therapy with oral agents As discussed at the first Controversies in Obesity, Diabetes and Hypertension (CODHy) meeting, the rationale for combining insulin with oral therapy is minimization of the adverse effects of insulin treatment, i.e., hypoglycemia and weight gain (44). Combination of insulin with metformin is indeed associated with better glycemic control, fewer hypoglycemic events, and less weight gain than treatment with insulin alone (45). Therefore, metformin should be continued when patients are initiated on insulin therapy (i.e., providing there are no intolerable side effects). Data concerning the combination of insulin with either sulfonylureas alone, or with both metformin and sulfonylureas, compared with insulin-alone treatment regimens, are ambiguous (46). The only consistent advantage of such combined therapy is reduced insulin dose requirements, which may result in less daily injections, easier dose titration, and improved compliance (46). However, these potential benefits must be balanced against the side effects and higher cost of continuing sulfonylureas together with metformin compared with treatment with metformin and NPH insulin alone—although not versus long-acting insulin analogs and metformin alone (31,46)—and the possibility of reduced patient adherence when increasing numbers of pills are prescribed (47). An ongoing randomized trial comparing the continuation of sulfonylureas in combination with metformin and insulin glargine versus discontinuation of sulfonylureas with this combination regimen in insulin-naive type 2 diabetic patients will hopefully provide further evidence regarding this issue (ISRCTN29335793: www.controlled-trials.com). INTENSIFICATION OF INSULIN THERAPY When should insulin therapy be intensified? Because of progressive β-cell decline, treatment with once-daily basal insulin alone will eventually fail to maintain glycemic control in a substantial number of patients with type 2 diabetes. When the recommended A1C level of <7.0% is not reached, or maintained despite successful basal insulin dose titration maintaining fasting plasma glucose ≤100 mg/dl, or when aggressive titration is limited by hypoglycemia, treatment should be intensified by adding insulin injections. How should insulin therapy be intensified? The available options for additional insulin injections include a second injection of basal insulin, prandial insulin before one or more meals, or a switch to biphasic insulin. The choice between intensification of basal insulin versus the introduction of prandial or biphasic insulin should be individualized based on patients' diurnal blood glucose profiles. When considering the profiles obtained with NPH insulin or long-acting insulin analog once daily, the effect appears to wane during the day, even in patients starting insulin therapy, i.e., with remaining endogenous insulin secretion (33,37,48). These patients could benefit from adding a second injection of basal insulin (48). However, in the context of declining endogenous insulin secretion, daytime hyperglycemia is usually related to elevated postprandial glucose levels, favoring the initiation of prandial or biphasic insulin. Two recent studies established that in patients not achieving adequate glycemic control with once-daily basal insulin, basal-bolus therapy results in greater A1C reductions than biphasic insulin twice or thrice daily (49,50). However, when a more gradual intensification of insulin treatment is preferred, patients can be switched to biphasic insulin two, and subsequently three, times daily. The latter regimen has been shown to significantly improve A1C levels of patients previously treated with insulin glargine (50). Whether stepwise introduction of meal-time injections is as safe and effective as the rapid initiation of a full basal-bolus regimen is currently under investigation (51). Finally, regarding the choice of prandial insulin, rapid-acting insulin analogs are not superior to regular insulin in reducing A1C levels or rates for overall and nocturnal hypoglycemia, despite improving postprandial control (18). In some studies, treatment with rapid-acting analogs was associated with fewer severe hypoglycemic episodes and improved treatment satisfaction (18), the latter probably being related to increased convenience because of injection immediately before meals. In conclusion, there is no compelling reason to overall favor rapid-acting insulin analogs over regular insulin in type 2 diabetes. Whereas in some countries the price of rapid-acting analogs has been lowered to the level of regular insulin, in others, it remains around twice as high (31). Continuous subcutaneous insulin infusion In patients with type 2 diabetes already using at least one daily insulin injection, the introduction of intensive insulin therapy with continuous subcutaneous insulin infusion resulted in comparable glycemic control, weight gain, and hypoglycemia risk as multiple daily injection therapy (52,53). Although continuous subcutaneous