In addition, GLP-1 receptor agonists have been shown to slow the rate of decline in eGFR and prevent worsening of albuminuria. See 'Microvascular outcomes' below and "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus" and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".

Of note, we avoid use of SGLT2 inhibitors in patients with frequent bacterial urinary tract infections or genitourinary yeast infections, low bone density and high risk for falls and fractures, foot ulceration, and factors predisposing to diabetic ketoacidosis eg, pancreatic insufficiency, drug or alcohol abuse disorder because of increased risk while using these agents.

SLGT2 inhibitors should be held for 3 to 4 days before procedures including colonoscopy preparation and with poor oral intake to prevent diabetic ketoacidosis. See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Contraindications and precautions'.

Repaglinide acts at the sulfonylurea receptor to increase insulin secretion but is much shorter acting than sulfonylureas and is principally metabolized by the liver, with less than 10 percent renally excreted.

Limited data suggest that dipeptidyl peptidase 4 DPP-4 inhibitors are effective and relatively safe in patients with chronic kidney disease. However, linagliptin is the only DPP-4 inhibitor that does not require a dose adjustment in the setting of kidney failure.

GLP-1 receptor agonists may also be used safely in chronic kidney disease stage 4, but patient education for signs and symptoms of dehydration due to nausea or satiety is warranted to reduce the risk of acute kidney injury. Insulin may also be used, with a greater portion of the total daily dose administered during the day due to the risk of hypoglycemia, especially overnight, in chronic kidney disease and end-stage kidney disease ESKD.

See "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic kidney disease or end-stage kidney disease", section on 'Patients not on dialysis'.

Without established cardiovascular or kidney disease — For patients without established CVD or kidney disease who cannot take metformin , many other options for initial therapy are available table 1.

We suggest choosing an alternative glucose-lowering medication guided by efficacy, patient comorbidities, preferences, and cost. Although historically insulin has been used for type 2 diabetes only when inadequate glycemic management persists despite oral agents and lifestyle intervention, there are increasing data to support using insulin earlier and more aggressively in type 2 diabetes.

By inducing near normoglycemia with intensive insulin therapy, both endogenous insulin secretion and insulin sensitivity improve; this results in better glycemic management, which can then be maintained with diet, exercise, and oral hypoglycemics for many months thereafter.

Insulin may cause weight gain and hypoglycemia. See "Insulin therapy in type 2 diabetes mellitus", section on 'Indications for insulin'. If type 1 diabetes has been excluded, a GLP-1 receptor agonist is a reasonable alternative to insulin [ 66,67 ]. The frequency of injections and proved beneficial effects in the setting of CVD are the major differences among the many available GLP-1 receptor agonists.

In practice, given the high cost of this class of medications, formulary coverage often determines the choice of the first medication within the class. Cost and insurance coverage may limit accessibility and adherence. See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Patient selection'.

Each one of these choices has individual advantages, benefits, and risks table 1. See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus" and "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Patient selection' and "Dipeptidyl peptidase 4 DPP-4 inhibitors for the treatment of type 2 diabetes mellitus", section on 'Patient selection' and "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Potential indications'.

See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Weight loss' and "Dipeptidyl peptidase 4 DPP-4 inhibitors for the treatment of type 2 diabetes mellitus", section on 'Patient selection' and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Weight loss'.

The choice of sulfonylurea balances glucose-lowering efficacy, universal availability, and low cost with risk of hypoglycemia and weight gain. Pioglitazone , which is generic and another relatively low-cost oral agent, may also be considered in patients with specific contraindications to metformin and sulfonylureas.

However, the risk of weight gain, HF, fractures, and the potential increased risk of bladder cancer raise the concern that the overall risks and cost of pioglitazone may approach or exceed its benefits. See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus" and "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Potential indications'.

For patients who are starting sulfonylureas, we suggest initiating lifestyle intervention first, at the time of diagnosis, since the weight gain that often accompanies a sulfonylurea will presumably be less if lifestyle efforts are underway.

However, if lifestyle intervention has not produced a significant reduction in symptoms of hyperglycemia or in glucose values after one or two weeks, then the sulfonylurea should be added. Side effects may be minimized with diabetes self-management education focusing on medication reduction or omission with changes in diet, food accessibility, or activity that may increase the risk of hypoglycemia.

