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Insulin therapy in type 2 diabetes mellitus

Insulin therapy in type 2 diabetes mellitus
Author:
Deborah J Wexler, MD, MSc
Section Editor:
David M Nathan, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Dec 2022. | This topic last updated: Oct 27, 2022.

INTRODUCTION — Type 2 diabetes is the most common type of diabetes in adults. It is characterized by hyperglycemia and variable degrees of insulin deficiency and resistance. Its prevalence rises markedly with increasing weight.

Management of patients with type 2 diabetes mellitus includes education, evaluation for microvascular and macrovascular complications, achievement of target glycemia, treatment of cardiovascular risk factors, and avoidance of drugs that can aggravate abnormalities of glucose or lipid metabolism. Weight reduction, diet, and oral medication (typically metformin) can all be used initially to improve glycemic management, although the majority of patients with type 2 diabetes will require additional therapy over time to maintain glycemic targets. The therapeutic options for such patients include adding a second or third oral agent or an injectable agent, such as a glucagon-like peptide 1 (GLP-1) receptor agonist or insulin, or switching to insulin.

The role of insulin in achieving optimal glycemic control in nonpregnant patients with type 2 diabetes will be reviewed here. Options for initial therapy, options for the management of persistent hyperglycemia, and other therapeutic issues in diabetes management, such as the frequency of monitoring and evaluation for microvascular and macrovascular complications, are discussed separately. Insulin treatment of pregnant women with diabetes is also reviewed separately.

(See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)

(See "Management of persistent hyperglycemia in type 2 diabetes mellitus".)

(See "Overview of general medical care in nonpregnant adults with diabetes mellitus".)

(See "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control", section on 'Insulin pharmacotherapy'.)

(See "Gestational diabetes mellitus: Glucose management and maternal prognosis", section on 'Insulin'.)

(Related Pathway(s): Diabetes: Initial therapy for non-pregnant adults with type 2 DM.)

(Related Pathway(s): Diabetes: Medication selection for non-pregnant adults with type 2 DM and persistent hyperglycemia despite monotherapy.)

(Related Pathway(s): Diabetes: Initiation and titration of insulin therapy in non-pregnant adults with type 2 DM.)

GENERAL PRINCIPLES

Insulin preparations — In type 2 diabetes, insulin is generally provided in three ways:

As a basal supplement with an intermediate-acting to long-acting preparation (neutral protamine Hagedorn [NPH], detemir, glargine, or the very long-acting degludec) to suppress hepatic glucose production and maintain glucose levels at target in the fasting state

As a pre-meal (prandial) bolus dose of short-acting (regular) or rapid-acting (lispro, aspart, glulisine) insulin to cover the extra requirements after food is absorbed

As a premixed combination of intermediate-acting and short-acting or rapid-acting insulin

The approximate time of onset, half-life, effective peak, and duration of action of the most commonly used insulins are reviewed in the table (table 1) and in more detail elsewhere. There is substantial intra-individual and inter-individual variability in onset and duration of insulin action related to the volume injected, the injection site, injection technique, and multiple other factors; therefore, insulin must be adjusted based on patient response. (See "General principles of insulin therapy in diabetes mellitus", section on 'Insulin preparations'.)

Physiologic insulin replacement — Insulin is secreted in a pulsatile manner; pulses occur under basal (unstimulated) conditions and in response to meals [1]. Basal insulin secretion represents approximately 50 percent of 24-hour insulin production, with the remainder accounted for by prandial (mealtime) excursions.

The term "intensive insulin therapy" has been used to describe complex regimens that include basal insulin (given as one to two daily injections of intermediate-acting or long-acting insulin) and superimposed injections of short-acting or rapid-acting insulins three or more times daily before meals to limit postprandial glycemic excursions. While intensive regimens are the preferred regimen for patients with type 1 diabetes using multiple daily insulin injections (rather than an insulin pump), they may be used for patients with type 2 diabetes as well, especially for patients taking high doses of insulin and for those with insulin deficiency.

Disadvantages of insulin therapy — The major drawbacks associated with insulin therapy in type 2 diabetes are weight gain and hypoglycemia. These adverse effects should be reviewed at every visit in those taking insulin, and weight loss or weight maintenance should be emphasized. Glycemic targets may need to be relaxed to reduce the risk of hypoglycemia and/or insulin-associated weight gain. (See 'Troubleshooting' below.)

The safety of human insulin versus insulin analogs, including concerns about diabetic complications and risk of cancer, is reviewed in detail elsewhere. (See "General principles of insulin therapy in diabetes mellitus", section on 'Safety'.)

Monitoring glycemia

Glycated hemoglobin (A1C) – A1C is the most widely used clinical test to monitor chronic glycemic management. Target A1C levels in patients with type 2 diabetes taking insulin should be tailored to the individual, balancing the reduction in microvascular complications (figure 1) with the risk of hypoglycemia and insulin-associated weight gain. A reasonable goal of therapy for most patients might be an A1C value ≤7.0 percent (using an assay aligned to the Diabetes Control and Complications Trial [DCCT] in which the upper limit of normal is 6.0 percent) (calculator 1). The A1C goal should be set somewhat higher for older patients, patients with comorbidities, and those with a limited life expectancy. (See "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target'.)

Blood glucose monitoring – Measurements of instantaneous glucose levels (self-monitoring of blood glucose [with fingersticks and a glucose meter] and real-time continuous glucose monitoring) are used to manage diabetes from hour to hour and from day to day, to aid in dose selection in insulin-treated patients, and for safety.

In general, for healthy young and middle-aged adults to achieve an A1C goal ≤7.0 percent, a fasting glucose of 80 to 130 mg/dL (4.4 to 7.2 mmol/L) and a postprandial glucose (90 to 120 minutes after a meal) less than 180 mg/dL (10 mmol/L) are generally given as targets, but higher achieved levels may suffice [2,3]. In older patients, those with chronic kidney disease, or those with other risk factors for hypoglycemia, in whom the A1C goal is set higher, a higher fasting glucose target (eg, 90 or 100 to 150 mg/dL [5 to 8.3 mmol/L]) may be used.

Cardiovascular effects — Compared with oral agents and independent of the level of glycemia achieved, insulin does not appear to prevent or increase major adverse cardiovascular events. In addition, the type of insulin does not affect cardiovascular outcomes.

Addition of insulin

Oral agent(s) plus glargine versus oral agent(s) only – Glargine therapy does not appear to reduce or increase cardiovascular outcomes compared with oral agent(s) in populations at relatively high risk for cardiovascular disease (CVD), as illustrated by the findings of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, or in populations with diabetes and low risk for CVD, as shown in the Glycemia Reduction Approaches in Diabetes (GRADE) trial [4,5].

In the ORIGIN trial, over 12,500 patients with cardiovascular risk factors plus type 2 diabetes or prediabetes were randomly assigned to an evening dose of glargine or to standard care [4]. Approximately 60 percent of the patients with prior diabetes were using oral glucose-lowering agents (predominantly metformin or sulfonylurea). The glargine was titrated to achieve a fasting glucose level of <95 mg/dL (5.3 mmol/L). After a median follow-up of six years, the achieved median fasting glucose levels were 94 and 123 mg/dL (5.2 and 6.8 mmol/L), respectively.

The rates of incident cardiovascular outcomes were similar in the glargine and standard care groups (2.94 and 2.85 per 100 person-years, respectively). Only 11 percent of the patients in the standard therapy group received insulin. A1C values were similar at baseline (6.4 percent) and at study end (6.2 and 6.5 percent). Approximately 60 percent of patients in both groups were treated with statins and 75 percent with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).

In the GRADE trial, 5047 patients with type 2 diabetes and low cardiovascular disease prevalence taking maximum tolerated doses of metformin were randomly assigned to one of four second glucose-lowering medications [5]. Treatment with glargine, sitagliptin, or glimepiride led to comparable incidence of major adverse cardiovascular events (5.2, 5.5, and 4.7 percent, respectively) and hospitalization for heart failure (2.1, 2.4, and 2.4 percent, respectively) over five years of follow-up. Importantly, the cardiovascular safety of sitagliptin has been established in a large cardiovascular outcome trial [6]. The GRADE trial is discussed in more detail elsewhere. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Without established cardiovascular or kidney disease' and "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

Comparison of insulin types

Insulin degludec versus insulin glargine – In a two-year noninferiority trial, cardiovascular events were similar in patients randomly assigned to insulin degludec or glargine [7]. In this masked trial, 7637 patients with type 2 diabetes (mean A1C 8.4 percent) with or at high risk for CVD were randomly assigned to insulin degludec or glargine once daily. At baseline, approximately 60 percent of the patients were treated with metformin, 29 percent with sulfonylurea, and 84 percent with insulin. The primary composite outcome (first occurrence of a death from cardiovascular causes, nonfatal MI, or nonfatal stroke) occurred in 8.5 and 9.3 percent of the patients receiving degludec and glargine, respectively. Glycemic management was similar throughout the trial; rates of severe and nocturnal hypoglycemia were lower in patients taking degludec, although the absolute rates of hypoglycemia were very low in both treatment groups (eg, severe hypoglycemia occurred in 4.9 versus 6.6 percent of individuals over two years). The insulin titration target in this trial was a fasting glucose of 71 to 90 mg/dL (4 to 5 mmol/L), with the option to raise the target to 90 to 126 mg/dL (5 to 7 mmol/L) for older patients or per investigator discretion.

