Category: Diet

Insulin treatment guidelines

Insulin treatment guidelines

Please choose guideines single best answer to each question. Social determinants of health, Sustain long-lasting energy naturally nonadherence, and cost-reducing behaviors among Guideliness with diabetes: findings from the National Health Interview Survey. Metformin is associated with less weight gain than Effective fiber intake for improved digestion 21and Ibsulin better Gukdelines lowering and weight Recovery nutrition tips than DPP-4 inhibitors Information and advice on managing Diabetes in several languages is available by telephone, website, a mobile app and a collection of print resources. A consensus statement by the ADA indicates that this possible risk needs further research but should not be a limiting factor in treatment choice. DPP-4 inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors have been shown to be efficacious at further lowering glucose levels when combined with insulin therapy 87— Comparison of insulin degludec with insulin glargine in insulin-naive subjects with Type 2 diabetes: a 2-year randomized, treat-to-target trial.

Insulin treatment guidelines -

A patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include efficacy, hypoglycemia risk, history of atherosclerotic cardiovascular disease, impact on weight, potential side effects, renal effects, delivery method oral versus subcutaneous , cost, and patient preferences.

In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, antihyperglycemic therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality currently empagliflozin and liraglutide , after considering drug-specific and patient factors Table 8.

In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, after lifestyle management and metformin, the antihyperglycemic agent canagliflozin may be considered to reduce major adverse cardiovascular events, based on drug-specific and patient factors Table 8.

Continuous reevaluation of the medication regimen and adjustment as needed to incorporate patient factors Table 8.

For patients with type 2 diabetes who are not achieving glycemic goals, drug intensification, including consideration of insulin therapy, should not be delayed.

Metformin should be continued when used in combination with other agents, including insulin, if not contraindicated and if tolerated. See Section 12 for recommendations specific for children and adolescents with type 2 diabetes.

The use of metformin as first-line therapy was supported by findings from a large meta-analysis, with selection of second-line therapies based on patient-specific considerations Renal effects may also be considered when selecting glucose-lowering medications for individual patients.

Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes. CVD, cardiovascular disease; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; NASH, nonalcoholic steatohepatitis; RAs, receptor agonists; SQ, subcutaneous; T2DM, type 2 diabetes.

Metformin monotherapy should be started at diagnosis of type 2 diabetes unless there are contraindications. Metformin is effective and safe, is inexpensive, and may reduce risk of cardiovascular events and death Compared with sulfonylureas, metformin as first-line therapy has beneficial effects on A1C, weight, and cardiovascular mortality Patients should be advised to stop the medication in cases of nausea, vomiting, or dehydration.

Metformin is associated with vitamin B12 deficiency, with a recent report from the Diabetes Prevention Program Outcomes Study DPPOS suggesting that periodic testing of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy In patients with metformin contraindications or intolerance, consider an initial drug from another class depicted in Fig.

Insulin has the advantage of being effective where other agents may not be and should be considered as part of any combination regimen when hyperglycemia is severe, especially if catabolic features weight loss, ketosis are present.

Consider initiating combination insulin injectable therapy Fig. Antihyperglycemic therapy in type 2 diabetes: general recommendations. GLP-1 receptor agonists and DPP-4 inhibitors should not be prescribed in combination. If a patient with ASCVD is not yet on an agent with evidence of cardiovascular risk reduction, consider adding.

Combination injectable therapy for type 2 diabetes. FBG, fasting blood glucose; hypo, hypoglycemia. Adapted with permission from Inzucchi et al. Although there are numerous trials comparing dual therapy with metformin alone, few directly compare drugs as add-on therapy. A comparative effectiveness meta-analysis 36 suggests that each new class of noninsulin agents added to initial therapy generally lowers A1C approximately 0.

If the A1C target is not achieved after approximately 3 months and patient does not have atherosclerotic cardiovascular disease ASCVD , consider a combination of metformin and any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin Fig.

For patients with ASCVD, add a second agent with evidence of cardiovascular risk reduction after consideration of drug-specific and patient factors see p. Drug choice is based on patient preferences 37 , as well as various patient, disease, and drug characteristics, with the goal of reducing blood glucose levels while minimizing side effects, especially hypoglycemia.

If not already included in the treatment regimen, addition of an agent with evidence of cardiovascular risk reduction should be considered in patients with ASCVD beyond dual therapy, with continuous reevaluation of patient factors to guide treatment Table 8.

Table 8. Cost-effectiveness models of the newer agents based on clinical utility and glycemic effect have been reported Of note, prices listed are average wholesale prices AWP 39 and National Average Drug Acquisition Costs NADAC 40 and do not account for discounts, rebates, or other price adjustments often involved in prescription sales that affect the actual cost incurred by the patient.

While there are alternative means to estimate medication prices, AWP and NADAC were utilized to provide two separate measures to allow for a comparison of drug prices with the primary goal of highlighting the importance of cost considerations when prescribing antihyperglycemic treatments.

The ongoing Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study GRADE will compare four drug classes sulfonylurea, DPP-4 inhibitor, GLP-1 receptor agonist, and basal insulin when added to metformin therapy over 4 years on glycemic control and other medical, psychosocial, and health economic outcomes Pharmacology of available glucose-lowering agents in the U.

for the treatment of type 2 diabetes. no dose adjustment required for eGFR 30—59, but patients should be monitored for adverse effects and changes in kidney function;. clinical experience is limited with eGFR 15—29; patients should be monitored for adverse effects and changes in kidney function;.

GIP, glucose-dependent insulinotropic peptide; PPAR-γ, peroxisome proliferator—activated receptor γ. Median monthly cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.

Rapid-acting secretagogues meglitinides may be used instead of sulfonylureas in patients with sulfa allergies or irregular meal schedules or in those who develop late postprandial hypoglycemia when taking a sulfonylurea.

Other drugs not shown in Table 8. There are now three large randomized controlled trials reporting statistically significant reductions in cardiovascular events for two SGLT2 inhibitors empagliflozin and canagliflozin and one GLP-1 receptor agonist liraglutide where the majority, if not all patients, in the trial had ASCVD.

The empagliflozin and liraglutide trials demonstrated significant reductions in cardiovascular death. Exenatide once-weekly did not have statistically significant reductions in major adverse cardiovascular events or cardiovascular mortality but did have a significant reduction in all-cause mortality.

In contrast, other GLP-1 receptor agonists have not shown similar reductions in cardiovascular events Table 9. Whether the benefits of GLP-1 receptor agonists are a class effect remains to be definitively established.

Additional large randomized trials of other agents in these classes are ongoing. Of note, these studies examined the drugs in combination with metformin Table 9. For patients with type 2 diabetes who have ASCVD, on lifestyle and metformin therapy, it is recommended to incorporate an agent with strong evidence for cardiovascular risk reduction especially those with proven benefit on both major adverse cardiovascular events and cardiovascular death after consideration of drug-specific patient factors Table 8.

See Fig. Many patients with type 2 diabetes eventually require and benefit from insulin therapy. The progressive nature of type 2 diabetes should be regularly and objectively explained to patients.

Providers should avoid using insulin as a threat or describing it as a sign of personal failure or punishment. Equipping patients with an algorithm for self-titration of insulin doses based on self-monitoring of blood glucose improves glycemic control in patients with type 2 diabetes initiating insulin Comprehensive education regarding self-monitoring of blood glucose, diet, and the avoidance of and appropriate treatment of hypoglycemia are critically important in any patient using insulin.

Basal insulin alone is the most convenient initial insulin regimen, beginning at 10 units per day or 0.

Basal insulin is usually prescribed in conjunction with metformin and sometimes one additional noninsulin agent. When basal insulin is added to antihyperglycemic agents in patients with type 2 diabetes, long-acting basal analogs U glargine or detemir can be used instead of NPH to reduce the risk of symptomatic and nocturnal hypoglycemia 43 — Longer-acting basal analogs U glargine or degludec may additionally convey a lower hypoglycemia risk compared with U glargine when used in combination with oral antihyperglycemic agents 49 — While there is evidence for reduced hypoglycemia with newer, longer-acting basal insulin analogs, people without a history of hypoglycemia are at decreased risk and could potentially be switched to human insulin safely.

Thus, due to high costs of analog insulins, use of human insulin may be a practical option for some patients, and clinicians should be familiar with its use There have been substantial increases in the price of insulin over the past decade and the cost-effectiveness of different antihyperglycemic agents is an important consideration in a patient-centered approach to care, along with efficacy, hypoglycemia risk, weight, and other patient and drug-specific factors Table 8.

Median cost of insulin products in the U. Many individuals with type 2 diabetes may require mealtime bolus insulin dosing in addition to basal insulin. Rapid-acting analogs are preferred due to their prompt onset of action after dosing.

