Version July 2025
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 with increasing body weight, particularly with the accumulation of metabolically adverse adipose tissue (eg, central obesity, which is associated with visceral adiposity).
Management of patients with type 2 diabetes mellitus includes providing diabetes education, monitoring for microvascular and macrovascular complications, achieving target glycemia, treating cardiovascular risk factors, and avoiding drugs that adversely affect glucose or lipid metabolism. Initial glycemic management typically includes oral medication and behavioral intervention, but most patients with type 2 diabetes will require additional pharmacotherapy over time. In such patients, therapeutic options include adding an oral or injectable (glucagon-like peptide 1 [GLP-1]-based therapy or insulin) agent or switching to insulin monotherapy.
This topic will review the use of insulin therapy in nonpregnant patients with type 2 diabetes. The approach to initial pharmacotherapy and the management of persistent hyperglycemia are discussed separately, as are other therapeutic issues in diabetes management. Insulin therapy in pregnant individuals 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".)
GENERAL PRINCIPLES —
Endogenous insulin is secreted in a pulsatile manner; pulses occur under basal (unstimulated) conditions and in response to meals [1].
In type 2 diabetes, endogenous insulin secretion is insufficient to fully compensate for insulin resistance. In this setting, insulin therapy can supplement endogenous insulin secretion. The following strategies for insulin therapy are commonly used:
●Basal insulin – Basal insulin suppresses hepatic glucose production and maintains target glucose levels in the fasting state. Basal insulins may be intermediate-acting (neutral protamine Hagedorn [NPH], detemir [no longer available in the United States after April 2024]), long-acting (glargine), or ultralong-acting (degludec).
●Prandial (pre-meal) insulin – Short-acting (regular) or rapid-acting (lispro, aspart, glulisine) insulins maintain target glucose levels in the postprandial state.
●Premixed preparations – Premixed combinations of intermediate-acting and short- or rapid-acting insulins provide both basal and prandial insulin and may help reduce the frequency of injections.
For any insulin preparation, the onset and duration of insulin action show substantial intra-individual and inter-individual variability that is influenced by the volume injected, injection site, injection technique, and multiple other factors. The expected pharmacokinetics of the most commonly used insulins are presented in the table (table 1) and in more detail elsewhere. (See "General principles of insulin therapy in diabetes mellitus", section on 'Insulin preparations'.)
The term "intensive insulin therapy" has been used to describe complex regimens that include both basal insulin and multiple pre-meal injections of prandial insulin. Intensive regimens are commonly used in type 1 diabetes. They also may be used for patients with type 2 diabetes, especially for patients who require high doses of insulin and for those with more profound insulin deficiency.
INDICATIONS FOR INSULIN
Initial treatment — For most individuals with type 2 diabetes, metformin is used as initial pharmacotherapy in the absence of contraindications. However, some patients are candidates for initial therapy with insulin. (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:
Difficulty distinguishing type of diabetes — Insulin is indicated for initial treatment when the type of diabetes (eg, type 1 versus type 2) is unclear. Age of onset alone cannot distinguish between type 1 and type 2 diabetes. Although the peak incidence of type 1 diabetes occurs around the time of puberty, approximately 40 percent of cases present after 30 years of age [2,3].
Irrespective of age, the following clinical features suggest underlying type 1 diabetes:
●Marked and otherwise unexplained recent weight loss.
●Rapid evolution of severe hyperglycemia accompanied by polyuria and polydipsia.
●The presence of moderate or greater ketonuria. Diabetic ketoacidosis at first presentation suggests underlying type 1 diabetes and the need for lifelong insulin treatment, although exceptions exist [4]. These exceptions include other syndromes of ketosis-prone diabetes, which often present with a milder degree of diabetic ketoacidosis and may not require long-term insulin therapy. (See "Syndromes of ketosis-prone diabetes mellitus".)
●A personal or family history of autoimmune disease, particularly without family history of type 2 diabetes.
●Absence of overweight or obesity.
In individuals who present with any of these features, insulin therapy should be continued until the type of diabetes is established. The approach to classifying diabetes is reviewed in detail separately. (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'.)
Severe hyperglycemia — In individuals with type 2 diabetes, insulin may be indicated as initial therapy if the metabolic disturbance is severe [5,6]. Severe hyperglycemia (fasting glucose >250 mg/dL [13.9 mmol/L], random glucose consistently >300 mg/dL [16.7 mmol/L], and/or glycated hemoglobin (A1C) >9 percent [74.9 mmol/mol]) with ketonuria or weight loss indicates insulin deficiency and always requires insulin therapy initially.
For patients presenting with severe hyperglycemia in the absence of ketonuria or weight loss, options for initial therapy include insulin or a glucagon-like peptide 1 (GLP-1)-based therapy. Either is usually initiated with metformin, if no contraindications to metformin are present. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Symptomatic (catabolic) or severe hyperglycemia'.)
Pancreatic insufficiency — Insulin is also indicated for patients with secondary diabetes due to pancreatic insufficiency that can result from cystic fibrosis, chronic pancreatitis, or pancreatectomy. (See "Cystic fibrosis-related diabetes mellitus", section on 'Insulin therapy' and "Chronic pancreatitis: Management", section on 'Endocrine insufficiency (pancreatogenic diabetes)'.)
Remission induction (not widely used) — In individuals with type 2 diabetes, initial intensive insulin treatment for a brief period (two to four weeks) may induce remission for a year or longer [7-9]. Achieving near-normoglycemia with intensive insulin therapy improves both endogenous insulin secretion and insulin sensitivity [7,9-11]. Insulin secretion improves presumably because the deleterious effects of hyperglycemia on beta cell secretory function are mitigated. In some patients, glycemic targets achieved initially with intensive insulin regimens can be maintained subsequently with diet and exercise alone for months or even years [9]. Nonetheless, such regimens are not widely used at diagnosis, likely due to treatment complexity, limited duration of remissions, and patient and/or provider reluctance.