See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Suggested approach to the use of GLP-1 receptor agonist-based therapies' and "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Mechanism of action' and "Dipeptidyl peptidase 4 DPP-4 inhibitors for the treatment of type 2 diabetes mellitus", section on 'Mechanism of action' and "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Hypoglycemia'.

Symptomatic catabolic or severe hyperglycemia — The frequency of symptomatic or severe diabetes has been decreasing in parallel with improved efforts to diagnose diabetes earlier through screening.

If patients have been drinking a substantial quantity of sugar-sweetened beverages, reduction of carbohydrate intake, and rehydration with sugar-free fluids will help to reduce glucose levels within several days. See "Insulin therapy in type 2 diabetes mellitus", section on 'Initial treatment'.

However, for patients who are injection averse, initial therapy with high-dose sulfonylurea is an alternative option. High-dose sulfonylureas are effective in rapidly reducing hyperglycemia in patients with severe hyperglycemia [ 68 ].

Metformin monotherapy is not helpful in improving symptoms in this setting, because the initial dose is low and increased over several weeks. However, metformin can be started at the same time as the sulfonylurea, slowly titrating the dose upward.

Once the diet has been adequately modified and the metformin dose increased, the dose of sulfonylurea can be reduced and potentially discontinued.

Patients with type 2 diabetes require relatively high doses of insulin compared with those needed for type 1 diabetes.

Insulin preparations, insulin regimens, and timing of dosing are discussed in detail elsewhere. See "Insulin therapy in type 2 diabetes mellitus". See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Administration'.

We typically use glimepiride 4 or 8 mg once daily. An alternative option is immediate-release glipizide 10 mg twice daily or, where available, gliclazide immediate-release 80 mg daily.

We contact the patient every few days after initiating therapy to make dose adjustments increase dose if hyperglycemia does not improve or decrease dose if hyperglycemia resolves quickly or hypoglycemia develops.

See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Sulfonylureas'. Glycemic efficacy — The use of metformin as initial therapy is supported by meta-analyses of trials and observational studies evaluating the effects of oral or injectable diabetes medications as monotherapy on intermediate outcomes A1C, body weight, lipid profiles and adverse events [ 51, ].

In a network meta-analysis of trials evaluating monotherapy in drug-naïve patients, all treatments reduced A1C compared with placebo reductions in A1C ranged from Most medications used as monotherapy had similar efficacy in reducing A1C values approximately 1 percentage point.

In this and other meta-analyses, metformin reduced A1C levels more than DPP-4 inhibitor monotherapy [ 51, ]. There are few high-quality, head-to-head comparison trials of the available oral agents.

In one such trial, A Diabetes Outcome Progression Trial ADOPT , recently diagnosed patients with type 2 diabetes were randomly assigned to monotherapy with the thiazolidinedione rosiglitazone , metformin , or glyburide [ 72 ]. At the four-year evaluation, 40 percent of the subjects in the rosiglitazone group had an A1C value less than 7 percent, as compared with 36 percent in the metformin group and 26 percent in the glyburide group.

Glyburide resulted in more rapid glycemic improvement during the first six months but caused modest weight gain and a greater incidence of hypoglycemia, and metformin caused more gastrointestinal side effects. Rosiglitazone caused greater increases in weight, peripheral edema, and concentrations of low-density lipoprotein LDL cholesterol.

There was also an unexpected increase in fractures in women taking rosiglitazone. The study was limited by a high rate of withdrawal of study participants. Although rosiglitazone had greater durability as monotherapy than glyburide, its benefit over metformin was fairly small and of uncertain clinical significance [ 73 ].

See "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Safety'. Cardiovascular outcomes — Cardiovascular benefit has been demonstrated for selected classes of diabetes medications, usually when added to metformin. See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Monotherapy failure'.

The cardiovascular effects of diabetes drugs are reviewed in the individual topics. See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Dipeptidyl peptidase 4 DPP-4 inhibitors for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Insulin therapy in type 2 diabetes mellitus".

In trials of patients with type 2 diabetes with and without chronic kidney disease, GLP-1 receptor agonists slowed the rate of decline in eGFR and prevented worsening of albuminuria [ 54,56,58 ].