In September , the FDA approved a new faster-acting formulation of insulin aspart. The recommended starting dose of mealtime insulin is 4 units, 0. Premixed insulin products contain both a basal and prandial component, allowing coverage of both basal and prandial needs with a single injection.

The use of premixed insulin products has its advantages and disadvantages, as discussed below in combination injectable therapy.

Several concentrated insulin preparations are currently available. U regular insulin, by definition, is five times as concentrated as U regular insulin and has a delayed onset and longer duration of action than U regular, possessing both prandial and basal properties.

U glargine and U degludec are three and two times as concentrated as their U formulations and allow higher doses of basal insulin administration per volume used.

U glargine has a longer duration of action than U glargine. These concentrated preparations may be more comfortable for the patient and may improve adherence for patients with insulin resistance who require large doses of insulin.

While U regular insulin is available in both prefilled pens and vials a dedicated syringe was FDA approved in July , other concentrated insulins are available only in prefilled pens to minimize the risk of dosing errors.

Inhaled insulin is available for prandial use with a more limited dosing range. It is contraindicated in patients with chronic lung disease such as asthma and chronic obstructive pulmonary disease and is not recommended in patients who smoke or who recently stopped smoking.

It requires spirometry FEV 1 testing to identify potential lung disease in all patients prior to and after starting therapy. When initiating combination injectable therapy, metformin therapy should be maintained while other oral agents may be discontinued on an individual basis to avoid unnecessarily complex or costly regimens i.

In general, GLP-1 receptor agonists should not be discontinued with the initiation of basal insulin. Sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists are typically stopped once more complex insulin regimens beyond basal are used.

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Delay in treatment intensification increases the risks of cardiovascular events in patients with type 2 diabetes.

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search close. PREV Jan 1, NEXT. C 9 , 10 Consider initiating insulin replacement therapy when the blood glucose level is to mg per dL Also consider adding rapid-acting insulin in those patients taking basal insulin who are already on augmentation therapy but not attaining A1C goals.

C 9 , 10 Insulin analogues may be used to reduce the risk of hypoglycemia. A 28 , 29 The A1C goal should be individualized based on age, life expectancy, comorbid conditions, duration of diabetes, risk of hypoglycemia, adverse consequences related to hypoglycemia, or patient motivation and adherence.

Moderate control is generally better. American Geriatrics Society Do not use sliding scale insulin for long-term diabetes management for individuals residing in the nursing home.

American Medical Directors Associa. Concerns About Insulin Therapy. Not every patient will clearly fall into a particular category.

A total of at least 3 conditions is considered multiple, but many patients may have 5 or more. Initiation of Insulin. An approach to starting insulin in patients with type 2 diabetes mellitus based on American Diabetes Association guidelines.

Titration, Monitoring, and Goals of Therapy. If the patient has an elevated glucose level at lunchtime, the breakfast rapid-acting dose should be adjusted; if the patient has an elevated premeal glucose level at dinnertime, the lunchtime rapid-acting dose should be adjusted; if the patient has an elevated bedtime glucose level, the dinnertime rapid-acting dose should be adjusted.

Contributor Disclosures. Inaulin Insulin treatment guidelines Insluin Disclaimer at the end of this page. Type Sustain long-lasting energy naturally diabetes mellitus guiddelines a Natural energy snacks medical condition that occurs when the pancreas, an organ in the abdomen, produces very little or no insulin figure 1. Insulin is a hormone that helps the body to use glucose for energy. Glucose is a sugar that comes, in large part, from foods we eat. American Diabetes Association; 8. Pharmacologic Approaches Gguidelines Glycemic Treatment: Standards of Medical Buidelines in Diabetes— Trearment of the ADA Professional Tretment Committeea multidisciplinary expert committee, are responsible for updating the Standards of Recovery nutrition tips annually, or Stress relief through journaling Insulin treatment guidelines as warranted. Readers who wish to comment on the Standards of Care are invited to do so at professional. Most people with type 1 diabetes should be treated with multiple daily injections of prandial insulin and basal insulin or continuous subcutaneous insulin infusion. Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk. Consider educating individuals with type 1 diabetes on matching prandial insulin doses to carbohydrate intake, premeal blood glucose levels, and anticipated physical activity.

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Insulin treatment guidelines the desired glucose targets are not met, rapid-acting or short-acting bolus or prandial insulin can be added at mealtime to control the expected postprandial raise in glucose.

An insulin regimen should be adopted and individualized but should, to the extent possible, closely resemble a natural physiologic state and avoid, to the extent possible, wide fluctuating glucose levels C. Blood glucose monitoring is an integral part of effective insulin therapy and should not be omitted in the patient's care plan.

Fasting plasma glucose FPG values should be used to titrate basal insulin, whereas both FPG and postprandial glucose PPG values should be used to titrate mealtime insulin B.

Metformin combined with insulin is associated with decreased weight gain, lower insulin dose, and less hypoglycemia when compared with insulin alone C. Oral medications should not be abruptly discontinued when starting insulin therapy because of the risk of rebound hyperglycemia D.

Analogue insulin is as effective as human insulin but is associated with less postprandial hyperglycemia and delayed hypoglycemia B. The shortest needles currently the 4-mm pen and 6-mm syringe needles are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular IM injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them A.

Many patients in East Africa reuse syringes for various reasons, including financial. This is not recommended by the manufacturer and there is an association between needle reuse and lipohypertrophy.

However, patients who reuse needles should not be subjected to alarming claims of excessive morbidity from this practice A. Health care authorities and planners should be alerted to the risks associated with syringe or pen needles 6 mm or longer in children A.

Keywords: Diabetes mellitus; East Africa; Guidelines; Hyperglycemia; Hypoglycemia; Insulin therapy; Type 1 diabetes mellitus T1DM ; Type 2 diabetes mellitus T2DM. Abstract A diagnosis of diabetes or hyperglycemia should be confirmed prior to ordering, dispensing, or administering insulin A.

: Insulin treatment guidelines

Sliding Scale Therapy The recommendation to use metformin as the initial agent in most people is based on its efficacy in lowering A1C, its relatively mild side effect profile, long-term safety track record, affordability, negligible risk of hypoglycemia and lack of weight gain. It is not necessary to clean the skin with alcohol unless the skin is dirty. However, patients who reuse needles should not be subjected to alarming claims of excessive morbidity from this practice A. Email alerts Article Activity Alert. For more information, visit www. Surgery — If you are planning to have surgery, you may be instructed not to eat for 8 to 12 hours before the procedure. If you use a needle and syringe, it is advisable to start a new vial at least every 30 days.
EADSG Guidelines: Insulin Therapy in Diabetes The effect of oral antidiabetic agents on A1C levels: A systematic review and meta-analysis. Short or ultra-short acting insulin: types available in Australia include NovoRapid®, Humalog®, Apidra®, Actrapid®, and Humulin® R. INJECTING INSULIN. A Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy. On the other hand, injections that are too shallow are more painful and not absorbed well.
EADSG Guidelines: Insulin Therapy in Diabetes

Typically, patients with T1DM will require initiation with multiple daily injections at the time of diagnosis. This is usually short-acting insulin or rapid-acting insulin analogue given 0 to 15 min before meals together with one or more daily separate injections of intermediate or long-acting insulin.

Two or three premixed insulin injections per day may be used A. The target is chosen aiming at minimizing hyperglycemia, severe hypoglycemia, hypoglycemic unawareness, and reducing the likelihood of development of long-term complications B. For patients prone to glycemic variability, glycemic control is best evaluated by a combination of results with self-monitoring of blood glucose SMBG B.

Indications for exogenous insulin therapy in patients with type 2 diabetes mellitus T2DM include acute illness or surgery, pregnancy, glucose toxicity, contraindications to or failure to achieve goals with oral antidiabetic medications, and a need for flexible therapy B. If the desired glucose targets are not met, rapid-acting or short-acting bolus or prandial insulin can be added at mealtime to control the expected postprandial raise in glucose.

Insulin may later be tapered or discontinued once stability is achieved. In general, A1C will decrease by about 0. By and large, the higher the baseline A1C, the greater the A1C reduction seen for each given agent.

The maximum effect of noninsulin antihyperglycemic agent monotherapy is observed by 3 to 6 months 5,6. Evidence indicates that initial combination of metformin with another agent is associated with an additional mean 0. The initial use of combinations of submaximal doses of antihyperglycemic agents produces more rapid and improved glycemic control and fewer side effects compared to monotherapy at maximal doses 13— Table 1 lists all the available classes of antihyperglycemic therapies.

These include insulin and noninsulin therapies. Unless contraindicated, metformin should be the initial pharmacotherapy in people with type 2 diabetes.

The recommendation to use metformin as the initial agent in most people is based on its efficacy in lowering A1C, its relatively mild side effect profile, long-term safety track record, affordability, negligible risk of hypoglycemia and lack of weight gain.