Basal versus prandial insulin – The type of insulin (basal or prandial) does not appear to affect cardiovascular outcomes, as illustrated by the findings of the Hyperglycemia and its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus (HEART2D) trial, which was designed to evaluate the effects of prandial (lispro) or basal (NPH twice daily or insulin glargine once daily) insulin on cardiovascular outcomes in 1115 patients after MI [8]. At baseline, 50 percent of the patients were taking metformin, sulfonylureas, or both, whereas the remaining patients were treated with insulin monotherapy. At a mean follow-up of 2.7 years, the trial was stopped early due to lack of difference among treatment arms. There was no difference between the prandial and basal groups in the time to a subsequent cardiovascular event (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for an acute coronary syndrome).

INDICATIONS FOR INSULIN

Initial treatment — Although we suggest lifestyle intervention (diet, weight reduction, exercise) and metformin (in the absence of contraindications) for the initial treatment of type 2 diabetes, some patients are candidates for insulin as their initial therapy. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Initial pharmacologic therapy'.)

Indications for initial treatment with insulin include the following:

Severe hyperglycemia on presentation – Insulin may be indicated for initial treatment for some patients with type 2 diabetes, depending on the severity of the baseline metabolic disturbance [9,10].

For patients presenting with symptomatic (eg, weight loss, polydipsia, polyuria) or severe hyperglycemia with ketonuria, insulin is indicated for initial treatment.

For patients presenting with severe hyperglycemia (fasting glucose >250 mg/dL [13.9 mmol/L], random glucose consistently >300 mg/dL [16.7 mmol/L], A1C >9 percent [74.9 to 85.8 mmol/mol]) but without ketonuria or spontaneous weight loss, in whom type 1 diabetes is not likely, insulin (or a glucagon-like peptide 1 [GLP-1] receptor agonist) is an option, along with metformin, if no contraindications.

Difficulty distinguishing type of diabetes – Insulin is indicated for initial treatment in patients when the diagnosis of diabetes (type 1 versus type 2) is unclear.

Patients who are initially thought to have type 2 diabetes may actually have type 1 diabetes. Although the peak incidence of type 1 diabetes occurs around the time of puberty, approximately 42 percent of cases present after 30 years of age [11].

There are certain clinical features that, if present at any age, suggest the diagnosis of type 1 diabetes. These include marked and otherwise unexplained recent weight loss (irrespective of the initial weight), a short history with pronounced symptoms (polyuria, polydipsia), and the presence of moderate or greater ketonuria.

A personal or family history of autoimmune disease (eg, hypo- or hyperthyroidism, celiac sprue) without family history of type 2 diabetes, especially in a patient without a history of overweight, is also suggestive of type 1 diabetes. Diabetic ketoacidosis at first presentation, especially if severe, suggests that the patient has type 1 diabetes and will require lifelong insulin treatment, although there are exceptions to this general rule [12]. (See "Classification of diabetes mellitus and genetic diabetic syndromes" and "Syndromes of ketosis-prone diabetes mellitus".)

Some individuals with adult-onset type 1 diabetes may be indistinguishable clinically from a patient with type 2 diabetes at presentation but will slowly progress to insulin dependence. This is sometimes referred to as "latent autoimmune diabetes in adults" (LADA) (see "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Distinguishing type 1 from type 2 diabetes'). LADA can be distinguished from type 2 diabetes by the presence of pancreatic autoantibodies, such as glutamic acid decarboxylase (GAD) or tyrosine phosphatase (islet antigen-2 [IA2]) antibodies. These individuals may respond poorly to oral hypoglycemic drug therapy, and the use of sulfonylureas as initial therapy may cause earlier insulin dependence [13,14]. The best initial treatment strategy for LADA is unclear. Studies are required to determine whether early treatment with insulin or use of immunomodulator therapy may prevent disease progression.

Pancreatic insufficiency – Insulin is also indicated for patients with secondary diabetes due to pancreatic insufficiency, including from cystic fibrosis, chronic pancreatitis, or after pancreatectomy. (See "Cystic fibrosis-related diabetes mellitus", section on 'Insulin therapy' and "Chronic pancreatitis: Management", section on 'Endocrine insufficiency (pancreatogenic diabetes)'.)

Other – Initial intensive insulin treatment for a brief period (two to four weeks) may be beneficial in patients with type 2 diabetes and may induce a remission that can last for a year or more [15-17]. By inducing near-normoglycemia with intensive insulin therapy, both endogenous insulin secretion and insulin sensitivity improve [15,17,18]. The improvement in insulin secretion is presumably due to the elimination of the deleterious effects of hyperglycemia on beta cell secretory function, and, in some patients, it results in better glycemic management that can then be maintained with diet and exercise for many months or even years thereafter [17].

This was illustrated in a randomized trial of short-term (two to five weeks) intensive insulin therapy versus oral agents (gliclazide and/or metformin) in 410 Chinese patients with newly diagnosed type 2 diabetes (mean fasting glucose 202 mg/dL [11.2 mmol/L]) [19]. Insulin and oral agents were titrated to achieve a fasting glucose <110 mg/dL (6.1 mmol/L). Therapy was discontinued two weeks after achieving glycemic targets. The patients were instructed to continue diet and exercise alone and were closely followed for recurrence of hyperglycemia (fasting glucose >126 mg/dL [7 mmol/L] or postprandial glucose >180 mg/dL [10 mmol/L]).

A greater proportion of patients receiving insulin achieved glycemic goals in less time than those assigned to oral agents (over 90 percent within 4 to 5.6 days versus 84 percent in 9.3 days). Remission rates after one year were higher in the insulin groups (insulin pump or multiple daily injections) than in the oral hypoglycemic group (51 and 45 versus 27 percent). Patients in remission had lower initial fasting glucose levels and A1C, and they achieved glycemic goals more quickly than those with recurrent hyperglycemia.

Initial, short-term intensive insulin treatment is not widely used, possibly due to the complexity of introducing intensive insulin treatment at diagnosis, patient reluctance, and even provider reluctance (given the challenges with initiating basal insulin in patients with longstanding diabetes).

Persistent hyperglycemia on oral agents — Oral agents become less effective as beta cell function declines (figure 2). The therapeutic options for patients who have persistent hyperglycemia with lifestyle intervention and metformin are to add a second oral or injectable agent, including addition of insulin as an option, or to switch to insulin. For many patients, we prefer insulin or a GLP-1 receptor agonist (if the patient is not catabolic) for a second-line medication.

The GRADE trial showed that early use of basal insulin added to metformin lowers glucose more durably over five years than a sulfonylurea or dipeptidyl peptidase 4 (DPP-4) inhibitor, with relatively few adverse effects. The rate of severe hypoglycemia was lower with insulin (1.3 percent) than with sulfonylurea treatment (2.2 percent) over five years in the GRADE trial and lower than that observed in the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE; 6.6 percent over two years for basal insulin glargine), which had tighter glucose targets and a higher baseline prevalence of chronic kidney disease [7,20]. The approach for selecting a second medication, particularly in the presence of cardiovascular or kidney comorbidities, is reviewed in more detail separately. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'.)

Insulin is always effective and is preferred in insulin-deficient, catabolic diabetes (eg, polyuria, polydipsia, weight loss). Patients should be counseled that initiating insulin does not represent a personal "failure" and that many patients with type 2 diabetes will eventually require exogenous insulin, due to decline in endogenous insulin production (table 2).

DESIGNING AN INSULIN REGIMEN — We advise clinicians to familiarize themselves with a limited number of regimens (to facilitate addressing patient preferences, lifestyle [meal and activity patterns], etc) and use them consistently.

The glycemic differences achieved among different insulin regimens, assuming that they are adequately titrated, are modest. However, basal insulin is frequently suboptimally titrated in clinical practice [21]. The majority of studies evaluate the effect of insulin on glycemia but do not provide information regarding the effects of various insulin regimens on microvascular or macrovascular complications or mortality. When differences in A1C levels have been found, they are sometimes offset by adverse events such as hypoglycemia.

Insulin initiation — For patients who are initiating insulin (in addition to oral agents, in place of oral agents, or as initial treatment), we suggest initiating basal, rather than prandial, insulin.