These trials and other trials evaluating microvascular outcomes are reviewed in the individual topics. Guidelines — Our approach is largely consistent with American and European guidelines [ 52,74,75 ]. A consensus statement regarding the management of hyperglycemia in type 2 diabetes by the American Diabetes Association ADA and the European Association for the Study of Diabetes EASD was developed in and has been updated regularly, with the most recent revision published in [ 75 ].

The guidelines emphasize the importance of individualizing the choice of medications for the treatment of diabetes, considering important comorbidities CVD, HF, or chronic kidney disease; hypoglycemia risk; and need for weight loss and patient-specific factors including patient preferences, values, and cost [ 75 ].

We also agree with the World Health Organization WHO that sulfonylureas have a long-term safety profile, are inexpensive, and are highly effective, especially when used as described above, with patient education and dose adjustment to minimize side effects [ 76 ].

Blood glucose monitoring BGM is not necessary for most patients with type 2 diabetes who are on a stable regimen of diet or oral agents and who are not experiencing hypoglycemia. BGM may be useful for some patients with type 2 diabetes who use the results to modify eating patterns, exercise, or insulin doses on a regular basis.

See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'Type 2 diabetes'. The balance among efficacy in lowering A1C, side effects, and costs must be carefully weighed in considering which drugs or combinations to choose.

Avoiding insulin, the most potent of all hypoglycemic medications, at the expense of poorer glucose management and greater side effects and cost, is not likely to benefit the patient in the long term. See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'.

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: Diabetic kidney disease".

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 10 th to 12 th 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.

Weight reduction through diet, exercise, and behavioral modification can all be used to improve glycemic management, although the majority of patients with type 2 diabetes will require medication. See 'Diabetes education' above. Glycemic targets are generally set somewhat higher for older adults and for those with comorbidities or a limited life expectancy and little likelihood of benefit from intensive therapy.

See 'Glycemic management' above and "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target'. In the absence of specific contraindications, we suggest metformin as initial therapy for most patients Grade 2B.

Although some guidelines and experts endorse the initial use of alternative agents as monotherapy or in combination with metformin, we prefer initiating a single agent typically metformin and then sequentially adding additional glucose-lowering agents as needed.

See 'Metformin' above and 'Glycemic efficacy' above. We suggest initiating metformin at the time of diabetes diagnosis Grade 2C , along with consultation for lifestyle intervention. See 'When to start' above. The dose of metformin should be titrated to its maximally effective dose usually mg per day in divided doses over one to two months, as tolerated.

See 'Contraindications to or intolerance of metformin' above. See 'Established cardiovascular or kidney disease' above. The majority of patients in the cardiovascular and renal outcomes trials had established cardiovascular disease CVD or diabetic kidney disease DKD with severely increased albuminuria, and therefore, these are the primary indications for one of these drugs.

See 'Without established cardiovascular or kidney disease' above. Each one of these choices has individual advantages and risks table 1. Choice of medication is guided by efficacy, patient comorbidities, preferences, and cost.

Sulfonylureas remain a highly effective treatment for hyperglycemia, particularly when cost is a barrier. Side effects of hypoglycemia and weight gain can be mitigated with careful dosing and diabetes self-management education. For patients who are injection averse, initial therapy with high-dose sulfonylurea is an alternative, particularly for patients who have been consuming large amounts of sugar-sweetened beverages, in whom elimination of carbohydrates can be anticipated to cause a reduction in glucose within several days.

See 'Symptomatic catabolic or severe hyperglycemia' above and "Insulin therapy in type 2 diabetes mellitus". Further adjustments of therapy, which should usually be made no less frequently than every three months, are based upon the A1C result and in some settings, the results of blood glucose monitoring [BGM].

See 'Monitoring' above. See "Management of persistent hyperglycemia in type 2 diabetes mellitus" and "Insulin therapy in type 2 diabetes mellitus". Why UpToDate? Product Editorial Subscription Options Subscribe Sign in.

Learn how UpToDate can help you. Select the option that best describes you. View Topic. Font Size Small Normal Large. Initial management of hyperglycemia in adults with type 2 diabetes mellitus.

Formulary drug information for this topic. No drug references linked in this topic. Find in topic Formulary Print Share. View in. Language Chinese English.

