Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy

 [bib_ref] The effect of long-term intensified insulin treatment on the development of microvascular..., Reichard [/bib_ref] [bib_ref] Intensive blood glucose control and vascular outcomes in patients with type 2..., The Advance Collaborative [/bib_ref] [bib_ref] Glycaemic separation and risk factor control in the Veterans Affairs Diabetes Trial:..., Abraira [/bib_ref] [bib_ref] Finding new treatments for diabetes-how many, how fast . . . how..., Nathan [/bib_ref] [bib_ref] Initial management of glycemia in type 2 diabetes mellitus, Nathan [/bib_ref] [bib_ref] Current therapeutic options in type 2 diabetes mellitus: a practical approach, Sheehan [/bib_ref] [bib_ref] Oral antihyperglycemic therapy for type 2 diabetes, Inzucchi [/bib_ref] 

## Process
The guidelines and algorithm that follow are derived from two sources. One source is the clinical trials that address the effectiveness and safety of the different modalities of therapy. Here, the writing group reviewed a wide variety of studies related to the use of drugs as monotherapy or in combination to lower glycemia. Unfortunately, the paucity of high-quality evidence in the form of well-controlled clinical trials that directly compare different diabetes treatment regimens remains a major impediment to recommending one class of drugs, or a particular combination of therapies, over another.
The second source of material that informed our recommendations was clinical judgement, that is, our collective knowledge and clinical experience, which takes into account benefits, risks, and costs in the treatment of diabetes. As in all clinical decision making, an evidence-based review of the literature must also be supplemented by value judgements, where the benefits of treatment are weighed against risks and costs in a subjective fashion. While we realize that others may have different judgements, we believe that the recommendations made in this new iteration of our treatment algorithm will guide therapy and result in improved glycemic control and health status over time.
Glycemic goals of therapy Controlled clinical trials, such as the Diabetes Control and Complications Trial (DCCT) (4) and the Stockholm Diabetes Study in type 1 diabetes (5) and the UK Prospective Diabetes Study (UKPDS) (6,7) and Kumamoto study [bib_ref] Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese..., Ohkubo [/bib_ref] in type 2 diabetes, have helped to establish the glycemic goals of therapy that result in improved long-term outcomes. The clinical trials, in concert with epidemiological data [bib_ref] Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy, Klein [/bib_ref] [bib_ref] Glucose control and the renal and retinal complications of insulin-dependent diabetes, Chase [/bib_ref] , support decreasing glycemia as an effective means of reducing long-term microvascular and neuropathic complications. The most appropriate target levels for blood glucose, on a day-today basis, and A1C, as an index of chronic glycemia, have not been systematically studied. However, both the DCCT (4) and the UKPDS (6,7) had as their goals the achievement of glycemic levels in the nondiabetic range. Neither study was able to maintain A1C levels in the nondiabetic range in their intensive treatment groups, achieving mean levels over time of 7%, which is 4 SDs above the nondiabetic mean.
The most recent glycemic goal recommended by the American Diabetes Association, selected on the basis of practicality and the projected reduction in complications over time, is, in general, an A1C level of 7% (1). The most recent glycemic goal set by the International Diabetes Federation is an A1C level of 6.5%. The upper limit of the nondiabetic range is 6.1% (mean  SD. A1C level of 5  2%) with the DCCT/UKPDSstandardized assay, which has been prom u l g a t e d t h r o u g h t h e N a t i o n a l Glycohemoglobin Standardization Program (NGSP) and adopted by the vast majority of commercially available assays [bib_ref] The National Glycohemoglobin Standardization Program (NGSP): a five year progress report, Little [/bib_ref]. Several recent clinical trials have aimed for A1C levels 6.5% with a variety of interventions [bib_ref] Intensive blood glucose control and vascular outcomes in patients with type 2..., The Advance Collaborative [/bib_ref]. The results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, which had the primary objective of decreasing CVD with interventions aimed at achieving an A1C level of 6.0% vs. interventions aimed at achieving an A1C level of 7.9%, showed excess CVD mortality in the intensive treatment group. Results from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial and the Veterans Affairs Diabetes Trial, both of which had different interventions and study populations than ACCORD, did not demonstrate any excess total or CVD mortality with intensive regimens that achieved A1C levels comparable with the 6.5% in ACCORD [bib_ref] Intensive blood glucose control and vascular outcomes in patients with type 2..., The Advance Collaborative [/bib_ref] [bib_ref] Glycaemic separation and risk factor control in the Veterans Affairs Diabetes Trial:..., Abraira [/bib_ref]. However, none of the studies has demonstrated a benefit of intensive glycemic control on their primary CVD outcomes. Our consensus is that an A1C level of 7% should serve as a call to action to initiate or change therapy with the goal of achieving an A1C level of 7%. We are mindful that this goal is not appropriate or practical for some patients, and clinical judgement based on the potential benefits and risks of a more intensified regimen needs to be applied for every patient. Factors such as life expectancy, risk of hypoglycemia, and the presence of CVD need to be considered for every patient before intensifying the therapeutic regimen.
Assiduous attention to abnormalities other than hyperglycemia that accompany type 2 diabetes, such as hypertension and dyslipidaemia, has been shown to improve microvascular and cardiovascular complications. Readers are referred to published guidelines for a discussion of the rationale and goals of therapy for the nonglycemic risk factors, as well as recommendations on how to achieve them [bib_ref] Implications of recent clinical trials for the National Cholesterol Education Program Adult..., Grundy [/bib_ref].