Compared to sulfonylureas, metformin monotherapy has comparable A1C-lowering effects, but better glycemic durability 18 , a lower risk of hypoglycemia 19 , less weight gain 19,20 and lower CV risk Metformin is associated with less weight gain than thiazolidinediones 21 , and has better A1C lowering and weight loss than DPP-4 inhibitors The demonstrated CV benefit of metformin monotherapy in newly diagnosed participants who were overweight in the UKPDS trial 17 is also cited as a reason to select metformin as first-line treatment, although other evidence from a meta-analysis of metformin trials has been equivocal on this matter 21, Metformin should be started at a low dose and gradually increased over several weeks to minimize the risk of gastrointestinal side effects.

If metformin is contraindicated or if initial combination therapy is required, then a second agent should be chosen based on individual patient characteristics and the efficacy and safety profile of other agents see Table 1 and Figure 2.

DPP-4 inhibitors, GLP-1 receptor agonists or SGLT2 inhibitors should be considered over other antihyperglycemic agents as they are associated with less hypoglycemia and weight gain 19,23—27 , provided there are no contraindications and no barriers to affordability or access.

Insulin may be used at diagnosis in individuals with marked hyperglycemia and can also be used temporarily during illness, pregnancy, stress or for a medical procedure or surgery.

The use of intensive insulin therapy may lead to partial recovery of beta cell function when used in people with metabolic decompensation, and studies suggest that early insulin treatment may induce remission in people with newly diagnosed type 2 diabetes 28,29— Trials of this approach are ongoing.

The natural history of type 2 diabetes is that of ongoing beta cell function decline, so blood glucose BG levels often increase over time even with excellent adherence to healthy behaviours and therapeutic regimens Treatment must be responsive as therapeutic requirements may increase with longer duration of disease.

If A1C target is not achieved or maintained with current pharmacotherapy, treatment intensification is often required. A review of potential precipitants of increasing A1C e.

infection, ischemia and medication adherence should first be conducted, and current therapy may need to be modified if there are significant barriers to adherence. Healthy behaviour interventions, including nutritional therapy and physical activity, should continue to be optimized while pharmacotherapy is being intensified.

Metformin should be continued with other agents unless contraindicated. In general, when combining antihyperglycemic agents with or without insulin, classes of agents that have different mechanisms of action should be used.

sulfonylureas and meglitinides or DPP-4 inhibitors and GLP-1 receptor agonists is currently untested, may be less effective at improving glycemia and is not recommended at this time. Table 1 identifies the mechanism of action for all classes of antihyperglycemic agents to aid the reader in avoiding the selection of agents with overlapping mechanisms.

A1C , glycated hemoglobin; CHF , congestive heart failure; CV , cardiovascular; CVD , cardiovascular disease; DKA , diabetic ketoacidosis; eGFR , estimated glomerular filtration rate; HHS , hyperosmolar hyperglycemic state.

Figure 1 continued Management of hyperglycemia in type 2 diabetes. In deciding upon which agent to add after metformin, there must be consideration of both short-term effects on glycemic control and long-term effects on clinical complications. While intensive glycemic control with a variety of agents is associated with a reduction in microvascular complications 3 and possibly CV complications 34 see Targets for Glycemic Control chapter, p.

S42 , Table 1 highlights agent-specific effects on CV or microvascular complications e. CKD based on trials where glycemic differences between treatment arms were minimized.

The effect of exogenous insulin on the risk of CV complications has been shown to be neutral 35, There was a neutral effect on CV outcomes and cancer, and a slight increase in hypoglycemia and weight 36, Earlier trials evaluated effects of thiazolidinediones on CV events. Meta-analyses of smaller studies suggested possible higher risk of myocardial infarction MI with rosiglitazone 38,39 ; however, CV events were not significantly increased in a larger randomized clinical trial 40, Conversely, the evidence for pioglitazone suggests a possible reduced risk of CV events, but the primary CV outcome was neutral 42, While these agents have comparable glucose-lowering effects to other drugs, the edema, weight gain, risk of congestive heart failure CHF 44 , increased risk of fractures 45,46 and inconsistent data regarding MI risk with rosiglitazone 38—40 and bladder cancer risk with pioglitazone significantly limit the clinical utility of this drug class 47, Based on controversies regarding rosiglitazone, in , the United States Food and Drug Administration FDA required that all new antidiabetic therapies undergo evaluation for CV safety at the time of approval.

Subsequently, several industry-sponsored placebo-controlled trials were initiated to evaluate CV outcomes of drugs from 3 newer classes: DPP-4 inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors see Table 2. Trial durations are from 1. Therefore, findings from these trials are directly relevant to people with established type 2 diabetes and clinical CV disease or multiple risk factors.

Studies have not evaluated whether findings are generalizable to people with new-onset type 2 diabetes or those at average or lower CV risk. Three DPP-4 inhibitor trials have been completed Table 2.

None have shown inferiority or superiority compared to placebo for the risk of major CV events 49, There was a non-statistically significant increase in hospitalizations for CHF with alogliptin in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care EXAMINE trial 49 and there is limited experience treating people with a history of CHF with linagliptin; therefore, these agents should be used with caution in that setting.

Moreover, a secondary analysis of the data suggested a possibly higher relative risk of unstable angina and all-cause mortality with saxagliptin in those under 65 years The significance of these findings is unclear and further studies are needed. The GLP-1 receptor agonist, lixisenatide, was also shown to be non-inferior to placebo after a median 2.

Figure 2 Antihyperglycemic medications and renal function. Based on product monograph precautions. CKD, chronic kidney disease; CV , cardiovascular; GFR , glomerular filtration rate; TZD , thiazolidinedione. Three approved and one unapproved antihyperglycemic agent, thus far, have shown benefit in reducing major CV outcomes in individuals with clinical CVD, the SGLT2 inhibitors empagliflozin 53 and canagliflozin 54 , and the GLP-1 receptor agonists liraglutide 55 and semaglutide Those treated with empagliflozin had significantly fewer CV events CV death, nonfatal MI, nonfatal stroke compared to placebo-treated participants after a median 3.

In a secondary analysis, empagliflozin was associated with a significant reduction in hospitalizations for CHF 4. Recent meta-analyses of SGLT2 inhibitors confirmed a significant benefit of this class of agents on major CV outcomes, which was largely driven by EMPA-REG OUTCOME results 58— The CANagliflozin cardioVascular Assessment Study CANVAS program, which integrated findings from 2 placebo-controlled trials CANVAS and CANVAS-R , evaluated the CV effects of canagliflozin The trials enrolled 10, participants 4, in CANVAS and 5, in CANVAS-R with type 2 diabetes mean duration Over a median follow up of 2.

There were no statistical differences in the individual components of the composite outcome. There was a reduction in hospitalization for heart failure and in several adverse renal outcomes; however, these were considered exploratory outcomes due to pre-specified rules of evidence hierarchy.

While one-third of participants did not have CVD, a significant decrease in the primary endpoint was only found in those with CVD. Therefore, as with other CV outcome trials, these results largely apply to people with type 2 diabetes requiring add-on antihyperglycemic therapy who have established clinical CVD.

Canagliflozin was also associated with an increase in fracture rates HR 1. Importantly, canagliflozin was associated with doubling in the risk of lower extremity amputation HR 1.

This risk was strongest in participants with a prior amputation. Canagliflozin should, therefore, be avoided in people with a prior amputation, as the harms appear to be greater than the benefits in that population. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results LEADER trial enrolled 9, participants with longstanding type 2 diabetes median duration Over a median follow up of 3.

Therefore results are most applicable to people with type 2 diabetes with clinical CVD requiring add-on antihyperglycemic therapy. The Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes SUSTAIN-6 enrolled 3, participants with a mean duration of type 2 diabetes of After a median follow up of 2.

There was, however, a higher rate of diabetic retinopathy complications in the semaglutide group compared to placebo group 3.

It is unclear at this time if there is a direct effect of semaglutide or other explanations for this unexpected difference in retinopathy complication rates, although the risk appeared greatest in individuals with pre-existing retinopathy and rapid lowering of A1C. All 4 trials reported lower rates of kidney disease progression in the treated groups compared to placebo 53,55, It should also be noted that the majority of people in these trials had pre-existing CVD and required add-on antihyperglycemic therapy.

In addition, because these were placebo-controlled trials, no conclusions can be made about how the cardioprotective properties of empagliflozin, canagliflozin, liraglutide and semaglutide compare to those of other agents.

CV outcome trials for other agents are expected to be completed by ; therefore, based on evidence to date, a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated CV outcome benefit should be considered as initial add-on therapy for people with pre-existing type 2 diabetes and clinical CV disease who have not achieved target A1C on existing treatment to reduce CV risk.

A careful review of the methods and findings from these trials was conducted by an independent committee. While primary analyses results were similar for canagliflozin, empagliflozin and liraglutide, it was concluded that the strength of evidence for CV benefit was weaker for canagliflozin than for the other agents.