insulin infusion was associated with greater improvements in treatment satisfaction in one study (53), we recommend that its use be restricted to selected patients in experienced centers only. DRAWBACKS OF INSULIN THERAPY Hypoglycemia Intensive glucose-lowering therapy inevitably results in an increased rate of hypoglycemia, which was once again confirmed in the recent ACCORD study with annualized rates of hypoglycemic episodes requiring medical assistance of 3.1 and 1.0% in the intensive and standard therapy groups, respectively (6). Iatrogenic hypoglycemia hampers tight glycemic control and is considered the limiting factor in diabetes management (54). Opinions are divided on the extent of the problem, with cited event rates for severe hypoglycemia in insulin-treated type 2 diabetic patients ranging from between 1 and 3 (5) to between 10 and 73 per 100 patient-years (55). Of note, the relatively low rates were found in clinical trials (2,56), whereas the higher figures were reported in retrospective and population-based studies (57 –59). The difference is probably explained by varying durations of disease or insulin therapy in the cited studies. The risks of mild and severe hypoglycemia are low among type 2 diabetic patients just beginning insulin therapy (30) and appear to increase with increasing durations of diabetes and insulin treatment (57 –59). To conclude, in type 2 diabetes, the frequency of hypoglycemia is generally lower than that in type 1 diabetes (54). This is presumably the result of relative protection of type 2 diabetic patients against hypoglycemia by residual endogenous (i.e., physiologically regulated) insulin and glucagon secretion, insulin resistance, and higher glycemic thresholds for counterregulatory and symptomatic responses to hypoglycemia (60,61). Therefore, when initiating insulin therapy, attempts to attain A1C goals should not be hampered too much by concerns about hypoglycemia. However, iatrogenic hypoglycemia appears to become a more frequent problem at the insulin-deficient stage of the disease, warranting more vigilance as the disease advances (54). Weight gain The ∼2- to 4-kg increase in body weight associated with insulin therapy has traditionally been explained by reductions of glucosuria and resting energy expenditure when glycemic control is improved (5,46). Other explanations are snacking to prevent, or in response to, hypoglycemia or restoration of the weight loss usually preceding insulin initiation to the weight before onset of diabetes. In contrast, a recent study found that the mean weight gain of 1.8 kg in 23 type 2 diabetic patients during the first 6 months of insulin therapy was not accompanied by a change in glucosuria, resting energy expenditure, or physical activity. The authors concluded that increased energy intake was the only plausible explanation for the observed weight increments (62). Although the mechanisms underlying insulin-associated weight gain are still not fully understood, it is thought to be proportional to the number of insulin injections, or the total daily insulin dose (32,45,46). Interestingly, when considering studies investigating basal insulin initiation in type 2 diabetes, we found no evidence for such a dose-response relationship (Fig. 1 C). Finally, when directly comparing the mean increases in body weight during insulin initiation with NPH insulin versus long-acting insulin analogs, insulin glargine is associated with similar weight gain (27,35 –37). Treatment with insulin detemir, on the other hand, appears to result in less weight gain than NPH insulin (28,33). However, considering the limited magnitude of the reported weight-sparing effect, we still recommend NPH insulin for the initiation of insulin therapy in patients with type 2 diabetes. CONCLUSIONS Although insulin has no upper dose limit and numerous trials established that glycemic goals can be attained by using adequate doses, in clinical practice, many patients experience years of uncontrolled hyperglycemia. Because most type 2 diabetic patients have residual endogenous insulin secretion, the rationale for imitating the physiological insulin secretion pattern is less convincing than in type 1 diabetes. Glycemic treatment should be stepwise with swift introduction of successive interventions after treatment failure (i.e., A1C ≥7.0%). Insulin should be initiated when A1C is ≥7.0% after 2–3 months of dual oral therapy. The preferred regimen for insulin initiation in type 2 diabetes is once-daily basal insulin. In addition to timely initiation, rapid titration of the dose is indispensable for successful insulin therapy. Hypoglycemia risk is very low among type 2 diabetic patients just starting insulin therapy, making NPH insulin the most cost-effective drug. When glycemic goals are not attained despite successful basal insulin dose titration (i.e., fasting plasma glucose ≤100 mg/dl), or when titration is limited by hypoglycemia, treatment should be intensified by addition of prandial or biphasic insulin.