## Principles in selecting antihyperglycemic interventions
Our choice of specific antihyperglycemic agents is predicated on their effectiveness in lowering glucose, extraglycemic effects that may reduce long-term complications, safety profiles, tolerability, ease of use, and expense.

## Effectiveness in lowering glycaemia
Except for their differential effects on glycemia, there are insufficient data at this time to support a recommendation of one class of glucose-lowering agents, or one combination of medications, over others with regard to effects on complications. In other words, the salutary effects of therapy on long-term complications appear to be predicated predominantly on the level of glycemic control achieved rather than on any other specific attributes of the in-tervention(s) used to achieve glycemic goals. The UKPDS compared three classes of glucose-lowering medications (sulfonylurea, metformin, or insulin) but was unable to demonstrate clear superiority of any one drug over the others with regard to diabetes complications (6,7). However, the different classes do have variable effectiveness in decreasing glycemic levels [fig_ref] Table 1 -: Summary of glucose-lowering interventions [/fig_ref] , and the overarching principle in selecting a particular intervention will be its ability to achieve and maintain glycemic goals. In addition to their intention-to-treat analyses demonstrating the superiority of intensive versus conventional interventions, the DCCT and UKPDS demonstrated a strong correlation between mean A1C levels over time and the development and progression of retinopathy and nephropathy [bib_ref] The association between glycemic exposure and longterm diabetic complications in the Diabetes..., Dcct Research Group [/bib_ref] [bib_ref] National Institutes of Health: Clinical Guidelines on the Identification, Evaluation, and Treatment..., Stratton [/bib_ref]. Therefore, we think it is reasonable to judge and compare blood glucoselowering medications, as well as combinations of such agents, primarily on the basis of their capacity to decrease and maintain A1C levels and according to their safety, specific side effects, tolerability, ease of use, and expense.

## Nonglycemic effects of medications
In addition to variable effects on glycemia, specific effects of individual therapies on CVD risk factors, such as hypertension or dyslipidemia, were also considered important. We also included the effects of interventions that may benefit or worsen the prospects for long-term glycemic control in our recommendations. Examples of these would be changes in body mass, insulin resistance, or insulin secretory capacity in type 2 diabetic patients.
Choosing specific diabetes interventions and their roles in treating type 2 diabetes Numerous reviews have focused on the characteristics of the specific diabetes interventions listed below (25-34). In addition, meta-analyses and reviews have summarized and compared the glucoselowering effectiveness and other characteristics of the medications [bib_ref] Efficacy and safety of incretin therapy in type 2 diabetes: a systematic..., Amori [/bib_ref] [bib_ref] Comparison of different drugs as add-on treatments to metformin in type 2..., Monami [/bib_ref] [bib_ref] Systematic review: comparative effectiveness and safety of oral medications for type 2..., Bolen [/bib_ref]. The aim here is to provide enough information to justify the choices of medications, the order in which they are recommended, and the use of combinations of therapies. Unfortunately, there is a dearth of high-quality studies that provide headto-head comparisons of the ability of the medications to achieve the currently recommended glycemic levels. The authors

# Consensus statement
highly recommend that such studies be conducted. However, even in the absence of rigorous, comprehensive studies that directly compare the efficacy of all available glucose-lowering treatments and their combinations, we feel that there are enough data regarding the characteristics of the individual interventions to provide the guidelines below.
An important intervention that is likely to improve the probability that a patient will have better long-term control of diabetes is to make the diagnosis early, when the metabolic abnormalities of diabetes are usually less severe. Lower levels of glycemia at the time of initial therapy are associated with lower A1C levels over time and decreased long-term complications [bib_ref] Are lower fasting plasma glucose levels at diagnosis of type 2 diabetes..., Colagiuri [/bib_ref].