Basal insulin will improve nocturnal and fasting glucose levels [22], whereas prandial (pre-meal) bolus insulin will decrease postprandial glucose excursions. Whether a basal or a prandial strategy is more effective in improving microvascular complications remains uncertain. The type of insulin regimen (basal or prandial) does not appear to affect cardiovascular outcomes. (See 'Cardiovascular effects' above.)

Initiation of insulin therapy with a basal insulin has the advantage of convenience and simplicity in patients who are using insulin for the first time. Although basal and prandial insulin are similarly effective in improving A1C when insulin doses are aggressively titrated to achieve glycemic goals, basal insulin is associated with greater patient satisfaction and less frequent hypoglycemia [23,24]. As examples:

In a randomized trial of once-daily insulin glargine versus prandial insulin lispro in 415 patients who were inadequately managed with metformin and a sulfonylurea, there were similar improvements in A1C (mean decrease of 1.7 and 1.9 percent, respectively) and target A1C concentrations between 6.5 and 7.0 percent were achieved by 27 and 30 percent of subjects, respectively [23]. Basal insulin was associated with greater patient satisfaction and less hypoglycemia.

The Hyperglycemia and its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus (HEART2D) trial was designed to evaluate the effects of prandial (lispro) or basal (NPH twice daily or insulin glargine once daily) insulin on cardiovascular outcomes in 1115 patients after myocardial infarction (MI) [8]. At baseline, 50 percent of the patients were taking metformin, sulfonylureas, or both, whereas the remaining patients were treated with insulin monotherapy. At a mean follow-up of 2.7 years, the trial was stopped early due to lack of difference among treatment arms. There was no difference between the prandial and basal groups in A1C (7.7 versus 7.8 percent). The cardiovascular outcomes are reviewed above. (See 'Cardiovascular effects' above.)

Patients are usually not eager to start insulin. Reasons for reluctance to start insulin should be explored and addressed (table 2).

Choice of basal insulin — A single daily dose of either insulin NPH or detemir given at bedtime or insulin glargine or degludec given in the morning or at bedtime is a reasonable initial regimen (table 1). In practice, payer coverage is often an important consideration in the selection of basal insulin. (See "General principles of insulin therapy in diabetes mellitus", section on 'Insulin preparations'.)

The basal insulin preparations do not differ significantly in glycemic efficacy [25,26]. Among basal insulin preparations, insulin glargine, detemir, and degludec may have less nocturnal hypoglycemia (but not always total hypoglycemia) compared with NPH, with the important disadvantage of higher cost. There does not appear to be any difference in hypoglycemia-related hospital admissions or emergency department visits. As examples:

In meta-analyses of trials comparing once-daily insulin glargine or detemir with once-daily or twice-daily NPH insulin, there were similar improvements in A1C with all types of basal insulin [26-29]. However, in some of the meta-analyses, the rates of overall symptomatic and nocturnal hypoglycemia (while relatively infrequent with either basal insulin) were lower in patients treated with either insulin glargine or detemir compared with NPH [26-28,30,31].

In a retrospective observational study using data from a large health care delivery system (>25,000 patients initiating basal insulin), there was no benefit of insulin analogs compared with NPH in reducing emergency department or hospital admissions for hypoglycemia (11.9 versus 8.8 events per 1000 person-years, respectively) despite slightly better glycemic management in the NPH group (achieved A1C 8.2 versus 7.9 percent with NPH, suggesting they were not treated with less aggressive doses) [32].

Insulin degludec appears to have similar glycemic efficacy as that of insulin glargine and, in some trials, a lower rate of hypoglycemia, especially if aiming for more stringent glycemic targets [7,33-37]. As an example, in a 65-week, double-blind, crossover trial, 721 adults with type 2 diabetes (mean A1C 7.6 percent) and at least one risk factor for hypoglycemia were randomly assigned to receive once-daily insulin degludec or insulin glargine for 32 weeks and then crossed over to the alternate insulin treatment for the next 32 weeks [38]. The rate of overall (185.6 versus 265.4 episodes per 100 patient-years of exposure) and nocturnal (55.2 versus 93.6 episodes) symptomatic hypoglycemia was lower with degludec (rate ratios 0.70, 95% CI 0.61-0.80 and 0.58, 95% CI 0.46-0.74, respectively). There was no difference in relatively rare severe hypoglycemia (nonsignificant reduction of 0.62 episodes per 100 patient-years with degludec). Overall glycemic management was similar (A1C 7 to 7.1 percent).

Although degludec significantly reduced overall and nocturnal hypoglycemia, the modest benefit (on average, one episode less every five years) must be balanced against its relatively higher cost and its briefer clinical experience. [39].

Initial dose — For patients with type 2 diabetes, the initial dose of insulin (whether in addition to oral agents, in place of oral agents, or as initial treatment) is similar [28,40,41]. Many algorithms have been published; one simple and conservative algorithm is presented here (algorithm 1) (related Pathway(s): Diabetes: Initiation and titration of insulin therapy in non-pregnant adults with type 2 DM). We start with bedtime NPH or detemir, taken at 10:00 PM if the person is testing his or her fasting glucose at 7:00 or 8:00 AM, or bedtime or morning glargine or degludec. Since glargine and degludec can be administered any time of day, the timing of daily insulin glargine or degludec is based on patient preference to facilitate adherence.

The initial dose for NPH, detemir, glargine, or degludec is 0.2 units per kg (minimum 10 units, up to 15 to 20 units) daily. If fasting glucose levels are very elevated (>250 mg/dL [13.9 mmol/L]), A1C is >8 percent, or if a patient is known to be very insulin resistant, initial doses of basal insulin can be higher (eg, 0.3 units per kg or up to 15 to 20 units daily as an initial dose). Subsequent modifications should be made according to daily measurement of fasting glucose and every three-month measurement of A1C. (See 'Titrating dose' below.)

Combination therapy – The rationale for combination oral hypoglycemic drug and insulin therapy is that using glucose-lowering medications with different mechanisms of action may achieve glucose targets while minimizing total insulin requirements and weight gain [42]. Metformin is often continued with the addition of insulin. Other agents including glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors can also be continued when insulin is added, especially if they are being used for cardiac or kidney benefit. In the absence of this rationale for combination therapy, the putative advantages of doing so must be balanced against the downside of regimen complexity (polypharmacy) and increased cost. Dipeptidyl peptidase 4 (DPP-4) inhibitors add complexity and cost and are relatively weak, so may be stopped when insulin is initiated. Sulfonylureas, meglitinides, and pioglitazone are usually tapered and stopped when starting insulin, especially prandial insulin, due to reduced efficacy in comparison with other combinations and to adverse effects [43]. However, there are some situations where one of these agents may be combined with insulin (eg, using a thiazolidinedione in a patient with lipodystrophy and severe insulin resistance). (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Insulin initiation and intensification' and "Lipodystrophic syndromes", section on 'Treatment of lipodystrophy'.)

Insulin monotherapy – Switching to insulin monotherapy may be cheaper than combined oral agent-insulin therapy depending on the combination used (metformin is very inexpensive) but may result in slightly more weight gain, depending on the combination, and more episodes of hypoglycemia, few of which are severe [42]. The oral agent may be discontinued when insulin is initially added or after the patient is on an adequate dose of basal insulin. The former approach may be associated with elevations in glucose levels until the dose of injected insulin is sufficient to achieve metabolic control. (See "Interactive diabetes case 2: Switching from oral agents to insulin in type 2 diabetes".)

Titrating dose — The basal insulin regimen is adjusted based on fasting glucose levels, A1C values, and frequently, bedtime glucose. For many patients with type 2 diabetes, basal insulin alone is often adequate for glycemic management because it reduces glucose toxicity, thereby increasing endogenous insulin secretion, which is sufficient for postprandial excursions. However, patients with type 2 diabetes and persistently elevated A1C despite fasting blood glucose in target range or people on very high doses of insulin may require pre-meal insulin, similar to treatment for type 1 diabetes. Pre-meal insulin regimens require self-monitoring of glucose levels in addition to fasting levels (ie, before the meals when rapid-acting insulin is used) to help determine and subsequently adjust preprandial dosing.

Persistent fasting hyperglycemia — If the mean fasting glucose is above target (typically 130 to 140 mg/dL [7.2 to 7.7 mmol/L]), the basal insulin dose may be increased by 2 to 4 units approximately every three days to achieve the target range (algorithm 1) (related Pathway(s): Diabetes: Initiation and titration of insulin therapy in non-pregnant adults with type 2 DM) [40]. In this way, the basal insulin dose can be titrated over a period of several weeks or months. If fasting glucose levels are very elevated (>250 mg/dL [13.9 mmol/L]) or if a patient is known to be very insulin resistant, titration can be more aggressive, with the dosing increment decreasing as the patient approaches the target blood glucose. Patients should be proactively counseled to reduce the daily insulin dose if hypoglycemia develops.