The possibility of diabetes remission was illustrated in a trial that compared short-term (two to five weeks) intensive insulin therapy (insulin pump or multiple daily injections [MDI]) with 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]) [12]. Therapy was discontinued two weeks after achieving the glycemic target (fasting glucose <110 mg/dL [6.1 mmol/L]). Participants continued diet and exercise alone and were closely followed for recurrent hyperglycemia. Remission rates after one year were higher with insulin than with oral agents (51, 45, and 27 percent with insulin pump, MDI, and oral agents, respectively). Patients in remission at one year had lower initial glycemia and achieved glycemic goals more quickly than those with recurrent hyperglycemia.
Persistent hyperglycemia on oral agents — Oral agents become less effective as beta cell function declines (figure 1 and figure 2). The therapeutic options for patients with persistent hyperglycemia are to add a second oral or injectable agent (including insulin), or to switch to insulin monotherapy. For many patients, we prefer insulin or a GLP-1-based agent for a second-line medication. Insulin is always effective and is preferred in catabolic diabetes (polyuria, polydipsia, weight loss). The approach for selecting a second medication, particularly in the presence of cardiovascular or kidney comorbidities, is reviewed in detail separately. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'.)
The GRADE trial showed that adding basal insulin to metformin lowers glucose more durably over five years than a sulfonylurea or dipeptidyl peptidase 4 (DPP-4) inhibitor, with relatively few adverse effects [13]. Insulin also had the lowest rate of participant-requested discontinuation (ie, not protocol-mandated discontinuation; approximately 14 percent in the glargine group, 23 percent in the glimepiride and liraglutide groups, and 19 percent in the sitagliptin group).
DESIGNING AN INSULIN REGIMEN —
For clinicians who prescribe insulin infrequently, one strategy is to gain familiarity with a limited number of regimens and use them consistently. With adequate titration, insulin regimens vary only modestly in glycemic effectiveness. An overriding goal of insulin therapy in type 2 diabetes is to balance A1C lowering with adverse events including hypoglycemia or body weight gain, which should be minimized by reducing or adjusting the dose as needed for different settings or behaviors (eg, exercise, fasting). Few studies have assessed the impact of different insulin regimens on micro- or macrovascular complications or mortality.
Initial insulin regimen (basal insulin usually preferred) — For most patients initiating insulin therapy, we suggest basal, rather than prandial, insulin. Basal insulin improves nocturnal and fasting glucose levels [14], thereby facilitating endogenous prandial insulin secretion. While prandial (pre-meal) bolus insulin treatment decreases postprandial glucose excursions, it also suppresses endogenous insulin secretion. Whether basal and prandial insulin regimens differentially affect microvascular complications is uncertain. The type of insulin regimen does not appear to affect cardiovascular outcomes. (See 'Cardiovascular safety' below.)
Basal insulin therapy provides greater convenience and simplicity. When adequately titrated to achieve glycemic goals, basal and prandial insulin are similarly effective for A1C lowering, but basal insulin is associated with greater patient satisfaction and less frequent hypoglycemia [15-17]. However, basal insulin is often suboptimally titrated in clinical practice [18].
For example, 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, reductions in A1C were similar with basal and prandial insulin (mean decrease of 1.7 and 1.9 percent, respectively) [15]. Basal insulin led to greater patient satisfaction and less hypoglycemia (5.2 versus 24 events per patient per year with basal versus prandial insulin).
Choice of basal insulin — Initial basal insulin regimens may include 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 (table 1). In practice, payer coverage often influences regimen selection. (See "General principles of insulin therapy in diabetes mellitus", section on 'Insulin preparations'.)
●NPH versus insulin analogs – In usual practice with standard glycemic targets, the basal insulin preparations do not differ significantly in glycemic efficacy [19,20]. Among basal insulin preparations, insulins glargine, detemir, and degludec may cause less nocturnal hypoglycemia (but not always total hypoglycemia) compared with NPH, with the disadvantage of higher cost. As examples:
•In meta-analyses of trials comparing once-daily glargine or detemir with once- or twice-daily NPH, A1C similarly improved with all types of basal insulin [20-23]. However, in some meta-analyses, the rates of overall symptomatic and nocturnal hypoglycemia were lower with either insulin glargine or detemir compared with NPH [20-22,24-26].
•In a retrospective observational study using data from a large health care delivery system (>25,000 patients initiating basal insulin), insulin analogs were not associated with reduced emergency department or hospital admissions for hypoglycemia compared with NPH (11.9 versus 8.8 events per 1000 person-years, respectively), and glycemia was comparable with both preparations [27].
Thus, the data for differential hypoglycemia risk are somewhat inconsistent, but if individuals develop nocturnal hypoglycemia during NPH treatment, switching to another basal insulin preparation is reasonable. (See 'Hypoglycemia' below.)
●Insulin glargine versus insulin degludec – Insulin degludec and insulin glargine appear to have similar glycemic efficacy. In some trials, degludec conferred a lower rate of hypoglycemia, especially with use of more stringent glycemic targets (eg, fasting glucose 71 to 90 mg/dL [3.9 to 5 mmol/L]) [28-33]. As examples:
•In a 65-week 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 once-daily degludec or glargine for 32 weeks, followed by the alternate insulin treatment for 32 weeks [34]. Degludec led to a lower 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 (rate ratios 0.70, 95% CI 0.61-0.80 and 0.58, 95% CI 0.46-0.74, respectively). Groups did not differ significantly in severe hypoglycemia (nonsignificant reduction of 0.62 episodes per 100 patient-years with degludec) or A1C (7 to 7.1 percent).
•In a trial in 7637 patients with type 2 diabetes (mean A1C 8.4 percent) that compared treatment with degludec or glargine, rates of severe and nocturnal hypoglycemia were lower with degludec (eg, severe hypoglycemia in 4.9 versus 6.6 percent of participants over two years with degludec and glargine, respectively) [28].