## Lifestyle interventions
The major environmental factors that increase the risk of type 2 diabetes are overnutrition and a sedentary lifestyle, with consequent overweight and obesity [bib_ref] Risk factors for non-insulin dependent diabetes, Rewers [/bib_ref]. Not surprisingly, interventions that reverse or improve these factors have been demonstrated to have a beneficial effect on control of glycemia in established type 2 diabetes [bib_ref] Reduction in weight and cardiovascular disease risk factors in individuals with type..., Look Ahead Research [/bib_ref]. Unfortunately, the high rate of weight regain has limited the role of lifestyle interventions as an effective means of controlling glycemia in the long term. The most convincing long-term data indicating that weight loss effectively lowers glycemia have been generated in the follow-up of type 2 diabetic patients who have had bariatric surgery. In this setting, with a mean sustained weight loss of 20 kg, diabetes is virtually eliminated [bib_ref] Who would have thought it? An operation proves to be the most..., Pories [/bib_ref] [bib_ref] Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery, Sjostrom [/bib_ref] [bib_ref] Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized..., Dixon [/bib_ref] [bib_ref] Laparoscopic gastric banding prevents type 2 diabetes and arterial hypertension and induces..., Pontiroli [/bib_ref]. In addition to the beneficial effects of weight loss on glycemia, weight loss and exercise improve coincident CVD risk factors, such as blood pressure and atherogenic lipid profiles, and ameliorate other consequences of obesity [bib_ref] Reduction in weight and cardiovascular disease risk factors in individuals with type..., Look Ahead Research [/bib_ref] [bib_ref] Maturity onset diabetes mellitus: response to intensive dietary management, Hadden [/bib_ref]. There are few adverse consequences of such life- style interventions other than difficulty in incorporating them into usual lifestyle and sustaining them and the usually minor musculoskeletal injuries and potential problems associated with neuropathy, such as foot trauma and ulcers, that may occur as a result of increased activity. Theoretically, effective weight loss, with its pleiotropic benefits, safety profile, and low cost, should be the most cost-effective means of controlling diabetes-if it could be achieved and maintained over the long term. Given these beneficial effects, which are usually seen rapidly-within weeks to months-and often before there has been substantial weight loss (47), a lifestyle intervention program to promote weight loss and increase activity levels should, with rare exceptions, be included as part of diabetes management. Weight loss of as little as 4 kg will often ameliorate hyperglycemia. However, the limited long-term success of lifestyle programs to maintain glycemic goals in patients with type 2 diabetes suggests that the large majority of patients will require the addition of medications over the course of their diabetes.