As patients approach the glycemic target, it may be helpful to check a mid-sleep blood glucose to rule out hypoglycemia (this can be done when the patient spontaneously wakes overnight).

Persistent elevation in A1C with fasting glucose in target range — For patients with persistently elevated glycated hemoglobin (A1C) levels who have fasting glucose levels in the target range (80 to 130 mg/dL [4.4 to 7.2 mmol/L], or higher, depending on the individualized glycemic target), we advise the patient to check fingerstick capillary glucose levels fasting, pre-lunch, pre-dinner, and before bed while the insulin regimen is further adjusted. Prandial insulin is often started as a single injection before the largest meal of the day, but many strategies are possible (algorithm 1) (related Pathway(s): Diabetes: Initiation and titration of insulin therapy in non-pregnant adults with type 2 DM). Short-term monitoring with continuous glucose monitoring for two weeks may also be helpful in insulin dose adjustment. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus".)

Among patients whose A1C values remain above the individualized target despite insulin adjustments, diet and exercise patterns should be reviewed. We advise the patient to continue to check fingerstick capillary glucose levels fasting, pre-lunch, pre-dinner, and before bed while the regimen is further adjusted. In general, inadequate dosing, dietary indiscretion, and/or mismatch of food and insulin dose underlie the apparent failure of many insulin regimens. Total daily insulin doses (basal plus prandial) typically exceed 65 to 100 units per day and may sometimes be much higher in patients with type 2 diabetes and obesity. When the basal insulin dose is >80 units daily, absorption kinetics (which are proportional to volume injected) may be altered. In this setting, we administer basal insulin in divided doses twice daily. (See "General principles of insulin therapy in diabetes mellitus", section on 'Size of subcutaneous depot'.)

Pre-lunch glucose elevated — If pre-lunch glucose values are elevated, options include adding prandial insulin before breakfast (see 'Combining prandial and basal insulin' below), adding a GLP-1 receptor agonist, or, if the patient is taking bedtime detemir or NPH, adding a second dose of NPH or detemir at breakfast. Dietary modification at breakfast may also be effective.

When the insulin preparation is detemir, glycemic management over a 24-hour period may be more stable in patients taking two doses daily (table 1) [44]. If the goal is management of persistent hyperglycemia with a regimen that is simple and inexpensive, then twice-daily NPH will be effective in many patients [41,45]. One dosing strategy when switching from once-daily to twice-daily NPH or detemir is to give a total daily insulin dose of approximately 80 percent of the current bedtime dose of basal insulin, administering approximately 50 to 70 percent of it in the morning and 50 to 30 percent at bedtime. We typically use equally divided doses for detemir and 70/30 percent for NPH. For patients who are far from glycemic goals, the full total daily dose of detemir can be administered in equally divided doses. (See 'Choice of basal insulin' above.)

After this transition, insulin doses will need further adjustment based on glucose monitoring and meal pattern.

Pre-dinner or bedtime glucose elevated — If blood glucose values are elevated before dinner and/or bed, we typically add prandial insulin (see 'Combining prandial and basal insulin' below). Either short-acting (regular) or rapid-acting insulin can be given before lunch and/or dinner. It is often simpler to counsel smaller lunches, and then add a single injection of prandial insulin before dinner, which, for many people, is the largest meal of the day. If lunch is the largest meal of the day, the reverse approach may be used (eg, cover lunch with prandial insulin, eat a smaller dinner).

For patients taking bedtime NPH or detemir who have pre-dinner hyperglycemia, adding another dose of NPH or detemir insulin at breakfast is an alternative, particularly if pre-lunch glucose is also elevated. Adding a GLP-1 receptor agonist is another option. (See 'Pre-lunch glucose elevated' above.)

Combining prandial and basal insulin — For patients with type 2 diabetes who require prandial insulin, the goal is to adjust the dose of short-acting or rapid-acting insulin immediately prior to a meal, and therefore, we prefer to keep basal and pre-meal insulin injections separate and adjust them independently. Patients may draw up their pre-meal and NPH insulin in the same syringe prior to injection, whereas glargine, degludec, and detemir cannot be mixed with rapid-acting insulin. In the setting of multiple daily insulin injections, oral agents other than metformin are usually discontinued to reduce polypharmacy and cost. However, other oral or injectable GLP-1 receptor agonists may also be continued.

Choice of prandial insulin – The choice of prandial insulin is based upon availability, patient preference, cost, and payer coverage. Compared with regular insulin, the newer rapid-acting insulins have a minor glycemic advantage especially in patients with type 1 diabetes. The ability to inject the rapid-acting insulins 10 to 15 minutes before meals (as opposed to the 30 to 45 minutes before the meal with short-acting insulins) may improve adherence in all insulin-treated patients. There is little glycemic advantage of analog compared with regular insulins in type 2 diabetes [46,47]. This was illustrated in a meta-analysis of 10 randomized trials (involving 2751 patients with type 2 diabetes) that compared rapid-acting insulin analogs with regular insulin as pre-meal bolus doses [47]. No significant differences were seen in serum A1C concentrations or the number of hypoglycemic episodes.

Pre-meal insulin dosing – The optimal dose of pre-meal insulin depends upon many factors, including current and target blood glucose values, carbohydrate content of the meal, and activity. A typical starting dose is approximately 4 to 6 units or 10 percent of basal insulin dose (algorithm 1). The dose can be increased every three days until the postprandial blood glucose target is achieved.

Prandial insulin dose increases depend on how much prandial insulin the patient is using. As a rule of thumb:

≤10 units – Increase by 1 unit

11 to 20 units – Increase by 2 units

>20 units – Increase by 5 units (or more, depending on patient insulin resistance, meal size, and content)

A more complex method for adjusting pre-meal insulin is to match insulin delivery to the anticipated glucose excursion with meals. Many patients benefit from specific training in carbohydrate counting, which requires some arithmetical computations that some patients find difficult or burdensome. It is uncertain if there is a glycemic advantage to carbohydrate counting in patients with type 2 diabetes. As an example, in a 24-week, randomized trial in 277 adults with type 2 diabetes, there was no difference in A1C values when mealtime insulin adjustments were based upon a simple algorithm (according to previous weeks' blood glucose monitoring results) versus carbohydrate counting, using an insulin-to-carbohydrate ratio for each meal [48]. Either method is acceptable, and patient preference can guide the choice of method for pre-meal dosing. A simplified adaptation in which patients take a slightly higher dose of prandial insulin for high carbohydrate meals may yield many of the benefits of carbohydrate counting without the complexity and is more straightforward for most patients with type 2 diabetes. (See "Nutritional considerations in type 2 diabetes mellitus", section on 'Carbohydrate consistency'.)

For some patients, providing supplemental insulin in addition to prandial insulin is an option. In this framework, every prandial insulin dose can be considered to have two components: the part covering the meal (prandial) and the part correcting the hyperglycemia (supplemental insulin). For people with type 2 diabetes, 1 to 2 units for every 50 mg/dL above the target glucose may be added to the prandial insulin dose. Since the math can be confusing for many people, patients may be prescribed a "mealtime sliding scale" in which the recommended dose of insulin increases with the plasma glucose level. In this approach, the "mealtime sliding scale" includes the prandial and supplemental components. It is important to educate the patient that this combined scale could lead to insulin overdose if used for supplemental or correction insulin dosing when the patient is not eating. Patients should be counseled to reduce the insulin dose for exercise or for procedures that require limiting food intake. (See "Perioperative management of blood glucose in adults with diabetes mellitus", section on 'Glucose management'.)

Premixed insulin – Some insulins are commercially available in a premixed formulation. Most premixed (biphasic) preparations contain an intermediate-acting insulin and either a short-acting or a rapid-acting insulin. The major drawback of premixed insulin is limited flexibility in adjusting doses. However, premixed insulin is a reasonable option for patients with type 2 diabetes who are doing well on a stable, fixed ratio of short- and intermediate-acting insulin, or who are able to modify their diets to match the kinetics of premixed insulin. Premixed insulin works best when there is little day-to-day variability in breakfast, lunch, and dinner (with a small lunch) or when people are so insulin resistant that they are unlikely to develop hypoglycemia after smaller meals. Premixed insulin may rarely be used as initial insulin therapy for patients in whom a simplified insulin regimen is desirable. (See "General principles of insulin therapy in diabetes mellitus", section on 'Pre-mixed insulins'.)