Author: Deborah J Wexler, MD, MSc Section Editor: David M Nathan, MD Deputy Editor: Katya Rubinow, MD Contributor Disclosures. All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jan This topic last updated: Dec 23, TREATMENT GOALS Glycemic management — Target glycated hemoglobin A1C levels in patients with type 2 diabetes should be tailored to the individual, balancing the anticipated reduction in microvascular complications over time with the immediate risks of hypoglycemia and other adverse effects of therapy.

Summary of glucose-lowering interventions. UK Prospective Diabetes Study UKPDS Group. Lancet ; Holman RR, Paul SK, Bethel MA, et al. N Engl J Med ; Hayward RA, Reaven PD, Wiitala WL, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes.

ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes.

Rawshani A, Rawshani A, Franzén S, et al. Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.

Kazemian P, Shebl FM, McCann N, et al. Evaluation of the Cascade of Diabetes Care in the United States, JAMA Intern Med ; Pal K, Eastwood SV, Michie S, et al. Computer-based diabetes self-management interventions for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev ; :CD These drugs work quickly and do not stay in your system long.

So they are a good option if your meal schedule varies or is unpredictable. They also cause less weight gain than other oral diabetes medicines. Alpha-glucosidase inhibitors help control blood sugar levels by preventing the digestion of carbohydrates.

Carbohydrates include starchy foods like potatoes and corn. They also include most grains bread, rice, crackers, cereal and sugary sweets.

The two medicines in this group are acarbose and miglitol. These medicines may cause bloating, nausea, diarrhea, and flatulence gas. A newer class of diabetes medication, SGLT2, includes three medicines: canagliflozin, dapagliflozin, and empagliflozin. These drugs remove extra sugar from your body by sending the sugar out through your kidneys into your urine.

They also cause your body to be more sensitive to insulin. The most common side effects caused by SGLT2 are vaginal yeast infections and urinary tract infections. There are four medicines in this class of drugs. They are sitagliptin, saxagliptin, linagliptin, and alogliptin. DPP-4 inhibitors help your pancreas release more insulin after you eat.

These medicines also tell your liver to release less glucose. Some side effects from taking DPP-4 inhibitors may include nausea and diarrhea. This class of drugs pulls double duty. The medicine in this class, colesevelam, lowers cholesterol and reduces blood sugar levels.

So it could be a good choice if you have diabetes and high cholesterol levels. And because these drugs are not absorbed in the blood stream, they may be the best choice for someone who also has liver problems and cannot take some of the other diabetes medicines.

Side effects from bile acid sequestrants can include constipation and flatulence gas. Managing your blood sugar level is critical to your overall health. Often the focus is on keeping blood sugar levels low.

But if they are too low, it can put you at risk, too. Talk to you doctor if you are starting a new exercise program or starting a new diet. He or she may need to adjust your medicine. Last Updated: May 9, This information provides a general overview and may not apply to everyone. Talk to your family doctor to find out if this information applies to you and to get more information on this subject.

All people who have type 1 diabetes and some who have type 2 diabetes must take insulin. It helps…. All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jan This topic last updated: Jan 11, Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes Diabetes Care ; S Davies MJ, Aroda VR, Collins BS, et al.

Management of hyperglycaemia in type 2 diabetes, A consensus report by the American Diabetes Association ADA and the European Association for the Study of Diabetes EASD.

Diabetologia ; Kirkman MS, Briscoe VJ, Clark N, et al. Diabetes in older adults. Diabetes Care ; Wei N, Zheng H, Nathan DM. Empirically establishing blood glucose targets to achieve HbA1c goals. American Diabetes Association Professional Practice Committee. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes UKPDS UK Prospective Diabetes Study UKPDS Group.

Lancet ; United Kingdom Prospective Diabetes Study UKPDS. BMJ ; prospective diabetes study Overview of 6 years' therapy of type II diabetes: a progressive disease. Prospective Diabetes Study Group. Diabetes ; Turner RC, Cull CA, Frighi V, Holman RR.

Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies UKPDS JAMA ; GRADE Study Research Group, Nathan DM, Lachin JM, et al.

Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes. N Engl J Med ; Bressler P, DeFronzo RA. Drugs and diabetes. Diabetes Reviews ; Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes.