## Medications
The characteristics of currently available glucose-lowering interventions, when used as monotherapy, are summarized in [fig_ref] Table 1 -: Summary of glucose-lowering interventions [/fig_ref]. The glucose-lowering effectiveness of individual therapies and combinations demonstrated in clinical trials is predicated not only on the intrinsic characteristics of the intervention but also on the duration of diabetes, baseline glycemia, previous therapy, and other factors. A major factor in selecting a class of drugs, or a specific medication within a class, to initiate therapy or when changing therapy, is the ambient level of glycemic control. When levels of glycemia are high (e.g., A1C 8.5%), classes with greater and more rapid glucose-lowering effectiveness, or potentially earlier initiation of combination therapy, are recommended; however, patients with recent-onset diabetes often respond adequately to less intensive interventions than those with longer-term disease [bib_ref] Maximal dose glyburide in markedly symptomatic patients with type 2 diabetes: a..., Peters [/bib_ref]. When glycemic levels are closer to the target levels (e.g., A1C 7.5%), medications with lesser potential to lower glycemia and/or a slower onset of action may be considered.
Obviously, the choice of glycemic goals and the medications used to achieve them must be individualized for each patient, balancing the potential for lowering A1C and anticipated long-term benefit with specific safety issues, as well as other characteristics of regimens, including side effects, tolerability, ease of use, long-term adherence, expense, and the nonglycemic effects of the medications. Type 2 diabetes is a progressive disease characterized by worsening glycemia; higher doses and additional medications are required over time if treatment goals are to be met. Metformin. In most of the world, metformin is the only biguanide available. Its major effect is to decrease hepatic glucose output and lower fasting glycemia. Typically, metformin monotherapy will lower A1C levels by 1.5 percentage points [bib_ref] Metformin Study Group: Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus, Defronzo [/bib_ref]. It is generally well tolerated, with the most common adverse effects being gastrointestinal. Metformin monotherapy is not usually accompanied by hypoglycemia and has been used safely, without causing hypoglycemia, in patients with prediabetic hyperglycemia. Metformin interferes with vitamin B 12 absorption but is very rarely associated with anemia. The major nonglycemic effect of metformin is either weight stability or modest weight loss, in contrast with many of the other blood glucoselowering medications. The UKPDS demonstrated a beneficial effect of metformin therapy on CVD outcomes (7), which needs to be confirmed. Renal dysfunction is considered a contraindication to metformin use because it may increase the risk of lactic acidosis, an extremely rare (less than 1 case per 100,000 treated patients) but potentially fatal complication [bib_ref] Risk of fatal and nonfatal lactic acidosis with metformin use in type..., Salpeter [/bib_ref]. However, recent studies have suggested that metformin is safe unless the estimated glomerular filtration rate falls to 30 ml/min [bib_ref] Establishing pragmatic estimated GFR thresholds to guide metformin prescribing, Shaw [/bib_ref]. Sulfonylureas. Sulfonylureas lower glycemia by enhancing insulin secretion. In terms of efficacy, they appear to be similar to metformin, lowering A1C levels by 1.5 percentage points [bib_ref] Metformin Study Group: Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus, Defronzo [/bib_ref]. The major adverse side effect is hypoglycemia, which can be prolonged and life threatening, but such episodes, characterized by a need for assistance, coma, or seizure, are infrequent. However, severe episodes are relatively more frequent in the elderly. Chlorpropamide and glibenclamide (known as glyburide in the U.S. and Canada), are associated with a substantially greater risk of hypoglycemia than other second-generation sulfonylureas (gliclazide, glimepiride, glipizide, and their extended formulations), which are preferable [fig_ref] Table 1 -: Summary of glucose-lowering interventions [/fig_ref] [bib_ref] Lower incidence of severe hypoglycemia in patients with type 2 diabetes treated..., Holstein [/bib_ref]. In addition, weight gain of 2 kg is common following the initiation of sulfonylurea therapy.
Although the onset of the glucoselowering effect of sulfonylurea monotherapy is relatively rapid compared with, for example, the thiazolidinediones (TZDs), maintenance of glycemic targets over time is not as good as monotherapy with a TZD or metformin [bib_ref] Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, Kahn [/bib_ref]. Sulfonylurea therapy was implicated as a potential cause of increased CVD mortality in the University Group Diabetes Program (UGDP) study [bib_ref] The University Group Diabetes Program: a study of the effect of hypoglycemic..., Meinert [/bib_ref]. Concerns raised by the UGDP that sulfonylureas, as a drug class, may increase CVD mortality in type 2 diabetes were not substantiated by the UKPDS or ADVANCE study (6,12). The glycemic benefits of sulfonylureas are nearly fully realized at half-maximal doses, and higher doses should generally be avoided. Glinides. Like the sulfonylureas, the glinides stimulate insulin secretion, although they bind to a different site within the sulfonylurea receptor [bib_ref] Pharmacology of the meglitinide analogs: new treatment options for type 2 diabetes..., Malaisse [/bib_ref]. They have a shorter circulating half-life than the sulfonylureas and must be administered more frequently. Of the two glinides currently available in the U.S., repaglinide is almost as effective as metformin or the sulfonylureas, decreasing A1C levels by 1.5 percentage points. Nateglinide is somewhat less effective in lowering A1C than repaglinide when used as monotherapy or in combination therapy [bib_ref] Repaglinide versus nateglinide monotherapy: a randomized, multicenter study, Rosenstock [/bib_ref] [bib_ref] PRESERVE-beta: two year efficacy and safety of initial combination therapy with nateglinide..., Gerich [/bib_ref]. The risk of weight gain is similar to that for the sulfonylureas, but hypoglycemia may be less frequent, at least with nateglinide, than with some sulfonylureas [bib_ref] PRESERVE-beta: two year efficacy and safety of initial combination therapy with nateglinide..., Gerich [/bib_ref] [bib_ref] A double-blind randomized comparison of meal-related glycemic control by repaglinide and glyburide..., Damsbo [/bib_ref]. -Glucosidase inhibitors. -Glucosidase inhibitors reduce the rate of digestion of polysaccharides in the proximal small intestine, primarily lowering postprandial glucose levels without causing hypoglycemia. They are less effective in lowering glycemia than metformin or the sulfonylureas, reducing A1C levels by 0.5-0.8 percentage points [bib_ref] Alpha-glucosidase inhibitors for type 2 diabetes mellitus, Van De Laar [/bib_ref]. Since carbohydrate is absorbed more distally, malabsorption and weight loss do not occur; however, increased delivery of carbohydrate to the colon commonly results in increased gas production and gastrointestinal symptoms. In clinical trials, 25-45% of participants have discontinued -glucosidase inhibitor use as a result of this side effect [bib_ref] Alpha-glucosidase inhibitors for type 2 diabetes mellitus, Van De Laar [/bib_ref] [bib_ref] Acarbose treatment and the risk of cardiovascular disease and hypertension in patients..., Chiasson [/bib_ref].
One clinical trial examining acarbose as a means of preventing the development of diabetes in high-risk individuals with impaired glucose tolerance showed an unexpected reduction in severe CVD outcomes [bib_ref] Acarbose treatment and the risk of cardiovascular disease and hypertension in patients..., Chiasson [/bib_ref]. This potential benefit of -glucosidase inhibitors needs to be confirmed. Thiazolidinediones. Thiazolidinediones (TZDs or glitazones) are peroxisome proliferator-activated receptor  modulators; they increase the sensitivity of muscle, fat, and liver to endogenous and exogenous insulin ("insulin sensitizers") [bib_ref] Drug therapy: thiazolidinediones, Yki-Jarvinen [/bib_ref]. The data regarding the blood glucose-lowering effectiveness of TZDs when used as monotherapy have demonstrated a 0.5-1.4 percentage point decrease in A1C. The TZDs appear to have a more durable effect on glycemic control, particularly compared with sulfonylureas [bib_ref] Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, Kahn [/bib_ref]. The most common adverse effects with TZDs are weight gain and fluid retention, with peripheral edema and a twofold increased risk for congestive heart failure (61,62). There is an increase in adiposity, largely subcutaneous, with some reduction in visceral fat shown in some studies. The TZDs either have a beneficial (pioglitazone) or neutral (rosiglitazone) effect on atherogenic lipid profiles [bib_ref] A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone..., Khan [/bib_ref] [bib_ref] A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in..., Goldberg [/bib_ref]. Several meta-analyses have suggested a 30 -40% relative increase in risk for myocardial infarction (65,66) with rosiglitazone. On the other hand, the Prospective Pioglitazone Clinical Trial in macrovascular events (PROactive) demonstrated no significant effects of pioglitazone compared with placebo on the primary CVD outcome (a composite of all-cause mortality, nonfatal and silent myocardial infarction, stroke, major leg amputation, acute coronary syndrome, coronary artery bypass graft or percutaneous coronary intervention, and leg revascularization) after 3 years of follow-up [bib_ref] Secondary prevention of macrovascular events in patients with type 2 diabetes in..., Dormandy [/bib_ref]. Pioglitazone was associated with a 16% reduction in death, myocardial infarction, and stroke-a controversial secondary end point reported to have marginal statistical significance (67). Meta-analyses have supported a possible beneficial effect of pioglitazone on CVD risk [bib_ref] Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes..., Lincoff [/bib_ref]. Although the data are less than conclusive for a CVD risk with rosiglitazone or a CVD benefit with pioglitazone, we have previously advised (69) caution in using either TZD on the basis that they are both associated with increased risks of fluid retention and congestive heart failure and an increased incidence of fractures in women and perhaps in men [bib_ref] Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, Kahn [/bib_ref] [bib_ref] Singh S, Loke YK, Furberg CD: Thiazolidinediones and heart failure: a teleoanalysis, Home [/bib_ref] [bib_ref] Use of thiazolidinediones and fracture risk, Meier [/bib_ref]. Although the metaanalyses discussed above are not conclusive regarding the potential cardiovascular risk associated with rosiglitazone, given that other options are now recom-mended, the consensus group members unanimously advised against using rosiglitazone. Currently, in the U.S., the TZDs are approved for use in combination with metformin, sulfonylureas, glinides, and insulin. Insulin. Insulin is the oldest of the currently available medications and, therefore, the treatment with which we have the most clinical experience. It is also the most effective at lowering glycemia. Insulin can, when used in adequate doses, decrease any level of elevated A1C to, or close to, the therapeutic goal. Unlike the other blood glucose-lowering medications, there is no maximum dose of insulin beyond which a therapeutic effect will not occur. Relatively large doses of insulin (1 unit/kg), compared with those required to treat type 1 diabetes, may be necessary to overcome the insulin resistance of type 2 diabetes and lower A1C to the target level. Although initial therapy is aimed at increasing basal insulin supply, usually with intermediate-or long-actinginsulins, patients may also require prandial therapy with short-or rapid-acting insulins [fig_ref] Figure 1 -: Initiation and adjustment of insulin regimens [/fig_ref]. The very rapid-acting and long-acting insulin analogues have not been shown to lower A1C levels more effectively than the older, rapid-acting or intermediate-acting formulations [bib_ref] Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2..., Horvath [/bib_ref] [bib_ref] Initiating insulin therapy in type 2 diabetes, Raskin [/bib_ref] [bib_ref] Insulin glulisine provides improved glycemic control in patients with type 2 diabetes, Dailey [/bib_ref]. Insulin therapy has beneficial effects on triacylglycerol and HDL cholesterol levels, especially in patients with poor glycemic control [bib_ref] Glyburide or insulin for metabolic control in non-insulin-dependent diabetes mellitus: a randomized..., Nathan [/bib_ref] , but is associated with weight gain of 2-4 kg, which is probably proportional to the correction of glycemia and predominantly the result of the reduction of glycosuria. Insulin therapy is also associated with hypoglycemia, albeit much less frequently than in type 1 diabetes. In clinical trials aimed at normoglycemia and achieving a mean A1C of 7%, severe hypoglycemic episodes (defined as requiring help from another person to treat) occurred at a rate of between one and three per 100 patient-years [bib_ref] Hypoglycemia in patients with type 2 diabetes mellitus, Miller [/bib_ref] , compared with 61 per 100 patient-years in the DCCT intensive therapy group. Insulin analogues with longer, nonpeaking profiles decrease the risk of hypoglycemia modestly compared with NPH, and analogues with very short durations of action reduce the risk of hypoglycemia compared with regular insulin [bib_ref] Hypoglycemia in patients with type 2 diabetes mellitus, Miller [/bib_ref]. Glucagon-like peptide-1 agonists (exenatide). Glucagon-like peptide-1 (GLP-1) 7-37, a naturally occurring peptide produced by the L-cells of the small intestine, potentiates glucose-stimulated insulin secretion. Exendin-4 has homology with the human GLP-1 sequence but has a longer circulating half-life. It binds avidly to the GLP-1 receptor on the pancreatic -cell and augments glucosemediated insulin secretion [bib_ref] Biologic actions and therapeutic potential of the proglucagonderived peptides, Drucker [/bib_ref]. Synthetic exendin-4 (exenatide) was approved for use in the U.S. in 2005 and is administered twice per day by subcutaneous injection. Although there are less published data on this new compound than the other blood glucose-lowering medications, exendin-4 appears to lower A1C levels by 0.5-1 percentage points, mainly by lowering postprandial blood glucose levels . Exenatide also suppresses glucagon secretion and slows gastric motility. It is not associated with hypoglycemia but causes a relatively high frequency of gastrointestinal disturbances, with 30 -45% of treated patients experiencing one or more episodes of nausea, vomiting, or diarrhea . These side effects tend to abate over time. In published trials, exenatide is associated with weight loss of 2-3 kg over 6 months, some of which may be a result of its gastrointestinal side effects. Recent reports have suggested a risk for pancreatitis associated with use of GLP agonists; however, the number of cases is very small and whether the relationship is causal or coincidental is not clear at this time. Currently, exenatide is approved for use in the U.S. with sulfonylurea, metformin, and/or a TZD. Several other GLP-1 agonists and formulations are under development. Amylin agonists (pramlintide). Pramlintide is a synthetic analogue of the -cell hormone amylin. It is administered subcutaneously before meals and slows gastric emptying, inhibits glucagon production in a glucose-dependent fashion, and predominantly decreases postprandial glucose excursions [bib_ref] Amylin agonists: a novel approach in the treatment of diabetes, Schmitz [/bib_ref]. In clinical studies, A1C has been decreased by 0.5-0.7 percentage points [bib_ref] Pramlintide improved glycemic control and reduced weight in patients with type 2..., Riddle [/bib_ref]. The major clinical side effects of this drug are gastrointestinal in nature. 30% of treated participants in the clinical trials have developed nausea, but this side effect tends to abate with time on therapy. Weight loss associated with this medication is 1-1.5 kg over 6 months; as with exenatide, some of the weight loss may be the result of gastrointestinal side effects. Currently, pramlintide is approved for use in the U.S. only as adjunctive therapy with regular insulin or rapid-acting insulin analogues.