Premixed rapid-acting preparations may be slightly less effective for glycemic management than adequately titrated basal and bolus insulin. In an open-label trial, 708 patients with type 2 diabetes who were suboptimally managed with metformin and a sulfonylurea were randomly assigned to premixed biphasic insulin aspart (twice daily), prandial insulin aspart (three times daily), or basal insulin detemir (once or twice daily). There was no difference in median A1C levels among the three groups (7.1, 6.8, and 6.9 percent, respectively), but significantly more patients in the basal and prandial groups achieved an A1C level ≤6.5 percent than in the premixed biphasic group (43, 45, and 32 percent, respectively) [24]. The majority of all three treatment groups used a second type of insulin, per protocol, during the trial to obtain the stipulated glycemic goals. Patients in the basal group had the fewest episodes of hypoglycemia. In other trials, premixed rapid-acting preparations were more often associated with minor hypoglycemia and weight gain than long-acting insulin or oral agents [49].

Premixed insulin should always be dosed before meals because the fast-acting component is meant to cover prandial intake. To initiate, calculate the total daily dose based on weight (0.2 units per kg [minimum 10 units, up to 15 to 20 units] daily) or based on prior insulin dose. One approach is to administer two-thirds of the total daily dose before breakfast and one-third before dinner. Premixed insulin should be dosed relative to meal intake and may need to be reduced for smaller meals. For example, depending on the meal pattern (eg, small breakfast, large dinner), it may be appropriate to switch the ratio and give as little as one-third before breakfast and as much as two-thirds before dinner.

The initial dose is adjusted based on glucose monitoring. If pre-lunch and pre-dinner hyperglycemia is occurring, the morning dose can be increased by 2 to 3 units every two to three days. The pitfall is that this may result in pre-lunch hypoglycemia, highlighting the challenge of using premixed insulin formulations. Consequently, it may be necessary to relax glycemic targets to use premixed insulin safely.

Intensive insulin regimens – If intensive insulin therapy is chosen in a patient with type 2 diabetes, the pretreatment considerations, choice of regimen, and management issues are similar to those for patients with type 1 diabetes. For people who are very hyperglycemic, it is not necessary to achieve euglycemia rapidly. Advancing the regimen slowly (over weeks rather than days) reduces the risk of hypoglycemia as glucotoxicity resolves, allows a slow osmotic re-equilibration, and enables the patient to learn to use insulin safely.

Insulin pump therapy is used infrequently in patients with type 2 diabetes, but it may have a role in a select group of patients with poorly managed type 2 diabetes taking multiple daily injections or for people with limited dexterity when someone is available to help set up the device [50]. Intensive insulin and insulin pump therapy are reviewed in detail elsewhere. (See "Management of blood glucose in adults with type 1 diabetes mellitus" and "Continuous subcutaneous insulin infusion (insulin pump)", section on 'Types of insulin pumps'.)

There are several "patch pump" devices that may simplify prandial insulin dosing [51-53]. These devices, containing a reservoir filled with rapid-acting insulin, are applied to the abdomen with adhesive and are changed daily. Patients administer variable doses of insulin by pressing a button on the devices as many times as needed to deliver the desired dose (eg, 1 "click" for 2 units).

Use of an intensive insulin regimen (similar to that used in type 1 diabetes) targeting tight glycemic targets results in higher serum insulin concentrations and better glycemic management than that achieved with either an oral drug or conventional insulin therapy alone [54]. A potential problem is the weight gain (averaging 8.7 kg in one study) that can occur with intensive regimens that achieve near-normoglycemia [55]. This weight gain may, in some instances, be counterproductive or result in partial noncompliance with therapy. (See 'Insulin-associated weight gain' below and "Nutritional considerations in type 2 diabetes mellitus".)

Conversion between basal insulin products

Conversion from twice-daily to once-daily basal insulin – If the patient is taking NPH or detemir twice per day and prefers once-daily basal insulin dosing, a switch to glargine (U-100 or U-300) or degludec once daily may be safely done by reducing the total daily basal insulin dose by 10 to 20 percent and re-titrating based on blood glucose levels. If the patient is very hyperglycemic without any hypoglycemia and confirms adherence to the prescribed twice-daily dose, the equivalent total daily dose may be given as a once-daily long-acting insulin.

Conversion between once-daily basal insulins – If a patient is switching from once-daily detemir to once-daily glargine (U-100 or U-300 glargine) or degludec, we also reduce the dose by 10 to 20 percent and re-titrate based on blood glucose levels. If the patient is very hyperglycemic, the equivalent total daily dose may be used.

Basal insulin administered at bedtime suppresses nocturnal hepatic gluconeogenesis. The longer-acting basal insulins may have less effect overnight and more effect into the next day, which should not be harmful. However, we generally reduce the dose initially to avoid the risk of hypoglycemia, and then increase the dose as needed to maintain glycemic targets.

Use of automated insulin algorithms — In order to achieve glycemic goals, the dose of insulin must be titrated often. Most patients with type 2 diabetes adjust their insulin dose with clinician advice (rather than independently), but the adjustments are made less frequently than necessary, in part due to clinician time constraints. The use of automated insulin algorithms may facilitate more timely dose adjustments. A smart pen insulin delivery device (which uses aspart or lispro cartridges) is available for people who use multiple daily insulin injections. The smart pen provides decision support for dosing similar to a bolus calculator on an insulin pump. It also tracks dosing history, which facilitates monitoring of adherence [56].

In addition, handheld devices are under development that contain a glucose meter and use an insulin algorithm to determine each insulin dose, based on the glucose readings. The software analyzes glucose patterns and adjusts the insulin dose to meet patient needs. In a randomized trial in 181 insulin-requiring patients with type 2 diabetes (mean A1C 8.6 percent), the use of one such device along with clinician support reduced A1C compared with clinician support alone (from baseline to six months, -1.0 versus -0.3 percentage points) [57]. The frequency of hypoglycemia (glucose <54 mg/dL [3 mmol/L]) was similar in the two groups, whereas there was more weight gain in the intervention group (2.3 versus 0.7 percent above baseline). This type of device, and similar mobile phone applications, shows promise for improving glycemic management in patients with type 2 diabetes.

TROUBLESHOOTING

Hypoglycemia — An increased risk of hypoglycemia is a potential complication of insulin therapy. However, insulin-treated patients with type 2 diabetes experience much less frequent hypoglycemia than patients with type 1 diabetes at similar A1C levels [58]. In the GRADE comparative effectiveness trial with a mean follow-up of five years, the incidence of severe hypoglycemia was lower for glargine as an add-on treatment to metformin (1.3 percent) than for glimepiride (2.2 percent) and comparable with liraglutide (1 percent) and sitagliptin (0.7 percent) [20].

Although basal insulin is associated with less hypoglycemia than prandial insulin (see 'Insulin initiation' above), hypoglycemia can occur when the dose of basal insulin is increased to cover meals. If the patient subsequently eats less than usual, hypoglycemia may occur. Alternatively, some patients develop daytime hypoglycemia on a dose of basal insulin that controls fasting glucose. Both of these scenarios can lead to obligate snacking, which may fuel insulin-associated weight gain. This problem may be identified by asking about symptoms of hypoglycemia when meals are skipped or snacking to prevent hypoglycemia. Other potential hypoglycemia triggers (eg, changes in diet or activity, alcohol use) should be identified. Patients who make significant dietary changes (eg, starting a ketogenic diet) may require substantial reductions in insulin dosing (eg, ≥50 percent reduction). (See "Interactive diabetes case 18: A 61-year-old patient with type 2 diabetes and a recent change in diet (medical nutrition therapy)".)

Nocturnal hypoglycemia – The dose of basal insulin should be reduced (bedtime dosing if taking twice daily) by 4 units or 10 percent, whichever is greater (algorithm 1) (related Pathway(s): Diabetes: Initiation and titration of insulin therapy in non-pregnant adults with type 2 DM). If there was no clear hypoglycemia precipitant (eg, skipped meal or increased physical activity, increased alcohol intake), there should be a greater dose reduction (20 to 30 percent), with retitration as needed. If the patient is taking bedtime NPH, an alternative is to switch to detemir, insulin glargine, or degludec at 80 to 90 percent of the current total daily dose.

Among basal insulin preparations, insulin glargine, detemir, and degludec may have some relatively modest clinical advantages over NPH when pursuing tight glycemic targets (less symptomatic and nocturnal hypoglycemia) with the important disadvantage of high cost. (See 'Choice of basal insulin' above.)

Daytime hypoglycemia – If the patient is taking prandial insulin, the dose should be decreased at the appropriate meal(s) (eg, reduce breakfast prandial insulin if hypoglycemia occurs between breakfast and lunch). If the hypoglycemia is not severe, a typical approach is to decrease the dose based on how much prandial insulin the patient is taking at the relevant mealtime:

≤10 units – Decrease by 2 units

11 to 20 units – Decrease by 4 units

>20 units – Decrease by 6 to 10 units or 50 percent

If the hypoglycemia is serious or severe, it is prudent to reduce the dose substantially (by 20 to 50 percent) and repeat the titration or to discontinue the prandial insulin and reinitiate/re-titrate if needed.