●Once-weekly basal insulin (limited availability) – Once-weekly basal insulin formulations have been developed but have limited commercial availability [35-39]. For example, in a trial in 588 adults with type 2 diabetes (mean A1C approximately 8.6 percent) who had not previously used insulin therapy, participants were randomly assigned to treatment with once-weekly insulin icodec or daily insulin degludec [35]. After 26 weeks, icodec treatment led to slightly greater A1C reduction (7.0 versus 7.2 percent, estimated treatment difference -0.2 percentage points, 95% CI -0.3 to -0.1). The combined rate of level 2 or level 3 hypoglycemia was numerically higher with icodec than with degludec. Both treatments conferred modest body weight gain that did not differ between groups (mean change +2.8 kg with icodec versus +2.3 kg with degludec). In a separate trial in 582 adults with longstanding type 2 diabetes (mean duration 17.1 years) on multiple daily injection (MDI) insulin therapy, weekly insulin icodec and daily insulin glargine U-100 conferred comparable reductions in A1C with similar rates of hypoglycemia [40]. Insulin icodec has regulatory approval in Canada.
Initial dose — For patients with type 2 diabetes, the initial dose of insulin is similar whether insulin is used as initial therapy or added to an existing glucose-lowering regimen [22,41,42]. Many algorithms have been published; one simple and conservative algorithm is presented here (algorithm 1).
We start NPH or detemir at bedtime (eg, 10:00 PM if fasting glucose is measured at 7:00 or 8:00 AM). Glargine or degludec can be initiated at bedtime or morning; the choice of timing is based on patient preference to facilitate adherence.
The initial dose for any basal insulin is 0.2 units per kg daily (minimum 10 units, up to 15 to 20 units). If fasting glucose levels are very elevated (>250 mg/dL [13.9 mmol/L]), A1C is >8 percent, or insulin resistance is severe, initial doses of basal insulin in type 2 diabetes can be higher (eg, 0.3 units per kg or up to 20 units daily). Subsequent dose titration is based on daily fasting glucose measurements and monitoring of A1C. (See 'Monitoring and dose titration' below.)
Combination therapy versus insulin monotherapy — Combined therapy with insulin and other glucose-lowering medications may achieve glucose targets while minimizing total insulin requirements and weight gain [43]. The benefits of continuing non-insulin therapy should be weighed against the risks of polypharmacy and cost.
●Combination therapy – Metformin is usually continued with insulin therapy. Glucagon-like peptide 1 (GLP-1)-based therapies and sodium-glucose cotransporter 2 (SGLT2) inhibitors also can be continued, especially if used for cardiac, body weight loss, and/or kidney benefit. Dipeptidyl peptidase 4 (DPP-4) inhibitors may be stopped when prandial insulin is initiated but may be helpful for managing postprandial glucose when combined with basal insulin; in most cases, we favor discontinuing these agents. Sulfonylureas, meglitinides, and pioglitazone are usually tapered and stopped when starting insulin, particularly prandial insulin, due to reduced relative efficacy and adverse effects [44]. However, pioglitazone may be combined with insulin in individuals with severe insulin resistance (eg, lipodystrophy). (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Insulin initiation and intensification' and "Lipodystrophy syndromes: Management", section on 'Diabetes mellitus'.)
●Insulin monotherapy – Insulin monotherapy may be less expensive than combined therapy depending on the regimen but may result in more weight gain and hypoglycemia [43]. Background therapy may be discontinued once insulin is added or tapered during insulin titration. The former approach may cause transient hyperglycemia during insulin dose titration. (See "Interactive diabetes case 2: Switching from oral agents to insulin in type 2 diabetes".)
Patient counseling and safety — Patients are usually not eager to start insulin. Reasons for patient reluctance should be explored and addressed (table 2). Evidence of sustained effectiveness over time and high rates of adherence compared with alternative agents may be useful to share with patients as part of shared decision-making [13]. 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. Other patients may have concerns about insulin-related problems associated with older preparations (eg, higher risk of hypoglycemia) or complications suffered by family members. It is important to assess and address these and other concerns.
The major drawbacks of insulin therapy in type 2 diabetes are hypoglycemia and body weight gain, although data suggest that these are not common or severe with use of basal insulin alone [13]. Nonetheless, patients may express concerns about these adverse effects, which should be addressed at insulin initiation and reviewed at every visit thereafter. Glycemic targets may need to be relaxed to reduce the risk of hypoglycemia and/or insulin-associated weight gain. (See 'Troubleshooting' below.)
Patients also may have concerns about the cardiovascular safety of insulin, reviewed below. Data regarding risk of diabetes-related complications and cancer are reviewed in detail elsewhere. (See 'Cardiovascular safety' below and "General principles of insulin therapy in diabetes mellitus", section on 'Safety'.)
Hypoglycemia — Patients must be counseled about the risk of hypoglycemia with insulin therapy and strategies for risk mitigation in the setting of exercise, dietary change, and alcohol use. Patients also should be counseled about strategies for reversing hypoglycemia. (See "Hypoglycemia in adults with diabetes mellitus", section on 'Strategies to manage hypoglycemia' and "Hypoglycemia in adults with diabetes mellitus", section on 'Reversing hypoglycemia'.)
Risk of hypoglycemia with basal insulin alone appears relatively low. In the GRADE trial, the rate of severe hypoglycemia was lower with insulin glargine (1.3 percent) than with sulfonylurea treatment (2.2 percent) over five years [13]. In a prior trial that compared insulin degludec with insulin glargine, the rate of severe hypoglycemia was higher (6.6 percent over two years with insulin glargine), but this trial had tighter glucose targets and a higher baseline prevalence of chronic kidney disease [28].
Body weight gain — Patients with type 2 diabetes, insulin resistance, and obesity are particularly susceptible to insulin-associated weight gain, particularly if high-dose insulin is required. Patients should be aware of this risk and counseled on diet and lifestyle modifications to achieve body weight maintenance or weight loss. Body weight gain worsens insulin resistance and may prompt insulin dose escalation, leading to a vicious cycle. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Diabetes education'.)