## Dipeptidyl peptidase four inhibitors.
GLP-1 and glucose-dependent insulinotropic peptide (GIP), the main insulinotropic peptides of intestinal origin (incretins), are rapidly degraded by dipeptidyl peptidase four (DPP-4). DPP-4 is a member of a family of cell membrane proteins that are expressed in many tissues, including immune cells [bib_ref] Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus, Richter [/bib_ref]. DPP-4 inhibitors are small molecules that enhance the effects of GLP-1 and GIP, increasing glucose-mediated insulin secretion and suppressing glucagon secretion [bib_ref] Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in..., Raz [/bib_ref] [bib_ref] Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and..., Goldstein [/bib_ref]. The first oral DPP-4 inhibitor, sitagliptin, was approved by the Food and Drug Administration in October 2006 for use as monotherapy or in combination with metformin or TZDs. Another DPP-4 inhibitor, vildagliptin, was approved in Europe in February 2008, and several other compounds are under development. In clinical trials performed to date, DPP-4 inhibitors lower A1Clevels by 0.6 -0.9 percentage points and are weight neutral and relatively well tolerated [bib_ref] Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in..., Raz [/bib_ref] [bib_ref] Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and..., Goldstein [/bib_ref]. They do not cause hypoglycemia when used as monotherapy. A fixed-dose combination pill with metformin is available. The potential for this class of compounds to interfere with immune function is of concern; an increase in upper respiratory infections has been reported [bib_ref] Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus, Richter [/bib_ref].