The patient should be instructed on how to adjust the prandial dose for meal size and carbohydrate content. In addition, patients should be asked about the timing of their prandial insulin dose and have appropriate timing reinforced if it appears to be contributing to episodes of hypoglycemia (for example, if the patient is taking the insulin following a meal rather than prior to the meal).

If the patient is not taking prandial insulin, the dose of basal insulin should be reduced (by 4 units or 10 percent, whichever is greater); it may also be prudent to switch to a non-peaking, long-acting insulin analog in insulin-sensitive patients with hypoglycemia (algorithm 1). If hyperglycemia develops after meals (based on self-monitoring of blood glucose), prandial insulin should be added to cover mealtime excursions. (Related Pathway(s): Diabetes: Initiation and titration of insulin therapy in non-pregnant adults with type 2 DM.)

Severe hypoglycemia – If the patient has a concerning hypoglycemic event, especially one requiring the assistance of another person to actively administer carbohydrate (severe hypoglycemia) and there are no apparent changes in diet or activity to account for hypoglycemia, it is prudent to reduce the dose substantially (eg, by 20 to 50 percent) and repeat the titration of the basal insulin (and/or discontinue the prandial insulin and reinitiate/titrate, if needed).

Unexplained hypoglycemia – In general, if there is concerning hypoglycemia, either due to the severity of the event or the level of risk in the patient (eg, an older person who lives alone, a person who has variable diet or activity, variable alcohol intake), it is prudent to err on the side of safety, sometimes with a large dose reduction or even stopping the insulin (in a patient who is not insulin deficient), since incrementally reducing the insulin dose may not eliminate the hypoglycemia. It is not uncommon for aging patients who previously required insulin to manage diabetes to be able to transition off insulin, especially with weight loss, changes in appetite and diet, and/or decline in kidney function [59]. The insulin may be resumed and re-titrated as needed.

The management of hypoglycemia in patients with diabetes is reviewed in more detail separately. (See "Hypoglycemia in adults with diabetes mellitus".)

Insulin resistance — In patients with severe insulin resistance (eg, requiring more than 200 total units of insulin daily), concentrated insulins can be used to manage hyperglycemia. Concentrated insulin formulations permit equivalent dosing in a smaller volume than U-100 insulin and without the need for numerous injections to deliver high doses. The smaller volume of injected insulin improves the absorption kinetics. Individual patient response should be monitored closely since the concentrated insulins are very potent and the kinetics are often different from labeled pharmacokinetics.

U-500 regular insulin – U-500 regular insulin is now used less frequently than in the past given the availability of potent GLP-1 receptor agonists as well as concentrated forms of insulin analogs. U-500 insulin has been and may continue to be used for patients with obesity, immune-mediated insulin resistance, genetic abnormalities of the insulin receptor, and severe insulin resistance due to lipodystrophy [60,61]. The pharmacokinetics can be highly variable, and hypoglycemia remains a potential risk [62,63]. U-500 regular insulin has both prandial and basal properties; higher doses can result in significantly longer duration of insulin action, more similar to that of NPH (figure 3) [64-66].

Dispensing – U-500 insulin is available in a pen device that shows the number of units of insulin to be delivered in the dose window [67]. The pen delivers the volume that corresponds to the selected dose. The pen contains 1500 units (500 units/mL) of insulin. The pens are convenient and safe to use but are expensive.

U-500 insulin can also be dispensed with the U-500 insulin syringe [68]. The syringe contains scale markings from 25 to 250 units in 5-unit increments (syringe total volume 0.5 mL).

In the past, U-500 insulin was dispensed using Tuberculin or U-100 syringes (which required dose conversions to deliver the correct dose). If neither dedicated U-500 insulin syringes nor the U-500 insulin pen device is available, U-500 insulin can be dispensed using a Tuberculin syringe, rather than a U-100 insulin syringe, to emphasize that it is different from U-100 regular insulin. With the Tuberculin syringe, every 0.1 mL equals 50 units of U-500 regular insulin (in contrast to 10 units of U-100 insulin). The concern when using U-500 insulin with a Tuberculin syringe is the potential for confusion of volume and units.

Dosing

-Initial – Although treatment approaches vary [66,69], initial dosing depends on prevailing glycemic management. In a person who is far from their glycemic target, one strategy is to calculate 80 percent of the current total daily insulin dose and administer in two equal doses, before breakfast and dinner. Some clinicians administer slightly more before breakfast (eg, 60 percent pre-breakfast, 40 percent pre-dinner) [69]. Lower initial doses can be used for those closer to their glycemic goals (eg, 50 to 60 percent of the current total daily insulin dose).

For severely insulin-resistant patients, U-500 insulin can be administered three times daily, dividing the total daily dose before breakfast (40 percent), lunch (30 percent), and dinner (30 percent) [69,70].

-Adjustments – During initial titration, weekly dose adjustments are based on glucose measurements (pre-meal and bedtime, or continuous glucose monitoring). If glucose levels remain elevated, the dose can be increased by approximately 10 to 20 percent (eg, in 5-unit increments using a U-500 pen). The patient should call immediately if there are any glucose readings <70 mg/dL, for help reducing the dose. If severe hypoglycemia develops, the total daily dose should be decreased substantially, potentially by up to 50 percent, and followed by slow increase as needed; unexplained nonsevere hypoglycemia should still prompt a 20 to 30 percent dose reduction due to the potency and kinetics of U-500. Similar to use of premixed insulins, glycemic targets may need to be relaxed in order to use U-500 safely.

U-300 glargine – Glargine 300 units/mL is very similar to glargine but has a volume one-third of that for the same dose of glargine 100 units/mL. It is available in a prefilled pen, and the dose window shows the number of units of insulin to be delivered. U-300 glargine is used in individuals with or without insulin resistance and may be substituted on an equivalent unit-per-unit basis. The pharmacokinetics are slightly different, with less of a peak and a longer duration of action. Consequently, glargine 300 units/mL is more similar to degludec than to glargine 100 units/mL [71]. (See "General principles of insulin therapy in diabetes mellitus", section on 'Basal insulin analogs'.)

U-200 lispro and U-200 lispro-aabc – Concentrated rapid-acting insulin analogs (U-200 lispro and U-200 lispro-aabc) contain 200 units/mL instead of 100 units/mL in the U-100 preparation. They are useful for patients requiring high doses of prandial insulin and are available in prefilled pens to minimize the risk of dosing errors. The dose window shows the number of units of insulin to be delivered, and no conversion is needed. (See "General principles of insulin therapy in diabetes mellitus", section on 'Rapidly acting insulin analogs'.)

Insulin-associated weight gain — Patients initiating insulin therapy should be aware of the potential for weight gain, and major emphasis should be placed on diet and lifestyle modification to prevent it. It is crucial to educate patients about insulin dose reduction for anticipated increases in physical activity and with changes in diet and alcohol use to reduce the risk of hypoglycemia as well as weight gain.

Patients with type 2 diabetes, insulin resistance, and obesity are susceptible to insulin-associated weight gain. This can be due to continued dietary indiscretion, reduction in glycosuria with improved glycemic management, conscious or subconscious snacking to prevent hypoglycemia on an insulin dose that is too high, overtreatment of hypoglycemia, overly tight glycemic targets, or a combination of these factors. The resulting weight gain worsens insulin resistance and may prompt insulin dose escalation, leading to a vicious cycle.

The magnitude of the weight gain depends upon the intensity of regimen (dose and frequency of insulin) and the dietary pattern [72]. In the United Kingdom Prospective Diabetes Study (UKPDS), the average weight gain after 10 years of insulin therapy was approximately 7 kg for patients with type 2 diabetes, with the most rapid weight gain occurring when insulin was first initiated [73]. Less intensive therapy with either insulin or a sulfonylurea (which increases endogenous insulin secretion) was associated with a 3.5 to 4.8 kg weight gain at three years versus no change with metformin monotherapy [54].

Weight gain with basal insulin alone generally appears modest. As examples:

In the GRADE trial, patients who were randomly assigned to insulin glargine aiming to maintain A1C <7 percent exhibited weight stability over a mean follow-up of five years (mean 0.61 kg body weight loss) [20]. Notably, however, individual responses to therapy differ, as 13.1 percent of glargine-treated patients experienced body weight gain ≥10 percent.

In another trial, weight gain was greater with prandial than basal insulin (4.8 versus 3.1 kg) [8]; patients receiving prandial insulin also received a higher insulin dose, which could account for the small difference in weight gain. In other trials, premixed rapid-acting preparations (containing prandial insulin) were more often associated with weight gain than long-acting insulin or oral agents [49].