●Causes of weight gain – Weight gain may be due to one or more of the following factors:
•Dietary indiscretion
•Reduction in glycosuria with improved glycemic management (a common cause of early weight gain after insulin initiation)
•Snacking to prevent insulin-induced hypoglycemia
•Overtreatment of hypoglycemia
•Overly stringent glycemic targets
At each visit, we ask patients about the frequency and severity of hypoglycemia, approach to correcting hypoglycemia, and overall dietary patterns.
●Magnitude of weight gain – The magnitude of weight gain depends on both the intensity of the insulin regimen and diet [45]. 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 early after insulin initiation [46]. Less intensive therapy with either insulin or a sulfonylurea was associated with a 3.5 to 4.8 kg weight gain at three years versus no change with metformin monotherapy [47].
Weight gain with basal insulin alone generally appears modest. As examples:
•In the GRADE trial, patients who were randomly assigned to insulin glargine titrated to maintain A1C <7 percent exhibited weight stability over a mean follow-up of five years (mean 0.61 kg body weight loss) [13]. 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 with basal insulin (4.8 versus 3.1 kg, respectively) over approximately 2.5 years [17]. Patients taking prandial insulin used a higher total insulin dose, which could account for this difference. In other trials, premixed rapid-acting preparations (containing prandial insulin) led to weight gain more often than long-acting insulin or oral agents [48].
●Impact of insulin-associated weight gain on diabetes complications – 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 [46]. In type 1 diabetes, intensive insulin therapy in Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) reduced microvascular complications and cardiovascular disease (CVD) despite weight gain [49]. 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 [50].
Cardiovascular safety
●Addition of basal insulin – In populations at relatively high risk for CVD, the addition of basal insulin glargine does not appear to impact cardiovascular outcomes compared with older oral agents. The trials below were conducted prior to the availability of newer agents with demonstrated cardiovascular benefit (ie, SGLT2 inhibitors and/or GLP-1 receptor agonists). (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
•Higher cardiovascular risk – In the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, over 12,500 patients with cardiovascular risk factors and type 2 diabetes or prediabetes were randomly assigned to an evening dose of glargine or to standard care [51]. After a median follow-up of six years, 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). In the standard care group, most participants were on one or two glucose-lowering agents at study end, most commonly metformin and/or a sulfonylurea.
•Lower cardiovascular risk – In the GRADE trial, 5047 patients with type 2 diabetes and low CVD prevalence were randomly assigned to one of four glucose-lowering medications added to maximally tolerated metformin [52]. 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 [53]. The liraglutide arm had more favorable cardiovascular outcomes than the other three arms. 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 – The cardiovascular safety of insulins degludec and glargine appears comparable. In a two-year trial, 7637 patients with type 2 diabetes (mean A1C 8.4 percent) with or at high risk for CVD were randomly assigned to degludec or glargine once daily [28]. At baseline, approximately 60 percent of participants were on metformin, 29 percent on a sulfonylurea, and 84 percent on insulin. The primary composite outcome (first occurrence of a death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in 8.5 and 9.3 percent of the patients receiving degludec and glargine, respectively.
•Basal versus prandial insulin – The type of insulin (basal or prandial) similarly does not appear to affect cardiovascular outcomes. The Hyperglycemia and its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus (HEART2D) trial evaluated the effects of prandial (lispro) or basal (NPH twice daily or glargine once daily) insulin on cardiovascular outcomes in 1115 patients after myocardial infarction [17]. At a mean follow-up of 2.7 years, the prandial and basal insulin groups did not differ in the time to a subsequent cardiovascular event (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for an acute coronary syndrome).
MONITORING AND DOSE TITRATION —
For many patients with type 2 diabetes, basal insulin alone is adequate for glycemic management because it reduces glucose toxicity, thereby increasing endogenous insulin secretion sufficiently to mitigate postprandial glucose excursions. However, some patients with type 2 diabetes also may require pre-meal insulin.
Monitoring glycemia — The initial basal insulin regimen is adjusted based on fasting glucose, glycated hemoglobin, and, frequently, bedtime glucose.
●Glycated hemoglobin (A1C) – A1C is the most widely used clinical test to monitor chronic glycemic management. Target A1C levels should be individualized, balancing the reduction in microvascular complications (figure 3) with risk of hypoglycemia and insulin-associated weight gain. A reasonable goal of therapy for most patients is an A1C <7.0 percent (calculator 1). The A1C goal should be set somewhat higher for older patients, patients with chronic kidney disease or other comorbidities, and those with a limited life expectancy. (See "Glycemic management and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target'.)
●Glucose monitoring – In insulin-treated patients, glucose levels are measured through blood glucose monitoring (BGM; with fingerstick and a glucose meter) and/or real-time continuous glucose monitoring (CGM). Glucose monitoring promotes safety and guides dose titration. When basal insulin is initiated, we typically ask patients to measure fasting glucose daily until target fasting glucose values are achieved with a stable insulin dose and without hypoglycemia. (See 'Insulin titration' below.)
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 postprandial (90 to 120 minutes after a meal) glucose values of <180 mg/dL (10 mmol/L) are reasonable targets, but higher achieved levels may suffice [54,55]. In patients with older age, chronic kidney disease, or other risk factors for hypoglycemia, a higher fasting glucose target (eg, 90 or 100 to 150 mg/dL [5 to 8.3 mmol/L]) may be used.
Insulin titration
Persistent fasting hyperglycemia — If fasting glucose is consistently above target (eg, >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) [56].
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 insulin resistance is severe, initial titration can be more aggressive (eg, 5 to 6 units approximately every three days, with reduced increments as the patient approaches glucose targets). Patients should be counseled to reduce the daily insulin dose and notify the treating provider if hypoglycemia develops.
As patients approach the glycemic target, the dosing increment and the frequency of dose adjustments should be decreased. A mid-sleep glucose measurement may be helpful to assess for nocturnal hypoglycemia. This can be done when the patient spontaneously wakes overnight.