## How to initiate diabetes therapy and advance interventions
Except in rare circumstances, such as diabetic ketoacidosis or patients who are extremely catabolic or hyperosmolar or who are unable to hydrate themselves adequately (see SPECIAL CONSIDERATIONS/PATIENTS below), hospitalization is not required for initiation or adjustment of therapy. The pa-tient is the key player in the diabetes care team and should be trained and empowered to adjust medications with the guidance of health care professionals to achieve glycemic goals and to prevent and treat hypoglycemia. Many patients may be managed effectively with monotherapy; however, the progressive nature of the disease will require the use of combination therapy in many, if not most, patients over time, to achieve and maintain glycemia in the target range.
The measures of glycemia that are initially targeted on a day-to-day basis are fasting and preprandial glucose levels. Self-monitoring of blood glucose (SMBG) is an important element in adjusting or adding new interventions and, in particular, in titrating insulin doses. The need for and number of required SMBG measurements are not clear [bib_ref] Self-monitoring of blood glucose in patients with type 2 diabetes who are..., Welschen [/bib_ref] and are dependent on the medications used. Oral glucose-lowering regimens that do not include sulfonylureas or glinides, and are therefore not likely to cause hypoglycemia, usually do not require SMBG [bib_ref] Impact of self monitoring of blood glucose in the management of patients..., Farmer [/bib_ref]. However, SMBG may be used to determine whether therapeutic blood glucose targets are being achieved and for adjustment of treatment regimens without requiring the patient to have laboratory-based blood glucose testing. Insulin therapy requires more frequent monitoring.
The levels of plasma or capillary glucose (most meters that measure fingerstick capillary samples are adjusted to provide values equivalent to plasma glucose) that should result in long-term glycemia in the nondiabetic target range, as measured by A1C, are fasting and preprandial levels between 3.9 and 7.2 mmol/l (70 and 130 mg/dl). If A1C levels remain above the desired target despite preprandial levels that are in range, postprandial levels, usually measured 90 -120 min after a meal, may be checked. They should be 10 mmol/l (180 mg/dl) to achieve A1C levels in the target range.
Attempts to achieve target glycemic levels with regimens including sulfonylureas or insulin may be associated with modest hypoglycemia, with glucose levels in the 3.1-3.9 mmol/l (55-70 mg/dl) range. These episodes are generally well tolerated, easily treated with oral carbohydrate such as glucose tablets or 120 -180 ml (4 -6 oz) of juice or nondiet soda, and rarely progress to more severe hypoglycemia, including loss of consciousness or seizures.