Available data suggest that the benefits of insulin therapy for glucose lowering outweigh the adverse effects conferred by modest weight gain. Microvascular complications were reduced with insulin monotherapy in the UKPDS despite weight gain [73]. In type 1 diabetes, intensive insulin therapy in Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) resulted in major reductions in microvascular complications and cardiovascular disease (CVD) despite weight gain [74]. A subsequent analysis of the DCCT data, however, revealed that the CVD benefit of intensive therapy was attenuated by weight gain beginning after approximately 14 years of intensive therapy [75]. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Diabetes education'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults" and "Society guideline links: Diabetes mellitus in children" and "Society guideline links: Blood glucose monitoring".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Using insulin (The Basics)")

Beyond the Basics topics (see "Patient education: Type 2 diabetes: Insulin treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Indications for insulin

Severe hyperglycemia on presentation or difficulty distinguishing type of diabetes – Insulin is indicated as initial treatment for some patients with type 2 diabetes, depending on the severity of the baseline metabolic disturbance (eg, insulin is always indicated for patients presenting with symptomatic [eg, weight loss] or severe hyperglycemia with ketonuria, or in patients in whom it is difficult to distinguish type 1 from type 2 diabetes). (See 'Initial treatment' above.)

Persistent hyperglycemia on oral therapy – After a successful initial response to oral therapy, most patients have worsening glycemia over time (figure 2) and require additional therapy (add a second oral or injectable agent, including insulin, or switch to insulin). For many patients, we prefer insulin or a glucagon-like peptide 1 (GLP-1) receptor agonist (if the patient is not catabolic) for a second-line medication. Insulin is always effective and is preferred in insulin-deficient, catabolic diabetes (eg, polyuria, polydipsia, weight loss). (See 'Persistent hyperglycemia on oral agents' above and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'.)

Initial basal insulin – For patients who are initiating insulin (in addition to oral agents, in place of oral agents, or as initial treatment), we suggest initiating basal, rather than prandial, insulin (Grade 2B). This is predominantly due to a lower risk of hypoglycemia and greater convenience and simplicity for patients who are using insulin for the first time (algorithm 1). (See 'Insulin initiation' above.) (Related Pathway(s): Diabetes: Initiation and titration of insulin therapy in non-pregnant adults with type 2 DM.)

Choice of basal insulin – Either insulin neutral protamine Hagedorn (NPH) or detemir given at bedtime or insulin glargine or degludec given in the morning or at bedtime is a reasonable initial regimen (table 1). (See 'Choice of basal insulin' above.)

Initial dose and adjustment of basal insulin – The initial dose for NPH, detemir, glargine, or degludec is 0.2 units per kg (minimum 10 units) subcutaneously daily. Subsequent modifications can be made according to fasting glucose and A1C values, until the fasting glucose is in the target range (80 to 130 mg/dL [3.9 to 7.2 mmol/L] in young patients and with higher fasting glucose targets for older patients and those at risk of hypoglycemia) (algorithm 1). (See 'Initial dose' above.) (Related Pathway(s): Diabetes: Initiation and titration of insulin therapy in non-pregnant adults with type 2 DM.)

Persistent elevation in A1C with fasting glucose in target range – Among patients who are taking insulin and have A1C values above the desired target with fasting glucose levels in the target range, dietary and exercise patterns should be reviewed. We advise the patient to check fingerstick capillary glucose levels fasting, pre-lunch, pre-dinner, and before bed while the regimen is being adjusted. Prandial insulin is often started as a single injection before the largest meal of the day, but many strategies are possible (algorithm 1). (See 'Titrating dose' above.) (Related Pathway(s): Diabetes: Initiation and titration of insulin therapy in non-pregnant adults with type 2 DM.)

Combining basal and prandial insulin – For patients with type 2 diabetes who require prandial insulin, either short- (regular) or rapid-acting insulin can be given. The ability to inject the rapid-acting insulins 10 to 15 minutes before meals (as opposed to the 30 to 45 minutes before the meal recommended for short-acting insulins) may provide improved convenience for patients. In this setting of multiple daily insulin injections, oral agents other than metformin are usually discontinued to reduce polypharmacy and cost. Oral or injectable GLP-1 receptor agonists may also be continued. (See 'Combining prandial and basal insulin' above.)

Premixed insulin – For patients with type 2 diabetes who require prandial insulin, we suggest not using premixed insulin initially (Grade 2B). The goal is to adjust the dose of short-acting or rapid-acting insulin immediately prior to a meal, and therefore, we prefer to keep basal and pre-meal insulin injections separate and adjust them independently. However, premixed insulin is a reasonable option for patients with type 2 diabetes who are doing well on a stable, fixed ratio, especially if the meal pattern matches the kinetics of the premixed insulin (eg, large breakfast and dinner with small or low-carbohydrate lunch). (See 'Combining prandial and basal insulin' above and "General principles of insulin therapy in diabetes mellitus", section on 'Pre-mixed insulins'.)

Troubleshooting – Monitoring for complications of insulin (including hypoglycemia and weight gain) and identifying and addressing the triggers, if present (missed meals, alcohol, and unanticipated exercise for the former and dietary indiscretion and obligate snacking for the latter) should be performed at every visit to permit insulin regimen adjustment. Provide patient education at every visit to minimize these adverse effects of insulin therapy. (See 'Troubleshooting' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to an earlier version of this topic review.