In type 2 diabetes, failure to achieve target fasting glucose after basal insulin initiation should prompt review of adherence, injection technique (with teach-back demonstration by the patient), and glucose monitoring at other times of day. If midday or overnight hypoglycemia occurs, or the basal insulin dose is very high (eg, greater than approximately 0.5 units/kg/day), a basal-bolus or twice-daily insulin regimen should be considered as an alternative.
Persistent elevation in A1C with fasting glucose in target range — For patients with persistently elevated A1C but fasting glucose levels in the individualized target range, dietary and exercise patterns should be reviewed. We advise patients to check fingerstick capillary glucose levels fasting, pre-lunch, pre-dinner, and before bed to inform further adjustments to the insulin regimen. If indicated, prandial insulin is often started as a single injection before the largest meal of the day, but many strategies are possible (algorithm 1).
Short-term monitoring with CGM for two weeks may be helpful to guide insulin adjustments and to verify the accuracy of blood glucose monitoring. Long-term (personal) CGM use also is an option for individuals with type 2 diabetes using insulin therapy. Frequency of glucose monitoring may be decreased once the patient is on a stable regimen. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus".)
Pre-lunch glucose elevated — If pre-lunch glucose values are elevated, options include adding prandial insulin before breakfast or adding a glucagon-like peptide 1 (GLP-1)-based agent. For some individuals, dietary modification at breakfast may be sufficient. (See 'Combining prandial and basal insulin' below.)
For patients taking detemir or NPH at bedtime only, an alternative is adding a second dose at breakfast. With detemir, glycemia over a 24-hour period may be more stable with two daily doses (table 1) [57]. Twice-daily NPH offers a simple and inexpensive option that is effective in many patients [42,58]. When switching from once-daily to twice-daily NPH or detemir, one strategy is to give a total daily insulin dose of approximately 80 percent of the current bedtime dose of basal insulin. Approximately 50 to 70 percent of the total daily dose is administered in the morning and 50 to 30 percent at bedtime. We typically use equally divided doses (50/50 percent) for detemir but a higher dose of NPH in the morning than at bedtime (70/30 percent). For patients who are far from glycemic goals (eg, ≥1 percentage point in A1C), the full total daily dose of detemir or NPH can be administered. (See 'Choice of basal insulin' above.)
Pre-dinner or bedtime glucose elevated — If blood glucose values are elevated before dinner and/or bed, we typically add either a GLP-1-based agent or 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. To simplify the regimen, a single injection of prandial insulin may be administered before the larger meal, and patients generally should be counseled to reduce the size of the meal not covered by insulin. Inhaled insulin is uncommonly used as an alternative to injectable prandial insulin and is reviewed separately. (See "Inhaled insulin therapy in diabetes mellitus".)
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. (See 'Pre-lunch glucose elevated' above.)
Combining prandial and basal insulin — For patients with type 2 diabetes who use prandial insulin, we prefer to keep basal and pre-meal insulin injections separate and adjust them independently. Patients may draw up their prandial and NPH insulin in the same syringe prior to injection, whereas glargine, degludec, and detemir cannot be mixed with rapid-acting insulin. The decision whether to continue other glucose-lowering agents during insulin intensification is reviewed above. (See 'Combination therapy versus insulin monotherapy' above.)
●Choice of prandial insulin – The choice of prandial insulin is based upon availability, patient preference, cost, and payer coverage. Rapid-acting insulins are injected 10 to 15 minutes before meals, as opposed to 30 to 45 minutes before meals with regular (short-acting) insulin. This convenience may improve adherence.
In type 2 diabetes, rapid-acting insulins provide little glycemic advantage compared with regular insulin [59,60]. In a meta-analysis of 10 trials (involving 2751 patients with type 2 diabetes) that compared rapid-acting insulin analogs with regular insulin, A1C and the number of hypoglycemic episodes were not significantly different between groups [60].
●Pre-meal insulin dosing – The optimal dose of pre-meal insulin depends upon many factors, including pre-meal 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 the basal insulin dose (algorithm 1). The dose can be adjusted every three days until the postprandial blood glucose target is achieved.
•Dose adjustment for fixed-dose regimens – Prandial insulin dose adjustments depend on the current dose. As a rule of thumb for each current pre-meal dose:
-≤10 units – Adjust in 1-unit increments
-11 to 20 units – Adjust in 2-unit increments
->20 units – Adjust in 5-unit increments (or more, depending on patient insulin resistance and meal size and content)
•Carbohydrate counting – A more complex method for adjusting pre-meal insulin is to match insulin delivery to carbohydrates consumed during a meal. Carbohydrate counting often requires dedicated training and involves arithmetical computations that some patients find burdensome. In patients with type 2 diabetes, whether carbohydrate counting offers glycemic advantage is uncertain. For example, in a 24-week trial in 277 adults with type 2 diabetes, A1C values did not differ when mealtime insulin doses were adjusted with a simple algorithm (based on previous blood glucose values) versus carbohydrate counting with an insulin-to-carbohydrate ratio for each meal [61]. Patient preference therefore can guide the choice of method for pre-meal dosing. In a simplified strategy, patients can take a slightly higher dose of prandial insulin for high carbohydrate meals; this may yield some benefits of carbohydrate counting without the complexity. (See "Medical nutrition therapy for type 2 diabetes mellitus", section on 'Carbohydrate consistency'.)
•Supplemental (correction) insulin – Supplemental insulin may be added to prandial insulin to correct pre-meal hyperglycemia. With this strategy, every prandial insulin dose has two components: one part covers the meal (prandial) and one part corrects the hyperglycemia (supplemental). For people with type 2 diabetes, 1 to 2 units for every 50 mg/dL (2.8 mmol/L) above the target glucose is a reasonable correction factor.