## Algorithm
The algorithm [fig_ref] Figure 2 -: Algorithm for the metabolic management of type 2 diabetes [/fig_ref] takes into account the characteristics of the individual interventions, their synergies, and expense. The goal is to achieve and maintain A1C levels of 7% and to change interventions at as rapid a pace as titration of medications allows when target glycemic goals are not being achieved. Mounting evidence suggests that aggressive lowering of glycemia, especially with insulin therapy, in newly diagnosed diabetes can result in sustained remissions, i.e., normoglycemia without need for glucose-lowering medications [bib_ref] Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients..., Ilkova [/bib_ref] [bib_ref] Effect of intensive insulin therapy on beta-cell function and glycemic control in..., Weng [/bib_ref]. Type 2 diabetes is a progressive disease, and patients should be informed that they are likely to require the addition of glucose-lowering medications over time.
The amylin agonists, -glucosidase inhibitors, glinides, and DPP-4 inhibitors are not included in the two tiers of preferred agents in this algorithm, owing to their lower or equivalent overall glucoselowering effectiveness compared with the first-and second-tier agents and/or to their limited clinical data or relative expense [fig_ref] Table 1 -: Summary of glucose-lowering interventions [/fig_ref]. However, they may be appropriate choices in selected patients.
Tier 1: well-validated core therapies These interventions represent the best established and most effective and costeffective therapeutic strategy for achieving the target glycemic goals. The tier one algorithm is the preferred route of therapy for most patients with type 2 diabetes.
Step 1: lifestyle intervention and metformin. Based on the numerous demonstrated short-and long-term benefits that accrue when weight loss and increased levels of activity are achieved and maintained, as well as the cost-effectiveness of lifestyle interventions when they succeed,

## Titration of metformin
1. Begin with low-dose metformin (500 mg) taken once or twice per day with meals (breakfast and/or dinner) or 850 mg once per day. 2. After 5-7 days, if gastrointestinal side effects have not occurred, advance dose to 850, or two 500 mg tablets, twice per day (medication to be taken before breakfast and/or dinner). 3. If gastrointestinal side effects appear as doses advanced, decrease to previous lower dose and try to advance the dose at a later time. 4. The maximum effective dose can be up to 1,000 mg twice per day but is often 850 mg twice per day. Modestly greater effectiveness has been observed with doses up to about 2,500 mg/day. Gastrointestinal side effects may limit the dose that can be used. 5. Based on cost considerations, generic metformin is the first choice of therapy. A longer-acting formulation is available in some countries and can be given once per day.
the consensus is that lifestyle interventions should be initiated as the first step in treating new-onset type 2 diabetes [fig_ref] Figure 2 -: Algorithm for the metabolic management of type 2 diabetes [/fig_ref]. These interventions should be implemented by health care professionals with appropriate training-usually registered dietitians experienced in behavioral modification-and be sensitive to ethnic and cultural differences among populations. Moreover, lifestyle interventions to improve glucose, blood pressure, and lipid levels, and to promote weight loss or at least avoid weight gain, should remain an underlying theme throughout the management of type 2 diabetes, even after medications are used. For the 10 -20% of patients with type 2 diabetes who are not obese or overweight, modification of dietary composition and activity levels may play a supporting role, but medications are still generally required early in the course of diabetes (see SPECIAL CONSIDER-ATIONS/PATIENTS below).
The authors recognize that for most individuals with type 2 diabetes, lifestyle interventions fail to achieve or maintain the metabolic goals either because of failure to lose weight, weight regain, progressive disease, or a combination of factors. Therefore, our consensus is that metformin therapy should be initiated concurrently with lifestyle intervention at diagnosis. Metformin is recommended as the initial pharmacological therapy, in the absence of specific contraindications, for its effect on glycemia, absence of weight gain or hypoglycemia, generally low level of side effects, high level of acceptance, and relatively low cost. Metformin treatment should be titrated to its maximally effective dose over 1-2 months, as tolerated (see text box, entitled Titration of Metformin). Rapid addition of other glucose-lowering medications should be considered in the setting of persistent symptomatic hyperglycemia.
Step 2: addition of a second medication. If lifestyle intervention and the maximal tolerated dose of metformin fail to achieve or sustain the glycemic goals, another medication should be added within 2-3 months of the initiation of therapy or at any time when the target A1C level is not achieved. Another medication may also be necessary if metformin is contraindicated or not tolerated. The consensus regarding the second medication added to metformin was to choose either insulin or a sulfonylurea [fig_ref] Figure 2 -: Algorithm for the metabolic management of type 2 diabetes [/fig_ref]. As discussed above, the A1C level will determine in part which agent is selected next, with consideration given to the more effective glycemia-lowering agent, insulin, for patients with an A1C level of 8.5% or with symptoms secondary to ehyperglycemia. Insulin can be initiated with a basal (intermediate-or long-acting) insulin (see [fig_ref] Figure 1 -: Initiation and adjustment of insulin regimens [/fig_ref] for suggested initial insulin regimens) [bib_ref] A real-world approach to insulin therapy in primary care practice, Hirsch [/bib_ref]. However, many newly diagnosed type 2 diabetic patients will usu-ally respond to oral medications, even if symptoms of ehyperglycemia are present [bib_ref] Maximal dose glyburide in markedly symptomatic patients with type 2 diabetes: a..., Peters [/bib_ref].
Step 3: further adjustments. If lifestyle, metformin, and sulfonylurea or basal insulin do not result in achievement of target glycemia, the next step should be to start, or intensify, insulin therapy [fig_ref] Figure 1 -: Initiation and adjustment of insulin regimens [/fig_ref]. Intensification of insulin therapy usually consists of additional injections that might include a short-or rapid-acting insulin given before selected meals to reduce postprandial glucose excursions [fig_ref] Figure 1 -: Initiation and adjustment of insulin regimens [/fig_ref]. When insulin injections are started, insulin secretagogues (sulfonylurea or glinides) should be discontinued, or tapered and then discontinued, since they are not considered to be synergistic. Although addition of a third oral agent can be considered, especially if the A1C level is close to target (A1C 8.0%), this approach is usually not preferred, as it is no more effective in lowering glycemia, and is more costly, than initiating or intensifying insulin (91).