  1. Polonsky KS, Given BD, Van Cauter E. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest 1988; 81:442.
  2. Wei N, Zheng H, Nathan DM. Empirically establishing blood glucose targets to achieve HbA1c goals. Diabetes Care 2014; 37:1048.
  3. American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2021. Diabetes Care 2021; 44:S73.
  4. ORIGIN Trial Investigators, Gerstein HC, Bosch J, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012; 367:319.
  5. GRADE Study Research Group, Nathan DM, Lachin JM, et al. Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes. N Engl J Med 2022; 387:1075.
  6. Green JB, Bethel MA, Armstrong PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2015; 373:232.
  7. Marso SP, McGuire DK, Zinman B, et al. Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes. N Engl J Med 2017; 377:723.
  8. Raz I, Wilson PW, Strojek K, et al. Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial. Diabetes Care 2009; 32:381.
  9. Wallia A, Molitch ME. Insulin therapy for type 2 diabetes mellitus. JAMA 2014; 311:2315.
  10. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2021. Diabetes Care 2021; 44:S111.
  11. Thomas NJ, Jones SE, Weedon MN, et al. Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank. Lancet Diabetes Endocrinol 2018; 6:122.
  12. Umpierrez GE, Casals MM, Gebhart SP, et al. Diabetic ketoacidosis in obese African-Americans. Diabetes 1995; 44:790.
  13. Maruyama T, Tanaka S, Shimada A, et al. Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus. J Clin Endocrinol Metab 2008; 93:2115.
  14. Brophy S, Davies H, Mannan S, et al. Interventions for latent autoimmune diabetes (LADA) in adults. Cochrane Database Syst Rev 2011; :CD006165.
  15. Ryan EA, Imes S, Wallace C. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care 2004; 27:1028.
  16. Ilkova H, Glaser B, Tunçkale A, et al. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Care 1997; 20:1353.
  17. Li Y, Xu W, Liao Z, et al. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of beta-cell function. Diabetes Care 2004; 27:2597.
  18. Garvey WT, Olefsky JM, Griffin J, et al. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes 1985; 34:222.
  19. Weng J, Li Y, Xu W, et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet 2008; 371:1753.
  20. GRADE Study Research Group, Nathan DM, Lachin JM, et al. Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes. N Engl J Med 2022; 387:1063.
  21. Berard L, Bonnemaire M, Mical M, Edelman S. Insights into optimal basal insulin titration in type 2 diabetes: Results of a quantitative survey. Diabetes Obes Metab 2018; 20:301.
  22. Cusi K, Cunningham GR, Comstock JP. Safety and efficacy of normalizing fasting glucose with bedtime NPH insulin alone in NIDDM. Diabetes Care 1995; 18:843.
  23. Bretzel RG, Nuber U, Landgraf W, et al. Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial. Lancet 2008; 371:1073.
  24. Holman RR, Farmer AJ, Davies MJ, et al. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med 2009; 361:1736.
  25. Madenidou AV, Paschos P, Karagiannis T, et al. Comparative Benefits and Harms of Basal Insulin Analogues for Type 2 Diabetes: A Systematic Review and Network Meta-analysis. Ann Intern Med 2018; 169:165.
  26. Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues versus NPH human insulin in type 2 diabetes: a meta-analysis. Diabetes Res Clin Pract 2008; 81:184.
  27. Rosenstock J, Dailey G, Massi-Benedetti M, et al. Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care 2005; 28:950.
  28. Horvath K, Jeitler K, Berghold A, et al. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007; :CD005613.
  29. Singh SR, Ahmad F, Lal A, et al. Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis. CMAJ 2009; 180:385.
  30. Owens DR, Traylor L, Mullins P, Landgraf W. Patient-level meta-analysis of efficacy and hypoglycaemia in people with type 2 diabetes initiating insulin glargine 100U/mL or neutral protamine Hagedorn insulin analysed according to concomitant oral antidiabetes therapy. Diabetes Res Clin Pract 2017; 124:57.
  31. Porcellati F, Lin J, Lucidi P, et al. Impact of patient and treatment characteristics on glycemic control and hypoglycemia in patients with type 2 diabetes initiated to insulin glargine or NPH: A post hoc, pooled, patient-level analysis of 6 randomized controlled trials. Medicine (Baltimore) 2017; 96:e6022.
  32. Lipska KJ, Parker MM, Moffet HH, et al. Association of Initiation of Basal Insulin Analogs vs Neutral Protamine Hagedorn Insulin With Hypoglycemia-Related Emergency Department Visits or Hospital Admissions and With Glycemic Control in Patients With Type 2 Diabetes. JAMA 2018; 320:53.
  33. Zinman B, Philis-Tsimikas A, Cariou B, et al. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long). Diabetes Care 2012; 35:2464.
  34. Garber AJ, King AB, Del Prato S, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet 2012; 379:1498.
  35. Hollander P, King AB, Del Prato S, et al. Insulin degludec improves long-term glycaemic control similarly to insulin glargine but with fewer hypoglycaemic episodes in patients with advanced type 2 diabetes on basal-bolus insulin therapy. Diabetes Obes Metab 2015; 17:202.
  36. Ratner RE, Gough SC, Mathieu C, et al. Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials. Diabetes Obes Metab 2013; 15:175.
  37. Vora J, Christensen T, Rana A, Bain SC. Insulin degludec versus insulin glargine in type 1 and type 2 diabetes mellitus: a meta-analysis of endpoints in phase 3a trials. Diabetes Ther 2014; 5:435.
  38. Wysham C, Bhargava A, Chaykin L, et al. Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial. JAMA 2017; 318:45.
  39. Torjesen I. FDA raises concerns about ultra-long acting insulins given green light in Europe and Japan. BMJ 2012; 345:e7323.
  40. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2006; 29:1963.
  41. Taylor R, Davies R, Fox C, et al. Appropriate insulin regimes for type 2 diabetes: a multicenter randomized crossover study. Diabetes Care 2000; 23:1612.
  42. Hemmingsen B, Christensen LL, Wetterslev J, et al. Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses. BMJ 2012; 344:e1771.
  43. Davies MJ, D'Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018; 41:2669.
  44. Rosenstock J, Davies M, Home PD, et al. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 2008; 51:408.
  45. Rosenstock J, Schwartz SL, Clark CM Jr, et al. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care 2001; 24:631.
  46. Mannucci E, Monami M, Marchionni N. Short-acting insulin analogues vs. regular human insulin in type 2 diabetes: a meta-analysis. Diabetes Obes Metab 2009; 11:53.
  47. Fullerton B, Siebenhofer A, Jeitler K, et al. Short-acting insulin analogues versus regular human insulin for adult, non-pregnant persons with type 2 diabetes mellitus. Cochrane Database Syst Rev 2018; 12:CD013228.
  48. Bergenstal RM, Johnson M, Powers MA, et al. Adjust to target in type 2 diabetes: comparison of a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine. Diabetes Care 2008; 31:1305.
  49. Qayyum R, Bolen S, Maruthur N, et al. Systematic review: comparative effectiveness and safety of premixed insulin analogues in type 2 diabetes. Ann Intern Med 2008; 149:549.
  50. Reznik Y, Cohen O, Aronson R, et al. Insulin pump treatment compared with multiple daily injections for treatment of type 2 diabetes (OpT2mise): a randomised open-label controlled trial. Lancet 2014; 384:1265.
  51. Meade LT, Battise D. Evaluation of Clinical Outcomes With the V-Go Wearable Insulin Delivery Device in Patients With Type 2 Diabetes. Clin Diabetes 2021; 39:297.
  52. Grunberger G, Rosenfeld CR, Bode BW, et al. Effectiveness of V-Go® for Patients with Type 2 Diabetes in a Real-World Setting: A Prospective Observational Study. Drugs Real World Outcomes 2020; 7:31.
  53. Bergenstal RM, Johnson ML, Aroda VR, et al. Comparing Patch vs Pen Bolus Insulin Delivery in Type 2 Diabetes Using Continuous Glucose Monitoring Metrics and Profiles. J Diabetes Sci Technol 2022; 16:1167.
  54. United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ 1995; 310:83.
  55. Henry RR, Gumbiner B, Ditzler T, et al. Intensive conventional insulin therapy for type II diabetes. Metabolic effects during a 6-mo outpatient trial. Diabetes Care 1993; 16:21.
  56. Bailey TS, Stone JY. A novel pen-based Bluetooth-enabled insulin delivery system with insulin dose tracking and advice. Expert Opin Drug Deliv 2017; 14:697.
  57. Bergenstal RM, Johnson M, Passi R, et al. Automated insulin dosing guidance to optimise insulin management in patients with type 2 diabetes: a multicentre, randomised controlled trial. Lancet 2019; 393:1138.
  58. Donnelly LA, Morris AD, Frier BM, et al. Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study. Diabet Med 2005; 22:749.
  59. Munshi MN, Slyne C, Segal AR, et al. Simplification of Insulin Regimen in Older Adults and Risk of Hypoglycemia. JAMA Intern Med 2016; 176:1023.
  60. Cochran E, Musso C, Gorden P. The use of U-500 in patients with extreme insulin resistance. Diabetes Care 2005; 28:1240.
  61. Davidson MB, Navar MD, Echeverry D, Duran P. U-500 regular insulin: clinical experience and pharmacokinetics in obese, severely insulin-resistant type 2 diabetic patients. Diabetes Care 2010; 33:281.
  62. Ballani P, Tran MT, Navar MD, Davidson MB. Clinical experience with U-500 regular insulin in obese, markedly insulin-resistant type 2 diabetic patients. Diabetes Care 2006; 29:2504.
  63. Shrestha RT, Kumar AF, Taddese A, et al. Duration and onset of action of high dose U-500 regular insulin in severely insulin resistant subjects with type 2 diabetes. Endocrinol Diabetes Metab 2018; 1:e00041.
  64. Ma X, Benson CT, Prescilla R, et al. Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin Administered via Continuous Subcutaneous Insulin Infusion Versus Subcutaneous Injection in Adults With Type 2 Diabetes and High-Dose Insulin Requirements. J Diabetes Sci Technol 2022; 16:401.
  65. de la Peña A, Riddle M, Morrow LA, et al. Pharmacokinetics and pharmacodynamics of high-dose human regular U-500 insulin versus human regular U-100 insulin in healthy obese subjects. Diabetes Care 2011; 34:2496.
  66. Granata JA, Nawarskas AD, Resch ND, Vigil JM. Evaluating the effect of u-500 insulin therapy on glycemic control in veterans with type 2 diabetes. Clin Diabetes 2015; 33:14.
  67. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018780s135s152lbl.pdf (Accessed on February 23, 2016).
  68. FDA approves a dedicated syringe to be used with Humulin R U-500 insulin. US Food and Drug Administration. https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-dedicated-syringe-be-used-humulin-r-u-500-insulin (Accessed on August 02, 2022).
  69. Bergen PM, Kruger DF, Taylor AD, et al. Translating U-500R Randomized Clinical Trial Evidence to the Practice Setting: A Diabetes Educator/Expert Prescriber Team Approach. Diabetes Educ 2017; 43:311.
  70. Hood RC, Arakaki RF, Wysham C, et al. TWO TREATMENT APPROACHES FOR HUMAN REGULAR U-500 INSULIN IN PATIENTS WITH TYPE 2 DIABETES NOT ACHIEVING ADEQUATE GLYCEMIC CONTROL ON HIGH-DOSE U-100 INSULIN THERAPY WITH OR WITHOUT ORAL AGENTS: A RANDOMIZED, TITRATION-TO-TARGET CLINICAL TRIAL. Endocr Pract 2015; 21:782.
  71. Rosenstock J, Cheng A, Ritzel R, et al. More Similarities Than Differences Testing Insulin Glargine 300 Units/mL Versus Insulin Degludec 100 Units/mL in Insulin-Naive Type 2 Diabetes: The Randomized Head-to-Head BRIGHT Trial. Diabetes Care 2018; 41:2147.
  72. Pontiroli AE, Miele L, Morabito A. Increase of body weight during the first year of intensive insulin treatment in type 2 diabetes: systematic review and meta-analysis. Diabetes Obes Metab 2011; 13:1008.
  73. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837.
  74. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353:2643.
  75. Purnell JQ, Braffett BH, Zinman B, et al. Impact of Excessive Weight Gain on Cardiovascular Outcomes in Type 1 Diabetes: Results From the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study. Diabetes Care 2017; 40:1756.
Topic 1801 Version 49.0

References