Since such regimens can be confusing, a chart with a "mealtime sliding scale" may be helpful for patients. These charts indicate the appropriate dose of mealtime insulin for any pre-meal glucose level (eg, <100 mg/dL, 100 to 149 mg/dL, 150 to 199 mg/dL), and the indicated doses include both the prandial and supplemental components. Patients should be counseled to administer these doses only when eating a full meal to avoid insulin overdose. The charts may be customized to include doses for small, medium, or large meals, as well as snacks, or for meals consumed before or after exercise. (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 meeting glycemic goals on a stable, fixed ratio of short- and intermediate-acting insulin, or those who can match their diets to the kinetics of premixed insulin. Premixed insulin works best for individuals with minimal day-to-day variability in the timing and composition of meals and with low risk of hypoglycemia. It rarely may be used as initial insulin therapy for patients who require a simplified insulin regimen. (See "General principles of insulin therapy in diabetes mellitus", section on 'Pre-mixed insulins'.)
•Dosing and administration – Premixed insulin should always be administered before meals because it contains a prandial insulin component. The initial total daily dose is calculated based on body weight (0.2 units per kg daily [minimum 10 units, up to 15 to 20 units]) or based on current insulin doses. One approach is to administer two-thirds of the total daily dose before breakfast and one-third before dinner. For individuals who consume a small breakfast and large dinner, an inverted ratio may be appropriate with as little as one-third of the total daily dose before breakfast and as much as two-thirds before dinner. Patients should be counseled to maintain a consistent daily meal pattern and to reduce the dose if eating less than usual.
The initial regimen is adjusted based on glucose monitoring. If pre-lunch and pre-dinner hyperglycemia persist, the morning dose can be increased by 2 to 3 units every two to three days. The pitfall is that dose increments to address pre-dinner hyperglycemia may result in midday hypoglycemia, highlighting a key drawback of premixed insulin formulations. Relaxed glycemic targets may be needed for safety.
•Efficacy – Premixed rapid-acting preparations may have slightly less glycemic efficacy than adequately titrated basal and prandial insulin. In an open-label trial, 708 patients with type 2 diabetes (mean A1C in the mid 8 percent range) treated 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). More patients in the basal and prandial groups achieved an A1C ≤6.5 percent than in the premixed biphasic group (43, 45, and 32 percent, respectively) [16]. Patients in the basal insulin group had the fewest episodes of hypoglycemia. In other trials, premixed preparations caused more hypoglycemia and weight gain than long-acting insulin or oral agents [48].
●Intensive insulin regimens – For individuals with type 2 diabetes who initiate intensive insulin therapy due to persistent, marked hyperglycemia, euglycemia should not necessarily be achieved 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 safe insulin use.
Insulin pump therapy is used infrequently in patients with type 2 diabetes, but it may it may be useful in selected patients with poorly managed glycemia on multiple daily insulin (MDI) injection therapy or individuals with limited dexterity, provided a caregiver is available to help operate the device [62,63]. Intensive insulin and insulin pump therapy (including automated insulin delivery systems) 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'.)
"Patch pump" devices may simplify prandial insulin administration [64-66]. These devices are applied to the abdomen with adhesive and contain a reservoir filled with rapid-acting insulin that can be delivered as both basal and prandial insulin at variable doses. The pump is changed daily or every few days, depending on the specific device. Patients administer variable doses of insulin by pressing a button on the device as many times as needed to deliver the desired dose (eg, 1 "click" for 2 units).
Use of an intensive insulin regimen to achieve 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 [47]. However, intensive regimens that achieve near-normoglycemia can result in substantial weight gain (averaging 8.7 kg in one study) [67]. Weight gain may complicate diabetes management or result in therapy nonadherence. (See 'Body weight gain' above and "Medical nutrition therapy for type 2 diabetes mellitus".)
Conversion between basal insulin products — Compared with intermediate-acting insulins, longer-acting basal insulins may have less glucose-lowering effect overnight and more effect into the next day. Accordingly, when switching between basal insulins, we generally reduce the dose to decrease the risk of hypoglycemia, then increase the dose as needed to maintain glycemic targets.
●Conversion from twice-daily to once-daily basal insulin – To switch from NPH or detemir twice per day to once-daily basal insulin, we initially reduce the total daily basal insulin dose by 10 to 20 percent and re-titrate based on blood glucose levels. In patients with marked, persistent hyperglycemia despite insulin adherence, the equivalent total daily dose may be given as a once-daily long-acting insulin.
●Conversion between once-daily basal insulins – To switch from once-daily detemir to once-daily glargine (U-100 or U-300 glargine) or degludec, we reduce the dose by 10 to 20 percent and re-titrate based on glucose monitoring. In patients with marked hyperglycemia, the equivalent total daily dose may be used.
Use of automated insulin algorithms — In order to achieve glycemic goals, insulin doses must be titrated initially and with changes in diet, activity, and body weight. However, clinicians often make such dose adjustments less frequently than necessary. The use of automated insulin algorithms may facilitate more timely dose adjustments. A smart pen insulin delivery device (with aspart or lispro cartridges) is available for people who use MDI injections. The smart pen provides guidance for dosing similar to the bolus calculator on an insulin pump. It also tracks dosing history, which facilitates adherence monitoring [68]. Automated dosing guidance also is available through specialized smart device applications.
TROUBLESHOOTING
Persistent hyperglycemia — If A1C values remain above goal despite treatment intensification, dietary and exercise patterns should be reviewed, as dietary indiscretion and/or food-insulin mismatch underlie the apparent failure of many insulin regimens. Insulin injection technique should also be assessed to ensure that pens or syringes are being used appropriately, injection sites are rotated, and no lipohypertrophy or atrophy is present at injection sites. Persistent A1C elevation also may simply reflect inadequate insulin dosing. In individuals with type 2 diabetes, total daily insulin doses often exceed 65 to 100 units per day and may be much higher with progressive obesity or other causes of severe insulin resistance. 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. Concentrated insulin formulations are an alternative. (See "General principles of insulin therapy in diabetes mellitus", section on 'Size of subcutaneous depot' and 'Insulin resistance' below.)