## Tier 2: less well-validated therapies
In selected clinical settings, this secondtier algorithm may be considered. Specifically, when hypoglycemia is particularly undesirable (e.g., in patients who have hazardous jobs), the addition of exenatide or pioglitazone may be considered. Rosiglitazone is not recommended. If promotion of weight loss is a major consideration and the A1C level is close to target (8.0%), exenatide is an option. If these interventions are not effective in achieving target A1C, or are not tolerated, addition of a sulfonylurea could be considered. Alternatively, the tier two interventions should be stopped and basal insulin started.
Rationale for selecting specific combinations More than one medication will be necessary for the majority of patients over time.
Selection of the individual agents should be made on the basis of their glucoselowering effectiveness and other characteristics listed in [fig_ref] Table 1 -: Summary of glucose-lowering interventions [/fig_ref]. However, when adding second antihyperglycemic medications, the synergy of particular combinations and other interactions should be considered. In general, antihyperglycemic drugs with different mechanisms of action will have the greatest synergy. Insulin plus metformin (92) is a particularly effective means of lowering glycemia while limiting weight gain.

## Special considerations/patients
In the setting of severely uncontrolled diabetes with catabolism, defined as fasting plasma glucose levels 13.9 mmol/l (250 mg/dl), random glucose levels consistently above 16.7 mmol/l (300 mg/dl), A1C above 10%, or the presence of ketonuria, or as symptomatic diabetes with polyuria, polydipsia and weight loss, insulin therapy in combination with lifestyle intervention is the treatment of choice. Some patients with these characteristics will have unrecognized type 1 diabetes; others will have type 2 diabetes with severe insulin deficiency. Insulin can be titrated rapidly and is associated with the greatest likelihood of returning glucose levels rapidly to target levels. After symptoms are relieved and glucose levels decreased, oral agents can often be added and it may be possible to withdraw insulin, if preferred.

# Conclusions
Type 2 diabetes is epidemic. Its long-term consequences translate into enormous human suffering and economic costs; however, much of the morbidity associated with long-term microvascular and neuropathic complications can be substantially reduced by interventions that achieve glucose levels close to the nondiabetic range. Although new classes of medications and numerous combinations have been demonstrated to lower glycemia, current-day management has failed to achieve and maintain the glycemic levels most likely to provide optimal healthcare status for people with diabetes.

## Summary
The guidelines and treatment algorithm presented here emphasize the following:
- Achievement and maintenance of near normoglycaemia (A1C 7.0%) - Initial therapy with lifestyle intervention and metformin - Rapid addition of medications, and transition to new regimens, when target glycemic goals are not achieved or sustained - Early addition of insulin therapy in patients who do not meet target goals
Duality of interest D.M.N. has received a research grant for investigator-initiated research from sanofi aventis and support for educational programs from GlaxoSmithKline. J.B.B. has conducted research and/or served on advisory boards under contract between the
[fig] Figure 1 -: Initiation and adjustment of insulin regimens. Insulin regimens should be designed taking lifestyle and meal schedule into account. The algorithm can only provide basic guidelines for initiation and adjustment of insulin. See reference 90 for more detailed instructions. a Premixed insulins not recommended during adjustment of doses; however, they can be used conveniently, usually before breakfast and/or dinner, if proportion of rapid-and intermediate-acting insulins is similar to the fixed proportions available. bg, blood glucose. [/fig]
[fig] Figure 2 -: Algorithm for the metabolic management of type 2 diabetes; Reinforce lifestyle interventions at every visit and check A1C every 3 months until A1C is 7% and then at least every 6 months. The interventions should be changed if A1C is 7%. a Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide. b Insufficient clinical use to be confident regarding safety. See text box, entitled TITRATION OF METFORMIN. See Fig. 1 for initiation and adjustment of insulin. CHF, congestive heart failure. [/fig]
[table] Table 1 -: Summary of glucose-lowering interventions [/table]