This conclusion was based on three factors. First, in an interim analysis of the CANVAS study for medication approval necessitated unblinding of study data. A decision was then made to combine this study with the CANVAS-R study, presumably to provide greater power for CV outcomes.

The interim unblinding and protocol revision were viewed as potential threats to internal validity, thereby weakening the strength of evidence for benefit.

Second, while canagliflozin was associated with a significant decrease in the composite MACE outcome, there was no significant benefit on individual outcomes, such as all-cause or CV mortality.

Third, the findings of increased risk of fractures and amputations with canagliflozin treatment in the context of a noninferiority design where the comparator is placebo was particularly concerning, indicating that harms may outweigh benefits.

For these reasons, the committee decided that the uncertainty regarding benefits should be acknowledged with a lower grade of recommendation for canagliflozin than for other agents with demonstrated CV benefit.

In the absence of evidence for long-term clinical benefit, agents effective at A1C lowering should be considered in terms of both the degree of baseline hyperglycemia needing correction, and any heightened concerns regarding hypoglycemia e.

elderly people or those with renal or hepatic dysfunction see Diabetes in Older People chapter, p. While most medications added to metformin lower A1C to a similar extent, insulin and insulin secretagogues are associated with higher rates of hypoglycemia than other agents 21,23,24, In those who are stable, other agent-specific advantages and disadvantages should be weighed as treatment is individualized to best suit the patient's needs and preferences.

Each of the agents listed in Table 1 and Figure 1 has advantages and disadvantages to consider. Figure 2 illustrates the basis on which agent selection is influenced by renal function as dictated by product monograph precautions. Recent meta-analyses have summarized head-to-head comparisons of metformin-based combinations 19,24,62, Combinations of metformin with a sulfonylurea, a thiazolidinedione TZD , an SGLT2 inhibitor and a DPP-4 inhibitor have comparable A1C-lowering effects 19,24,62—66 , while the combination of metformin with a GLP-1 receptor agonist reduced A1C more than combination with a DPP-4 inhibitor.

TZDs, insulin and sulfonylureas are associated with the most weight gain 1. Hypoglycemia risk is also lower with TZDs, DPP-4 inhibitors, SGLT2 inhibitors and GLP-1 receptor agonists compared to sulfonylureas and insulin 19,24,62—65,67, Network meta-analyses that indirectly compared the net benefits of second- and third-line treatment options have found similar results 21,23,24,69— Evidence on comparative effectiveness of acarbose and orlistat is limited, although they are associated with a low risk of hypoglycemia and weight gain.

The safety of incretin agents, SGLT2 inhibitors and TZDs in pregnancy is unknown; therefore, these agents should be avoided or discontinued in women who are pregnant or planning a pregnancy see Diabetes and Pregnancy chapter, p. If a sulfonylurea is added to metformin, gliclazide should be considered as first choice as it is associated with a lower risk of hypoglycemia 67,72 , CV events and mortality relative to other sulfonylureas Glimepiride is also associated with a lower risk of CV events and mortality 73 , but has a similar rate of hypoglycemia 67,72 compared to other sulfonylureas.

For people already taking metformin and a sulfonylurea, the addition of either a DPP-4 inhibitor, a GLP-1 receptor agonist or SGLT2 inhibitor may be considered as they are associated with effective A1C lowering with less hypoglycemia than insulin or TZDs 21,69,70,74,75 ; GLP-1 receptor agonists and SGLT2 inhibitors are also associated with weight loss 70,71 see Weight Management in Diabetes chapter, p.

For instance, the combination of a DPP-4 inhibitor or a GLP-1 receptor agonist and an SGLT2 inhibitor added to metformin has been shown to be as safe and more efficacious at lowering A1C after 24 weeks than either agent alone 76, SGLT2 inhibitors and GLP-1 receptor agonists added to metformin have also been shown to reduce systolic BP compared to metformin alone, and add-on of SGLT2 inhibitors reduce systolic BP more than add-on of sulfonylureas or DPP-4 inhibitors A combination of noninsulin antihyperglycemic agents and insulin often effectively controls glucose levels.

Insulin treatment includes long-acting or intermediate-acting insulin analogue injections once or twice daily for basal glycemic control, and bolus injections at mealtimes for prandial glycemic control. Adding insulin to noninsulin antihyperglycemic agent s may result in better glycemic control with a smaller dose of insulin 78 , and may induce less weight gain and less hypoglycemia than that seen when non-insulin antihyperglycemic agents are stopped and insulin is used alone 79, A single injection of an intermediate-acting NPH 81 or long-acting insulin analogue insulin glargine U, insulin glargine U, insulin detemir or insulin degludec 82—84 may be added.

The addition of bedtime insulin to metformin therapy leads to less weight gain than insulin plus a sulfonylurea or twice-daily NPH insulin When insulin is used in type 2 diabetes, the insulin regimen should be tailored to achieve good metabolic control while trying to avoid hypoglycemia.

With intensive glycemic control, there is an increased risk of hypoglycemia, but this risk is lower in people with type 2 diabetes than in those with type 1 diabetes.

The mode of insulin administration continuous subcutaneous infusion vs. injections , the number of insulin injections 1 to 4 per day and the timing of injections may vary depending on each individual's situation As type 2 diabetes progresses, insulin requirements will likely increase and higher doses of basal insulin intermediate-acting or long-acting analogues may be needed.

DPP-4 inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors have been shown to be efficacious at further lowering glucose levels when combined with insulin therapy 87— A meta-analysis determined that the addition of a GLP-1 receptor agonist to basal insulin regimens results in greater A1C reduction, more weight loss and less hypoglycemia compared to the addition of bolus insulin A GLP-1 receptor agonist should, therefore, be considered before bolus insulin as add-on therapy in people on basal insulin with or without other agents who require antihyperglycemic treatment intensification if there are not barriers to affordability or access.

If glycemic control is suboptimal on treatment regimens that include basal insulin with other agents, bolus insulin at mealtimes short- or rapid-acting analogues may be added. Generally, once bolus insulin is introduced into a treatment regimen, either as a separate mealtime bolus or as part of a premixed containing regimen, insulin secretagogues, such as sulfonylureas and meglitinides, should be discontinued.

Concomitant therapy with metformin and, if applicable, a GLP-1 receptor agonist, DPP-4 inhibitor or SGLT2 inhibitor should be continued with regimens containing bolus insulin unless contraindicated, to allow for improved glycemic control with less risk of weight gain and hypoglycemia The reduction in A1C achieved with insulin therapy depends on the dose and number of injections per day A meta-analysis of 12 articles compared basal-bolus and biphasic insulin regimens, and found that both approaches are equally efficacious at lowering A1C, with comparable effects on hypoglycemia risk and weight—although basal-bolus regimens were modestly more efficacious in people with type 2 diabetes already on insulin Bolus insulin should be initiated using a stepwise approach starting with 1 injection at the largest meal and additional mealtime injections at 3-month intervals if needed , as it was shown to be as efficacious at A1C lowering as a full basal-bolus regimen, and is associated with less hypoglycemia and greater patient satisfaction after 1 year Lower rates of hypoglycemia have been observed in some studies of individuals with type 2 diabetes treated with rapid-acting insulin analogues insulin aspart, insulin lispro, insulin glulisine compared to those treated with short-acting regular insulin — Use of long-acting basal insulin analogues insulin detemir, insulin glargine, insulin degludec in those already on antihyperglycemic agents reduces the relative risk of symptomatic and nocturnal hypoglycemia compared to treatment with NPH insulin 83,,— Meta-analyses indicate a relative reduction of 0.

NPH Insulin degludec has been associated with lower rates of overall and nocturnal hypoglycemia compared to glargine U 82,84, After 32 weeks of treatment, insulin degludec was associated with a significantly lower rate of the primary endpoint of overall symptomatic hypoglycemic episodes rate ratio 0.

The proportions of patients with hypoglycemic episodes were 9. The Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events DEVOTE randomized patients with type 2 diabetes at high risk of CV disease to insulin degludec or glargine U, and found no difference in the primary outcome of CV events but a significant decrease in severe hypoglycemia with degludec 4.

There is also some evidence of lower hypoglycemia rates with glargine U compared to glargine U and may also be considered over glargine U if reducing hypoglycemia is a priority Efficacy and rates of hypoglycemia are similar between glargine U and detemir Aside from effects of some antihyperglycemic agents on the occurrence of hypoglycemia and weight, there are adverse effects unique to each agent Table 1.

Gastrointestinal side effects are more common with metformin, alpha glucosidase inhibitors, GLP-1 receptor agonists and orlistat than with other agents.

Metformin can cause diarrhea, which tends to resolve over time and is minimized with starting at a low dose and subsequent slow titration of the dosage. Extended-release metformin can also be used to improve tolerability in individuals experiencing gastrointestinal side effects with immediate-release metformin — Metformin is also associated with an approximate 2-fold increased incidence of vitamin B12 deficiency — , and vitamin B12 levels should be measured periodically in people taking metformin or with signs or symptoms of deficiency such as impaired proprioception or peripheral neuropathy.