Hypoglycemia — Hypoglycemia is a potential complication of insulin therapy. However, at similar A1C levels, insulin-treated patients with type 2 diabetes experience much less frequent hypoglycemia than patients with type 1 diabetes [69]. If hypoglycemia occurs, continuous glucose monitoring (CGM) can be helpful for identifying glycemic patterns and guiding adjustments to insulin therapy. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'Insulin treated'.)
Although basal insulin causes less hypoglycemia than prandial insulin, hypoglycemia is more likely if the basal insulin dose is inappropriately increased to cover meals. Hypoglycemia may then occur if patients miss a meal or consume less than usual. Nonetheless, some patients develop daytime hypoglycemia when the basal insulin is titrated appropriately for fasting glucose. Either of these scenarios can lead to obligate snacking, which may fuel insulin-associated weight gain. This problem can be identified by targeted glucose monitoring and asking about symptoms of hypoglycemia when meals are skipped or the need to snack 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 (≥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 – If nocturnal hypoglycemia occurs, the basal insulin dose (the bedtime dose for twice-daily regimens) should be reduced by 4 units or 10 percent, whichever is greater (algorithm 1).
If no clear precipitant of hypoglycemia (eg, skipped meal, increased physical activity, increased alcohol intake) is identified, a greater dose reduction (20 to 30 percent) is warranted, with subsequent re-titration as needed. For patients taking bedtime NPH, an alternative is to switch to glargine or degludec. (See 'Conversion between basal insulin products' above and 'Choice of basal insulin' above.)
If severe hypoglycemia occurs (ie, an episode requiring the assistance of another person), the proximate cause should be determined, and the insulin dose may need to be reduced by 20 to 50 percent, with subsequent re-titration as indicated.
●Daytime hypoglycemia
•Prandial insulin – 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 the current mealtime dose:
-≤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 severe, the dose should be reduced substantially (20 to 50 percent) with re-titration. Alternatively, prandial insulin may be discontinued and re-initiated/re-titrated only if needed.
The patient should be counseled to adjust prandial insulin doses for meal size and carbohydrate content. In addition, patients should be asked about the timing of their prandial insulin administration, as both premature and delayed administration can contribute to hypoglycemia.
Basal insulin only – For patients taking basal insulin alone, the dose should be reduced by 4 units or 10 percent, whichever is greater. For individuals with greater insulin sensitivity, use of a non-peaking, long-acting insulin analog may help reduce hypoglycemia risk (algorithm 1). If hyperglycemia develops, the approach to management is reviewed above. (See 'Insulin titration' above.)
If severe hypoglycemia occurs (ie, an episode requiring the assistance of another person), the dose should be reduced by 20 to 50 percent, with subsequent re-titration.
●Unexplained hypoglycemia – Hypoglycemia is particularly concerning if it is unexplained, severe, or occurs in an individual with high risk of morbidity. In such circumstances, erring on the side of safety is prudent. This may require a substantial insulin dose reduction or even insulin discontinuation. Aging patients in particular may develop diminished insulin requirements, especially with weight loss, changes in appetite and diet, and/or decline in kidney function [70]. Such individuals may be able to discontinue insulin completely; the insulin may be resumed and re-titrated as needed.
The management of hypoglycemia in people 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 ≥200 total units of insulin daily), concentrated insulins may be used to manage hyperglycemia. Concentrated insulin formulations permit equivalent dosing in a smaller volume than U-100 insulin without the need for multiple injections to deliver high doses. The smaller volume of injected insulin also improves the absorption kinetics. Individual patient response should be monitored closely since concentrated insulins are very potent and insulin action often differs from labeled pharmacokinetics.
●U-500 regular insulin – U-500 regular insulin is used less frequently given the availability of concentrated insulin analogs. U-500 insulin may be used in patients requiring very high insulin doses (>200 units daily) due to obesity, immune-mediated insulin resistance, genetic abnormalities of the insulin receptor, or severe insulin resistance due to lipodystrophy [71,72]. The pharmacokinetics can be highly variable, and hypoglycemia remains a potential risk [73,74]. U-500 regular insulin has both prandial and basal properties; it has a duration of insulin action that is closer to that of NPH (figure 4) [75-77].
•Dispensing – U-500 insulin is available in a pen device that shows the units of insulin to be delivered in the dose window [78]. The pen delivers the volume that corresponds to the selected dose. The pen contains 1500 units (500 units/mL) of insulin. Pens are convenient and safe but expensive. U-500 insulin also can be dispensed with the U-500 insulin syringe [79]. The syringe contains scale markings from 25 to 250 units in 5-unit increments (syringe total volume 0.5 mL).
U-500 insulin previously was dispensed using Tuberculin or U-100 syringes, which require 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; this underscores the difference from U-100 regular insulin. With the Tuberculin syringe, every 0.1 mL equals 50 units of U-500 regular insulin (versus 10 units of U-100 insulin). Dispensing U-500 insulin with a Tuberculin syringe introduces the potential for confusion between volume and units.
•Dosing
-Initial – Although treatment approaches vary [77,80], initial dosing depends on current glycemic management. Due the high potency and improved absorption of U-500 regular insulin, total daily dose should always be decreased when switching from a U-100 insulin formulation. If glycemia is well above target, 80 percent of the current total daily insulin dose may be administered in two equal doses before breakfast and dinner. Some clinicians administer slightly more before breakfast (eg, 60 percent pre-breakfast, 40 percent pre-dinner) [80]. For individuals closer to their glycemic goals, lower initial doses can be used (eg, 50 to 60 percent of the current total daily insulin dose).
For individuals with severe insulin resistance, 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 or less) [80,81].