Shah BR, Hux JE, Laupacis A, et al. Clinical inertia in response to inadequate glycemic control: do specialists differ from primary care physicians? Ziemer DC, Doyle JP, Barnes CS, et al. An intervention to overcome clinical inertia and improve diabetes mellitus control in a primary care setting: Improving Primary Care of African Americans with Diabetes IPCAAD 8.

Arch Intern Med ; Grant RW, Buse JB, Meigs JB, University HealthSystem Consortium UHC Diabetes Benchmarking Project Team. Quality of diabetes care in U. academic medical centers: low rates of medical regimen change.

Fanning EL, Selwyn BJ, Larme AC, DeFronzo RA. Improving efficacy of diabetes management using treatment algorithms in a mainly Hispanic population. Grant RW, Cagliero E, Sullivan CM, et al. A controlled trial of population management: diabetes mellitus: putting evidence into practice DM-PEP.

Das SR, Everett BM, Birtcher KK, et al. J Am Coll Cardiol ; Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes: A Systematic Review and Network Meta-analysis.

Ann Intern Med ; Maruthur NM, Tseng E, Hutfless S, et al. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Palmer SC, Mavridis D, Nicolucci A, et al.

Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis. Rodbard HW, Rosenstock J, Canani LH, et al. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial.

Lingvay I, Catarig AM, Frias JP, et al. Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes SUSTAIN 8 : a double-blind, phase 3b, randomised controlled trial. Lancet Diabetes Endocrinol ; Henry RR, Gumbiner B, Ditzler T, et al.

Intensive conventional insulin therapy for type II diabetes. Metabolic effects during a 6-mo outpatient trial.

Hemmingsen B, Christensen LL, Wetterslev J, et al. Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses. BMJ ; e Yki-Järvinen H, Ryysy L, Nikkilä K, et al.

Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial. Wulffelé MG, Kooy A, Lehert P, et al. Combination of insulin and metformin in the treatment of type 2 diabetes. Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus.

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes UKPDS Russell-Jones D, Vaag A, Schmitz O, et al.

Diamant M, Van Gaal L, Stranks S, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes DURATION-3 : an open-label randomised trial. Shyangdan DS, Royle P, Clar C, et al.

Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev ; :CD Singh S, Wright EE Jr, Kwan AY, et al. Glucagon-like peptide-1 receptor agonists compared with basal insulins for the treatment of type 2 diabetes mellitus: a systematic review and meta-analysis.

Diabetes Obes Metab ; Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. Curovic VR, Jongs N, Kroonen MYAM, et al. Optimization of Albuminuria-Lowering Treatment in Diabetes by Crossover Rotation to Four Different Drug Classes: A Randomized Crossover Trial.

Shields BM, Dennis JM, Angwin CD, et al. Patient stratification for determining optimal second-line and third-line therapy for type 2 diabetes: the TriMaster study. Nat Med ; Zheng SL, Roddick AJ, Aghar-Jaffar R, et al.

Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis.

Shi Q, Nong K, Vandvik PO, et al. Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. Marso SP, Bain SC, Consoli A, et al.

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. Mann JFE, Ørsted DD, Brown-Frandsen K, et al. Liraglutide and Renal Outcomes in Type 2 Diabetes.

Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes REWIND : a double-blind, randomised placebo-controlled trial. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.

Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter protein-2 SGLT-2 inhibitors and glucagon-like peptide-1 GLP-1 receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.

BMJ ; m Kanie T, Mizuno A, Takaoka Y, et al. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis.

Cochrane Database Syst Rev ; CD Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease.

Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.

Patorno E, Htoo PT, Glynn RJ, et al. Sodium-Glucose Cotransporter-2 Inhibitors Versus Glucagon-like Peptide-1 Receptor Agonists and the Risk for Cardiovascular Outcomes in Routine Care Patients With Diabetes Across Categories of Cardiovascular Disease.

Colling C, Atlas SJ, Wexler DJ. Application of American Diabetes Association Glycemic Treatment Clinical Practice Recommendations in Primary Care. Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes. Wexler DJ, de Boer IH, Ghosh A, et al. Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes: The GRADE Randomized Clinical Trial.