GLP-1 receptor agonists and, less commonly, DPP-4 inhibitors can cause nausea and GLP-1 receptor agonists can also cause diarrhea. A meta-analysis comparing the risk of congestive heart failure between antihyperglycemic therapies found an increased risk with TZDs and DPP-4 inhibitors driven by higher risk with saxagliptin 44 , although another meta-analysis and a large observational study of over one million participants failed to find an increased risk of heart failure with DPP-4 inhibitors compared to other agents.

Reports of acute pancreatitis have been noted with DPP-4 inhibitors and GLP-1 receptor agonists. A small significant increase in pancreatitis but not pancreatic cancer was seen with DPP4-inhibitors in a meta-analysis of 3 large randomized controlled trials of over 20, participants However, a recent large Canadian observational study of over 1.

SGLT2 inhibitors are associated with a 3- to 4-fold increased risk of genital mycotic infections 19,69,95 , as well as higher rates of urinary tract infections, volume depletion, rare acute kidney injury and rare DKA , Canagliflozin treatment is associated with an increased risk of fractures 54, and a twofold increased risk of amputations In a retrospective analysis, empagliflozin was not associated with an increased risk of amputations in the EMPA-REG trial There is evidence of a higher risk of bladder cancer with pioglitazone in some studies 47,48 but not others — , and some reports of increased bladder cancer risk with dapagliflozin GLP-1 receptor agonists have been shown to promote the development of pancreatic and medullary thyroid cancer in rodents, but an increased risk has not been seen in humans Semaglutide was associated with a higher risk of retinopathy in SUSTAIN-6 see above Earlier epidemiological evidence suggesting a possible link between insulin glargine and cancer has not been substantiated in review of clinical trial data for either glargine or detemir 36,, Insulin glargine U may be considered over insulin glargine U to reduce overall and nocturnal hypoglycemia [Grade C, Level 3 ].

A1C , glycated hemoglobin; BG , blood glucose; BP , blood pressure; CHF , congestive heart failure; CHD , coronary heart disease; CI , confidence interval; CV , cardiovascular; CVD , cardiovascular disease; DKA , diabetic ketoacidosis; HR , hazard ratio; MI ; myocardial infarct; NPH , neutral protamine Hagedorn; TZD , thiazolidinedione.

Appendix 9. Examples of Insulin Initiation and Titration Regimens in People With Type 2 Diabetes. Literature Review Flow Diagram for Chapter Pharmacologic Glycemic Management of Type 2 Diabetes in Adults.

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group P referred R eporting I tems for S ystematic Reviews and M eta- A nalyses: The PRISMA Statement.

PLoS Med 6 6 : e pmed For more information, visit www. Goldenberg reports personal fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, and Servier, outside the submitted work.

MacCallum reports personal fees from Janssen and Novo Nordisk, outside the submitted work. No other author has anything to disclose.

All content on guidelines. ca, CPG Apps and in our online store remains exactly the same. For questions, contact communications diabetes.

Become a Member Order Resources Home About Contact DONATE. Next Previous. Key Messages Recommendations Figures Full Text References. Chapter Headings Introduction Treatment Regimens Effects of Antihyperglycemic Agents on Microvascular and Cardiovascular Complications Effects of Antihyperglycemic Agents on Glycemic Control and Other Short-Term Outcomes Insulin Treatment in Type 2 Diabetes Adverse Effects Other Relevant Guidelines Relevant Appendices Author Disclosures.

Key Messages Healthy behaviour interventions should be initiated in people newly diagnosed with type 2 diabetes. In the absence of metabolic decompensation, metformin should be the initial agent of choice in people with newly diagnosed type 2 diabetes, unless contraindicated.

In people with clinical cardiovascular CV disease in whom A1C targets are not achieved with existing pharmacotherapy, an antihyperglycemic agent with demonstrated CV outcome benefit should be added to antihyperglycemic therapy to reduce CV risk.

In people receiving an antihyperglycemic regimen containing insulin, in whom glycemic targets are not achieved, the addition of a GLP-1 receptor agonist, DPP-4 inhibitor or SGLT2 inhibitor may be considered before adding or intensifying prandial insulin therapy to improve glycemic control with less weight gain and comparable or lower hypoglycemia risk.

Key Messages for People with Diabetes Some people who have type 2 diabetes can achieve their target blood glucose levels with nutrition guidance and physical activity alone, but most also need glucose-lowering medications.

The decision about which medications are best for you depends on many factors, including your blood glucose level, symptoms, other health problems you have and affordability of medications. Your health-care provider may even combine medications that act differently on your body to help you control your blood glucose.

Glucose-lowering medications for type 2 diabetes include: First-line glucose-lowering medication: Metformin: Metformin is generally the first choice for people with type 2 diabetes because of its safety, low cost and possible heart benefits.

It works by making your body respond better to insulin so that your body uses insulin more effectively. Metformin also lowers glucose production from the liver. Nausea and diarrhea are possible side effects and usually go away within 1 to 2 weeks as your body gets used to the medicine.

It is associated with a low risk of hypoglycemia and does not cause weight gain. If metformin and healthy behaviour changes are not enough to control your blood glucose level, other medications can be added. Second-line glucose-lowering medication: DPP-4 inhibitors: These medications work to lower blood glucose by increasing insulin levels after meals and lowering glucagon levels a hormone that raises blood glucose.

They do not cause weight gain and are associated with a low risk of hypoglycemia. GLP-1 receptor agonists: These injectable medications act when blood glucose increases after eating. They increase insulin levels, which helps lower blood glucose and lower glucagon levels a hormone that raises blood glucose.

They also slow digestion and reduce appetite. Possible side effects include nausea, which usually goes away with time.

They are associated with weight loss and a low risk of hypoglycemia. SGLT2 inhibitors: These medications work by eliminating glucose into the urine. Side effects may include genital yeast infections, urinary tract infections, increased urination and low blood pressure.

Insulin secretagogues meglitinides, sulfonylureas : These medications help your pancreas release more insulin. Possible side effects include hypoglycemia and weight gain. Thiazolidinediones: Like metformin, these medications make the body's tissues more sensitive to insulin.

Side effects include weight gain and an increased risk of heart failure and fractures. Insulin therapy: Some people who have type 2 diabetes need insulin therapy as well. Depending on your needs, your health-care provider may prescribe a mixture of insulin types to use throughout the day and night.

Often, people with type 2 diabetes start insulin use with 1 injection of long-acting insulin at night. Discuss the pros and cons of different treatment plans with your healthcare provider. Together, you can decide which medication is best for you after considering many factors, including costs and other aspects of your health.

Introduction People with type 2 diabetes form a heterogeneous group. Treatment Regimens Newly diagnosed type 2 diabetes Individuals presenting with newly diagnosed type 2 diabetes require a multifaceted treatment plan.

Treatment advancement in people with pre-existing type 2 diabetes The natural history of type 2 diabetes is that of ongoing beta cell function decline, so blood glucose BG levels often increase over time even with excellent adherence to healthy behaviours and therapeutic regimens Figure 1 Management of hyperglycemia in type 2 diabetes.

Effects of Antihyperglycemic Agents on Microvascular and Cardiovascular Complications In deciding upon which agent to add after metformin, there must be consideration of both short-term effects on glycemic control and long-term effects on clinical complications.

Effects of Antihyperglycemic Agents on Glycemic Control and Other Short-Term Outcomes In the absence of evidence for long-term clinical benefit, agents effective at A1C lowering should be considered in terms of both the degree of baseline hyperglycemia needing correction, and any heightened concerns regarding hypoglycemia e.

Insulin Treatment in Type 2 Diabetes A combination of noninsulin antihyperglycemic agents and insulin often effectively controls glucose levels.

Adverse Effects Aside from effects of some antihyperglycemic agents on the occurrence of hypoglycemia and weight, there are adverse effects unique to each agent Table 1.

Recommendations Treatment of Newly Diagnosed People with Type 2 Diabetes Healthy behaviour interventions should be initiated at diagnosis [Grade B, Level 2 2 ].

Metformin may be used at the time of diagnosis, in conjunction with healthy behaviour interventions [Grade D, Consensus].

Readers who wish to comment on the Standards of Care are invited to do so at professional. Most people with type 1 diabetes should be treated with multiple daily injections of prandial insulin and basal insulin or continuous subcutaneous insulin infusion.

Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk. Consider educating individuals with type 1 diabetes on matching prandial insulin doses to carbohydrate intake, premeal blood glucose levels, and anticipated physical activity.

Individuals with type 1 diabetes who have been successfully using continuous subcutaneous insulin infusion should have continued access to this therapy after they turn 65 years of age.