-Adjustments – During initial titration, weekly dose adjustments are based on glucose measurements (pre-meal and bedtime, or CGM). 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 contact the treating provider immediately if any glucose readings are <70 mg/dL (3.9 mmol/L). If severe hypoglycemia develops, the total daily dose should be decreased substantially (up to 50 percent), followed by slow re-titration as needed. Unexplained, nonsevere hypoglycemia should prompt a 20 to 30 percent dose reduction due to the potency and kinetics of U-500. Similar to use of premixed insulins, relaxed glycemic targets may be needed to use U-500 safely.
●Concentrated insulin analogs
•U-300 glargine – U-300 glargine (300 units/mL) has a volume one-third of that for the same dose of U-100 glargine (100 units/mL). It is available in a prefilled pen, and the dose window shows the units of insulin to be delivered. U-300 glargine may be substituted on an equivalent unit-per-unit basis. The pharmacokinetics are slightly different from U-100 glargine, with less of a peak and a longer duration of action. Consequently, glargine U-300 is more similar to degludec than to U-100 glargine [82]. (See "General principles of insulin therapy in diabetes mellitus", section on 'Basal insulin analogs'.)
•U-200 degludec – U-200 degludec (200 units/mL) has one-half the volume of an equivalently potent dose of U-100 degludec (100 units/mL). It is supplied in a prefilled pen and may be useful for patients on high-dose basal insulin. It is very similar and noninferior to U-100 degludec [83].
•U-200 lispro – Concentrated rapid-acting insulin analogs (eg, U-200 lispro) 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 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'.)
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
•Persistent hyperglycemia on oral therapy – Despite an initial response to oral therapy, most patients have worsening glycemia over time (figure 1 and figure 2). The therapeutic options for patients with persistent hyperglycemia after initial treatment are to add a second oral or injectable agent (including insulin), or to switch to insulin monotherapy. For many patients, we prefer basal insulin or a glucagon-like peptide 1 (GLP-1)-based therapy for a second-line medication. (See 'Persistent hyperglycemia on oral agents' above and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'.)
•Initial treatment – Insulin therapy is not typically used for initial treatment of type 2 diabetes. Insulin is indicated for initial treatment in the following settings (see 'Initial treatment' above):
-Severe hyperglycemia in association with ketonuria or weight loss, which always requires insulin treatment initially.
-Severe, persistent hyperglycemia (eg, fasting glucose >250 mg/dL [13.9 mmol/L], random glucose consistently >300 mg/dL [16.7 mmol/L], and/or glycated hemoglobin [A1C] >9 percent [74.9 to 85.8 mmol/mol]).
-When the type of diabetes (eg, type 1 versus type 2) is unclear.
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 (algorithm 1). (See 'Initial insulin regimen (basal insulin usually preferred)' above.)
•Choice of basal insulin – Reasonable initial insulin regimens include either insulin neutral protamine Hagedorn (NPH) or detemir (no longer available in the United States after April 2024) given at bedtime or insulin glargine or degludec given in the morning or at bedtime (table 1). (See 'Choice of basal insulin' above.)
Initial dose – 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 (algorithm 1). (See 'Initial dose' above.)
•Combination therapy versus insulin monotherapy – Combined therapy with insulin and other glucose-lowering medications may achieve glucose targets while minimizing total insulin requirements and weight gain. The benefits of continuing non-insulin therapy should be weighed against the risks of polypharmacy and cost. (See 'Combination therapy versus insulin monotherapy' above.)
●Patient counseling and safety – The major drawbacks of insulin therapy in type 2 diabetes are weight gain and hypoglycemia, although data suggest that these are not common or severe with use of basal insulin alone. These adverse effects should be addressed at insulin initiation and reviewed at every visit thereafter. Glycemic targets may need to be relaxed to reduce the risk of hypoglycemia and/or insulin-associated weight gain. (See 'Patient counseling and safety' above.)
●Monitoring and dose titration – The basal insulin dose is titrated based on fasting glucose and A1C values. The target range for fasting glucose is typically 80 to 130 mg/dL (3.9 to 7.2 mmol/L) for younger patients and higher for older patients and those at risk of hypoglycemia (algorithm 1). (See 'Monitoring glycemia' above and 'Persistent fasting hyperglycemia' above.)
Persistent elevation in A1C with fasting glucose in target range – If fasting glucose is in the target range but A1C remains elevated, dietary and exercise patterns should be reviewed along with adherence and injection technique. We advise the patient to check fingerstick capillary glucose levels fasting, pre-lunch, pre-dinner, and before bed while the regimen is adjusted. (See 'Persistent elevation in A1C with fasting glucose in target range' above.)
•Combining basal and prandial insulin – For patients with type 2 diabetes who require prandial insulin, either regular (short-acting) or rapid-acting insulin can be given. Prandial insulin is often started as a single injection before the largest meal of the day, but many strategies are possible (algorithm 1). (See 'Combining prandial and basal insulin' above.)
•Premixed insulin – For patients with type 2 diabetes who require prandial insulin, we rarely use premixed insulin for initial insulin therapy. We prefer to keep basal and pre-meal insulin injections separate to enable independent and more flexible titration. Premixed insulin is a reasonable option for patients with type 2 diabetes who are meeting glycemic goals on a stable, fixed ratio of short- and intermediate-acting insulin. (See 'Combining prandial and basal insulin' above and "General principles of insulin therapy in diabetes mellitus", section on 'Pre-mixed insulins'.)
●Troubleshooting – Persistent hyperglycemia, hypoglycemia, and severe insulin resistance may complicate insulin therapy. If A1C values remain above goal, dietary and exercise patterns, adherence, and injection technique should be reviewed. Persistent A1C elevation also may simply reflect inadequate insulin dosing. (See 'Persistent hyperglycemia' above.)
Hypoglycemia is a potential complication of insulin therapy. The approach to management depends on the timing and severity of hypoglycemic episodes. (See 'Hypoglycemia' above.)
In patients with severe insulin resistance (eg, requiring ≥200 total units of insulin daily), concentrated insulins can be used to manage hyperglycemia. (See 'Insulin resistance' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to earlier versions of this topic review.