Insulin is the mainstay of therapy for individuals with type 1 diabetes. Generally, the starting insulin dose is based on weight, with doses ranging from 0.

Education regarding matching prandial insulin dosing to carbohydrate intake, premeal glucose levels, and anticipated activity should be considered, and selected individuals who have mastered carbohydrate counting should be educated on fat and protein gram estimation 3 — 5.

Although most studies of multiple daily injections versus continuous subcutaneous insulin infusion CSII have been small and of short duration, a systematic review and meta-analysis concluded that there are minimal differences between the two forms of intensive insulin therapy in A1C combined mean between-group difference favoring insulin pump therapy —0.

A 3-month randomized trial in patients with type 1 diabetes with nocturnal hypoglycemia reported that sensor-augmented insulin pump therapy with the threshold suspend feature reduced nocturnal hypoglycemia without increasing glycated hemoglobin levels 7.

The U. Food and Drug Administration FDA has also approved the first hybrid closed-loop system pump.

The safety and efficacy of hybrid closed-loop systems has been supported in the literature in adolescents and adults with type 1 diabetes 8 , 9. The Diabetes Control and Complications Trial DCCT clearly showed that intensive therapy with multiple daily injections or CSII delivered by multidisciplinary teams of physicians, nurses, dietitians, and behavioral scientists improved glycemia and resulted in better long-term outcomes 13 — The study was carried out with short-acting and intermediate-acting human insulins.

Despite better microvascular, macrovascular, and all-cause mortality outcomes, intensive therapy was associated with a high rate of severe hypoglycemia 61 episodes per patient-years of therapy. Since the DCCT, a number of rapid-acting and long-acting insulin analogs have been developed.

These analogs are associated with less hypoglycemia, less weight gain, and lower A1C than human insulins in people with type 1 diabetes 16 — Longer-acting basal analogs U glargine or degludec may additionally convey a lower hypoglycemia risk compared with U glargine in patients with type 1 diabetes 19 , Rapid-acting inhaled insulin used before meals in patients with type 1 diabetes was shown to be noninferior when compared with aspart insulin for A1C lowering, with less hypoglycemia observed with inhaled insulin therapy However, the mean reduction in A1C was greater with aspart —0.

Because inhaled insulin cartridges are only available in 4-, 8-, and unit doses, limited dosing increments to fine-tune prandial insulin doses in type 1 diabetes are a potential limitation.

Postprandial glucose excursions may be better controlled by adjusting the timing of prandial bolus insulin dose administration. The optimal time to administer prandial insulin varies, based on the type of insulin used regular, rapid-acting analog, inhaled, etc.

Recommendations for prandial insulin dose administration should therefore be individualized. Pramlintide, an amylin analog, is an agent that delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety.

It is FDA-approved for use in adults with type 1 diabetes. It has been shown to induce weight loss and lower insulin doses. Concurrent reduction of prandial insulin dosing is required to reduce the risk of severe hypoglycemia.

Adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in patients with type 1 diabetes. In one study, metformin was found to reduce insulin requirements 6. A randomized clinical trial similarly found that, among overweight adolescents with type 1 diabetes, the addition of metformin to insulin did not improve glycemic control and increased risk for gastrointestinal adverse events after 6 months compared with placebo The Reducing With Metformin Vascular Adverse Lesions in Type 1 Diabetes REMOVAL trial investigated the addition of metformin therapy to titrated insulin therapy in adults with type 1 diabetes at increased risk for cardiovascular disease and found that metformin did not significantly improve glycemic control beyond the first 3 months of treatment and that progression of atherosclerosis measured by carotid artery intima-media thickness was not significantly reduced, although other cardiovascular risk factors such as body weight and LDL cholesterol improved Metformin is not FDA-approved for use in patients with type 1 diabetes.

Due to their potential protection of β-cell mass and suppression of glucagon release, glucagon-like peptide 1 GLP-1 receptor agonists 25 and dipeptidyl peptidase 4 DPP-4 inhibitors 26 are being studied in patients with type 1 diabetes but are not currently FDA-approved for use in patients with type 1 diabetes.

Sodium—glucose cotransporter 2 SGLT2 inhibitors provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal renal tubule by inhibiting SGLT2. These agents provide modest weight loss and blood pressure reduction in type 2 diabetes. There are three FDA-approved agents for patients with type 2 diabetes, but none are FDA-approved for the treatment of patients with type 1 diabetes 2.

SGLT2 inhibitors may have glycemic benefits in patients with type 1 or type 2 diabetes on insulin therapy The FDA issued a warning about the risk of ketoacidosis occurring in the absence of significant hyperglycemia euglycemic diabetic ketoacidosis in patients with type 1 or type 2 diabetes treated with SGLT2 inhibitors.

Symptoms of ketoacidosis include dyspnea, nausea, vomiting, and abdominal pain. Patients should be instructed to stop taking SGLT2 inhibitors and seek medical attention immediately if they have symptoms or signs of ketoacidosis Pancreas and islet transplantation have been shown to normalize glucose levels but require life-long immunosuppression to prevent graft rejection and recurrence of autoimmune islet destruction.

Given the potential adverse effects of immunosuppressive therapy, pancreas transplantation should be reserved for patients with type 1 diabetes undergoing simultaneous renal transplantation, following renal transplantation, or for those with recurrent ketoacidosis or severe hypoglycemia despite intensive glycemic management Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for the treatment of type 2 diabetes.

Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy.

In patients without atherosclerotic cardiovascular disease, if monotherapy or dual therapy does not achieve or maintain the A1C goal over 3 months, add an additional antihyperglycemic agent based on drug-specific and patient factors Table 8.

A patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include efficacy, hypoglycemia risk, history of atherosclerotic cardiovascular disease, impact on weight, potential side effects, renal effects, delivery method oral versus subcutaneous , cost, and patient preferences.

In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, antihyperglycemic therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality currently empagliflozin and liraglutide , after considering drug-specific and patient factors Table 8.

In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, after lifestyle management and metformin, the antihyperglycemic agent canagliflozin may be considered to reduce major adverse cardiovascular events, based on drug-specific and patient factors Table 8.

Continuous reevaluation of the medication regimen and adjustment as needed to incorporate patient factors Table 8. For patients with type 2 diabetes who are not achieving glycemic goals, drug intensification, including consideration of insulin therapy, should not be delayed.

Metformin should be continued when used in combination with other agents, including insulin, if not contraindicated and if tolerated. See Section 12 for recommendations specific for children and adolescents with type 2 diabetes. The use of metformin as first-line therapy was supported by findings from a large meta-analysis, with selection of second-line therapies based on patient-specific considerations Renal effects may also be considered when selecting glucose-lowering medications for individual patients.

Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes. CVD, cardiovascular disease; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; NASH, nonalcoholic steatohepatitis; RAs, receptor agonists; SQ, subcutaneous; T2DM, type 2 diabetes.

Metformin monotherapy should be started at diagnosis of type 2 diabetes unless there are contraindications. Metformin is effective and safe, is inexpensive, and may reduce risk of cardiovascular events and death Compared with sulfonylureas, metformin as first-line therapy has beneficial effects on A1C, weight, and cardiovascular mortality Patients should be advised to stop the medication in cases of nausea, vomiting, or dehydration.

Metformin is associated with vitamin B12 deficiency, with a recent report from the Diabetes Prevention Program Outcomes Study DPPOS suggesting that periodic testing of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy In patients with metformin contraindications or intolerance, consider an initial drug from another class depicted in Fig.

Insulin has the advantage of being effective where other agents may not be and should be considered as part of any combination regimen when hyperglycemia is severe, especially if catabolic features weight loss, ketosis are present. Consider initiating combination insulin injectable therapy Fig.

Antihyperglycemic therapy in type 2 diabetes: general recommendations. GLP-1 receptor agonists and DPP-4 inhibitors should not be prescribed in combination. If a patient with ASCVD is not yet on an agent with evidence of cardiovascular risk reduction, consider adding.

Combination injectable therapy for type 2 diabetes. FBG, fasting blood glucose; hypo, hypoglycemia. Adapted with permission from Inzucchi et al. Although there are numerous trials comparing dual therapy with metformin alone, few directly compare drugs as add-on therapy.

A comparative effectiveness meta-analysis 36 suggests that each new class of noninsulin agents added to initial therapy generally lowers A1C approximately 0. If the A1C target is not achieved after approximately 3 months and patient does not have atherosclerotic cardiovascular disease ASCVD , consider a combination of metformin and any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin Fig.

For patients with ASCVD, add a second agent with evidence of cardiovascular risk reduction after consideration of drug-specific and patient factors see p. Drug choice is based on patient preferences 37 , as well as various patient, disease, and drug characteristics, with the goal of reducing blood glucose levels while minimizing side effects, especially hypoglycemia.

If not already included in the treatment regimen, addition of an agent with evidence of cardiovascular risk reduction should be considered in patients with ASCVD beyond dual therapy, with continuous reevaluation of patient factors to guide treatment Table 8.

Table 8. Cost-effectiveness models of the newer agents based on clinical utility and glycemic effect have been reported Of note, prices listed are average wholesale prices AWP 39 and National Average Drug Acquisition Costs NADAC 40 and do not account for discounts, rebates, or other price adjustments often involved in prescription sales that affect the actual cost incurred by the patient.

While there are alternative means to estimate medication prices, AWP and NADAC were utilized to provide two separate measures to allow for a comparison of drug prices with the primary goal of highlighting the importance of cost considerations when prescribing antihyperglycemic treatments.

The ongoing Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study GRADE will compare four drug classes sulfonylurea, DPP-4 inhibitor, GLP-1 receptor agonist, and basal insulin when added to metformin therapy over 4 years on glycemic control and other medical, psychosocial, and health economic outcomes Pharmacology of available glucose-lowering agents in the U.

Insulin treatment guidelines -

It is very important to use this specially marked syringe only for U insulin. Using a U syringe with other insulins or using a U syringe with U can potentially result in dangerous errors in insulin dose. Injection technique — The following is a description of subcutaneous insulin injection:.

It is not necessary to clean the skin with alcohol unless the skin is dirty. Keep the skin pinched to avoid injecting insulin into the muscle. Depending upon your body type, you may not need to pinch up a fold of skin.

Hold the syringe and needle in place for 5 to 10 seconds. If blood or clear fluid insulin is seen at the injection site, apply pressure to the area for five to eight seconds. The area should not be rubbed, because this can cause the insulin to be absorbed too quickly.

Needles and syringes should only be used once and then thrown away. Needles and syringes should never be shared. Used needles and syringes should not be included with regular household trash but should instead be placed in a puncture-proof container also known as a sharps container , available from most pharmacies or hospital supply stores.

Alternatively, a puncture-proof container such as an old liquid laundry detergent bottle, which can be closed with a screw cap, can be used. Check your local rules concerning disposal of these containers. Injecting through clothing — Some people wonder about the safety of injecting insulin through their clothing.

While it may be possible to do this, it's best to seek guidance from your health care provider if you are interested in using this technique. Inhaled insulin — One formulation of inhaled insulin brand name: Afrezza is available for clinical use in the United States.

Once inhaled, it begins to work quickly, similar to rapid-acting insulin, and is therefore considered a prandial mealtime insulin. Inhaled insulin has not been shown to lower glycated hemoglobin A1C levels to the usual target level of less than 7 percent in most studies.

In addition, lung function testing is required before starting it and periodically during therapy. Insulin pump. General principles — Insulin can be continuously administered by an insulin pump, rather than through multiple daily injections with a pen injector or needle and syringe.

An insulin pump may be recommended based on your preference and willingness and ability to use it. The pump stores rapid-acting insulin in a cartridge. Pumps are programmed to give a small dose of rapid-acting insulin every few minutes through the day and night basal insulin. Before a meal, the pump needs to deliver a larger dose bolus of insulin, to prevent your blood sugar level from going too high after eating.

Most pumps deliver insulin through a long spaghetti-like catheter, the end of which you insert under the skin. The catheter is taken out and re-inserted approximately every two to three days.

You will be taught how to do this relatively painless and quick procedure. Other pumps are entirely self-contained, with a small catheter built right into the small, disposable pump unit that needs to be replaced every few days. For these "patch" pumps, insulin delivery is controlled by another device or compatible smartphone that you need to carry with you.

The pump can be taken off for up to one hour without impacting blood sugar control; if it is taken off for longer periods of time, insulin injections may be needed to control the blood sugar.

If available and affordable, people using multiple daily insulin injections or an insulin pump generally use a continuous glucose monitoring CGM device, which provides more information about blood sugar levels than traditional fingersticks and a glucose meter. These devices allow you to make better informed decisions about insulin dosing based on your blood sugar trends.

If you do not use CGM, you may need to check your blood sugar levels four to seven times daily before meals, bedtime, sometimes two to three hours after meals, and occasionally in the middle of the night while your doses are being adjusted. In addition, testing is recommended when low blood sugar is suspected; before, during, and after exercise; and before driving or engaging in a dangerous activity.

After doses are programmed initially in the pump, testing at least four times per day, including before meals, is required as you must direct the pump to give pre-meal insulin based upon your blood sugar level and amount and type of food you plan to eat. If insulin injection therapy is used, the pre-meal blood sugar and anticipated food intake are also used to help calculate the mealtime insulin dose injected.

Some insulin pumps communicate with CGMs, receiving glucose readings every five minutes. They can automatically adjust the basal rate of insulin delivery and deliver extra insulin to help correct for high blood sugars depending on the CGM results called a partial "artificial pancreas," "automated insulin delivery" [AID], or "hybrid closed-loop" system figure 5.

These devices can improve or maintain glucose control with less risk of hypoglycemia low blood sugar. The following devices, combining an insulin pump with CGM, are available or will become available in the future:. The insulin pump can be programmed to stop insulin delivery for up to two hours at a preset glucose value "low glucose suspend" feature or to reduce or stop insulin infusion if the system "predicts" that your blood sugar will soon go too low "predictive low glucose suspend" feature.

These features reduce the frequency and duration of hypoglycemia that may occur while you are sleeping. Some systems will also deliver extra insulin to help correct for hyperglycemia high blood sugar when there is insufficient insulin on board. You need to manually direct delivery of insulin doses prior to meals.

Use of these systems has been associated with less hypoglycemia low blood sugar and more blood sugar readings in the target range. An investigational bihormonal system uses two commercially available pumps, with one delivering insulin and the other glucagon. These systems are also fully automated, in that the delivery of the insulin and glucagon is determined completely automatically by an algorithm that is, in turn, dependent on CGM results.

These devices have not yet been approved and are not commercially available. The insulin pump has advantages and disadvantages; it may be helpful to talk with a person who uses a pump before deciding to try it. Most pump manufacturers have a list of people willing to speak with prospective pump users.

It may also be possible to use a trial pump for a few days before committing to it. Advantages — Insulin pumps have the advantage of increasing flexibility in the timing of meals and other day-to-day events. This can be of great benefit for children or adults whose schedule varies from one day to the next.

People who use an insulin pump do not require multiple daily injections; most people who use the pump change their injection insulin infusion site every 48 to 72 hours.

Another major advantage of an insulin pump is that there is less variation in the amount of insulin absorbed compared with when insulin is given with a needle and syringe or pen. This can help reduce day-to-day variations in blood sugar levels. Insulin pumps can deliver smaller amounts of insulin at a time than injection therapy.

The greatest advantage is for people with type 1 diabetes having blood glucose readings that are too low hypoglycemia and too high hyperglycemia. The use of an insulin pump with CGM in an automated system can help reduce hypoglycemia and increase time in the target range. Disadvantages — The cost of an insulin pump and supplies is greater than the cost of insulin syringes and needles or pens, although most insurance carriers cover some portion of the expenses.

Some people develop pump-associated problems, including skin irritation or infection at the infusion site or pump malfunction. You must take care to monitor your blood sugar levels carefully; stopping insulin, even for a short time, can lead to a significant increase in blood sugar.

Some people find the pump awkward, unpleasant, or embarrassing although others find that they are able to adjust to it fairly easily. However, you can disconnect the pump for brief periods, if desired.

FACTORS AFFECTING INSULIN ACTION. Dose of insulin injected — The dose of insulin injected affects the rate at which your body absorbs it. For example, larger doses of insulin may be absorbed more slowly than a small dose. With larger doses of insulin, the insulin may peak later or last longer than with small doses.

This could mean that your blood sugar level is higher than expected within a few hours after eating but then becomes low.

Injection technique — In general, we recommend the use of short insulin needles 4 or 5 mm to minimize tissue damage and reduce the likelihood of inadvertently injecting into muscle.

The angle and depth of an insulin injection are important, as mentioned above. See 'Needle and syringe' above.

Site of injection — Clinicians usually recommend changing your injection site to minimize tissue irritation. However, it is important to keep in mind that insulin is absorbed at different rates in different areas of the body. For some types of insulin, the insulin is absorbed fastest from the abdominal area, slowest from the leg and buttock, and at an intermediate rate from the arm.

This may vary with the amount of fat under the skin; the more fat, the more slowly insulin is absorbed figure 2. Because of variations in absorption, it is reasonable to use the same general area for injections at a particular time of the day.

Pre-meal insulin injections are absorbed fastest from the abdominal area, allowing for optimal coverage of carbohydrates consumed in a meal. Injection into the thigh or buttock may be best for the evening dose because the insulin will be absorbed more slowly during the night.

Subcutaneous blood flow — Any factor that alters the rate of blood flow to the body's tissues will alter insulin absorption. Smoking decreases blood flow to the tissues and decreases absorption of injected insulin, whereas running increases blood flow to the lower body, speeding up absorption of insulin injected into a leg.

Factors that increase the skin temperature such as exercise, saunas, hot baths, and massage of the injection site will also increase insulin absorption. Time since opening the insulin bottle or pen — In general, insulin bottles vials , pens, and pen cartridges are good until their expirations date, if left unopened in a refrigerator.

Insulin should never be allowed to freeze or get hot. All rights reserved. University of California, San Francisco About UCSF Search UCSF UCSF Medical Center. Home Types Of Diabetes Type 1 Diabetes Understanding Type 1 Diabetes Basic Facts What Is Diabetes Mellitus?

What Are The Symptoms Of Diabetes? Diagnosing Diabetes Treatment Goals What is Type 1 Diabetes? What Causes Autoimmune Diabetes? Pens are especially useful for accurately injecting very small doses of insulin and may be easier to use for people with vision or dexterity problems.

Pens are more expensive than traditional syringes and needles. A number of different insulin pens are available; each comes with specific instructions for use, and video tutorials are available online. Needle and syringe — Some people use a needle and syringe rather than a pen injector to give themselves insulin.

This involves drawing up insulin from a bottle using the syringe, then injecting it with the needle. Drawing up insulin — There are many different types of syringes and needles, so it's best to get specific instructions for drawing up insulin from your health care provider.

The basic steps are listed in the table table 2. See 'Insulin pen injectors' above. Before drawing up insulin, it is important to know the dose and type of insulin needed; if you use more than one type of insulin, you will need to calculate the total dose needed your health care provider will show you how to do this.

Some people, including children and those with vision problems, may need assistance. Magnification and other assistive devices are available. If you have difficulty drawing up your insulin, let your health care provider know, as there are ways to help with this.

One type of insulin, called U regular insulin, might come in a pen or a vial. When it comes in a vial, it requires a special U syringe; this syringe makes it easier to measure the right dose.

If you use this type of insulin, your health care provider can show you how to use the U syringe. It's very important to use this specially marked syringe only for U insulin.

Using a U syringe with other insulins can cause a dangerous insulin overdose. Because it can be confusing to figure out how to accurately measure the correct dose, U insulin and other concentrated insulins U lispro or degludec should be prescribed in an insulin pen device under most circumstances.

Injection angle — Insulin is usually injected under the skin figure 3. It is important to use the correct injection angle since injecting too deeply could deliver insulin to the muscle, where it is absorbed too quickly. On the other hand, injections that are too shallow are more painful and not absorbed well.

The best angle for insulin injection depends on your body type, injection site, and length of the needle used. Your health care provider can help you figure out what length needle to use and the angle at which to inject your insulin. Injection technique — These are the basic steps for injecting insulin:.

You do not need to clean the skin with alcohol unless your skin is dirty. Keep the skin pinched to avoid injecting insulin into the muscle. Hold the syringe and needle in place for 5 seconds for syringes and 10 seconds for insulin pens. If you see blood or clear fluid insulin at the injection site, apply pressure to the area for a few seconds.

Do not rub the skin, as this can cause the insulin to be absorbed too quickly. Each needle and syringe should be used once and then thrown away; needles become dull quickly, potentially increasing the pain of injection.

Needles and syringes should never be shared. Used needles and syringes should not be included with regular household trash but should instead be placed in a puncture-proof container eg, a hard laundry detergent bottle or a sharps container, which is available from most pharmacies or hospital supply stores.

FACTORS AFFECTING INSULIN ACTION. Dose of insulin injected — The dose of insulin injected affects the rate at which the body absorbs it.

Larger doses of insulin may be absorbed more slowly than smaller doses. Site of injection — It is very important to rotate injection sites ie, avoid using the same site each time to minimize tissue irritation or damage. When changing sites, it is important to keep in mind that insulin is absorbed at different rates in different areas of the body.

Insulin is absorbed fastest from the abdominal area, slowest from the leg and buttock, and at an intermediate rate from the arm. This may vary with the amount of fat present; areas with more fat under the skin absorb insulin more slowly figure 1.

It is reasonable to use the same general area for injections given at the same time of the day. Sometimes abdominal injections, which are absorbed more quickly, are preferred before meals. Injection into the thigh or buttock may be best for the evening dose because the insulin will be absorbed more slowly during the night.

Smoking and physical activity — Any factors that alter the rate of blood flow through the skin and fat will change insulin absorption. Smoking decreases blood flow, which in turn decreases insulin absorption. In contrast, activities that increase blood flow such as exercise, saunas, hot baths, and massaging the injection site increase insulin absorption and can result in hypoglycemia low blood sugar.

For these reasons, it is best to avoid injecting your insulin immediately after any of these activities. Your health care provider might also recommend taking a lower dose of insulin before or after exercise. Decreased potency over time — Most insulin remains potent and effective for up to one month after the bottle has been opened if kept in the refrigerator between injections.

However, the potency of intermediate-acting and long-acting insulin begins to decrease after 30 days. This can be a problem for people who require very small doses of insulin, for whom a vial might last two months or more.

If you use a needle and syringe, it is advisable to start a new vial at least every 30 days. Insulin pens come with specific instructions about how to store and use the device. Unopened insulin pens are usually stored in the refrigerator.

Once the pen is opened, most pen injectors can be kept at room temperature eg, in a purse or jacket pocket for up to 14 to 28 days, depending on the type of insulin premixed insulin loses potency more quickly. It's important to avoid exposing the pen to extreme temperatures hot or cold.

After the specified number of days, or if there is suspicion that the insulin has lost potency for example, if the pen was left in a hot car , a new insulin cartridge or pen should be used, even if there is insulin left in the old device. Individual differences — The same dose of the same type of insulin may have different effects in different people with diabetes.

Some trial-and-error is usually necessary to find the ideal type s and dose of insulin and schedule for each person. Insulin needs often change over a person's lifetime. Changes in weight, diet, health conditions including pregnancy , activity level, and occupation can have an impact on the amount of insulin needed to control blood sugar levels.

Your health care provider should be able to teach you to adjust your own insulin dose as needed, but this will depend on your specific situation. See "Patient education: Care during pregnancy for patients with type 1 or 2 diabetes Beyond the Basics ".

Several situations can complicate insulin treatment for a person with diabetes. With advance planning and careful calculation, these situations are less likely to cause major fluctuations in your blood sugar control.

Your health care provider can assist you in handling these situations. Eating out — Eating out can be challenging since the ingredients used, calorie and fat content, and portion sizes are usually different from meals prepared at home.

If your insulin regimen involves injecting the same amount of insulin at the same time each day, being consistent about when and what you eat will help to improve blood sugar control. If meal timing and content varies widely, blood sugar levels will fluctuate as well, making it less likely that you will meet your goal A1C level.

When dining out, you can make healthy food choices by requesting nutrition information from the restaurant or referring to a web site, phone app, or reference book. See "Patient education: Type 2 diabetes and diet Beyond the Basics ". Hypoglycemia and hyperglycemia can occur more easily in situations where you are eating new or different foods; thus, it's important to keep a fast-acting source of carbohydrates such as hard candy or glucose tablets as well as a blood glucose monitor with you at all times.

See "Patient education: Hypoglycemia low blood glucose in people with diabetes Beyond the Basics ". Surgery — If you need to have surgery or another procedure, you may be instructed not to eat for 8 to 12 hours before their procedure.

In this situation, a health care provider can help you determine the dose and timing of insulin to use before and after the procedure. This is particularly important if you will be unable to eat a normal diet after the procedure. Infections — Infections such as a cold, sore throat, urinary tract infection, or any infection that causes fever can cause blood sugar levels to rise.

If you get sick, it's a good idea to talk with your health care provider, as you will need to carefully monitor your blood sugar levels and possibly increase your insulin dose. It is also important to drink plenty of fluids in order to avoid dehydration.

If you have nausea or vomiting, you may need medication to control your symptoms and avoid dehydration. Travel — Managing blood sugar levels and insulin treatment while traveling can be difficult, especially if you are traveling across multiple time zones.

In addition, activity levels and diet are often different while traveling, making it especially important to carefully monitor your blood sugar levels.

Insulin is secreted continuously by beta treament in a treat,ent manner throughout traetment day. Insulin treatment guidelines is also secreted in response guiddlines oral carbohydrate loads, Sustain long-lasting energy naturally a large first-phase insulin release Insulin treatment guidelines suppresses hepatic glucose production followed by a slower second-phase insulin release that covers ingested carbohydrates 1 Figure 1 2. Type 2 diabetes mellitus is associated with insulin resistance and slowly progressive beta-cell failure. By the time type 2 diabetes is diagnosed in patients, up to one-half of their beta cells are not functioning properly. Pain, weight gain, and hypoglycemia may occur with insulin therapy. Insulin treatment guidelines

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