JAMA Intern Med ; Hirst JA, Farmer AJ, Dyar A, et al. Estimating the effect of sulfonylurea on HbA1c in diabetes: a systematic review and meta-analysis. Nauck MA, Kahle M, Baranov O, et al. Addition of a dipeptidyl peptidase-4 inhibitor, sitagliptin, to ongoing therapy with the glucagon-like peptide-1 receptor agonist liraglutide: A randomized controlled trial in patients with type 2 diabetes.

Zaccardi F, Dhalwani NN, Dales J, et al. Comparison of glucose-lowering agents after dual therapy failure in type 2 diabetes: A systematic review and network meta-analysis of randomized controlled trials. Davies MJ, D'Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, A Consensus Report by the American Diabetes Association ADA and the European Association for the Study of Diabetes EASD.

Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes.

Chiasson JL, Josse RG, Hunt JA, et al. The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. A multicenter controlled clinical trial.

Johnston PS, Feig PU, Coniff RF, et al. Long-term titrated-dose alpha-glucosidase inhibition in non-insulin-requiring Hispanic NIDDM patients. In Brief: A new indication for colesevelam.

Med Lett Drugs Ther ; Ooi CP, Loke SC. Colesevelam for type 2 diabetes mellitus. Fonseca VA, Rosenstock J, Wang AC, et al. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy.

Goldberg RB, Fonseca VA, Truitt KE, Jones MR. Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy.

Bromocriptine Cycloset for type 2 diabetes. Cincotta AH, Meier AH, Cincotta Jr M.

The balance among efficacy in lowering A1C, side effects, and costs must be carefully weighed in considering which drugs or combinations to choose. Avoiding insulin, the most potent of all hypoglycemic medications, at the expense of poorer glucose management and greater side effects and cost, is not likely to benefit the patient in the long term.

See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'. 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: Diabetic kidney disease". 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 10 th to 12 th 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. Weight reduction through diet, exercise, and behavioral modification can all be used to improve glycemic management, although the majority of patients with type 2 diabetes will require medication.

See 'Diabetes education' above. Glycemic targets are generally set somewhat higher for older adults and for those with comorbidities or a limited life expectancy and little likelihood of benefit from intensive therapy.

See 'Glycemic management' above and "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target'.

In the absence of specific contraindications, we suggest metformin as initial therapy for most patients Grade 2B. Although some guidelines and experts endorse the initial use of alternative agents as monotherapy or in combination with metformin, we prefer initiating a single agent typically metformin and then sequentially adding additional glucose-lowering agents as needed.

See 'Metformin' above and 'Glycemic efficacy' above. We suggest initiating metformin at the time of diabetes diagnosis Grade 2C , along with consultation for lifestyle intervention. See 'When to start' above.

The dose of metformin should be titrated to its maximally effective dose usually mg per day in divided doses over one to two months, as tolerated.

See 'Contraindications to or intolerance of metformin' above. See 'Established cardiovascular or kidney disease' above. The majority of patients in the cardiovascular and renal outcomes trials had established cardiovascular disease CVD or diabetic kidney disease DKD with severely increased albuminuria, and therefore, these are the primary indications for one of these drugs.

See 'Without established cardiovascular or kidney disease' above. Each one of these choices has individual advantages and risks table 1.

Choice of medication is guided by efficacy, patient comorbidities, preferences, and cost. Sulfonylureas remain a highly effective treatment for hyperglycemia, particularly when cost is a barrier.

Side effects of hypoglycemia and weight gain can be mitigated with careful dosing and diabetes self-management education. For patients who are injection averse, initial therapy with high-dose sulfonylurea is an alternative, particularly for patients who have been consuming large amounts of sugar-sweetened beverages, in whom elimination of carbohydrates can be anticipated to cause a reduction in glucose within several days.

See 'Symptomatic catabolic or severe hyperglycemia' above and "Insulin therapy in type 2 diabetes mellitus". Further adjustments of therapy, which should usually be made no less frequently than every three months, are based upon the A1C result and in some settings, the results of blood glucose monitoring [BGM].

See 'Monitoring' above. See "Management of persistent hyperglycemia in type 2 diabetes mellitus" and "Insulin therapy in type 2 diabetes mellitus".

Why UpToDate? Product Editorial Subscription Options Subscribe Sign in. Learn how UpToDate can help you. Select the option that best describes you. View Topic. Font Size Small Normal Large. Initial management of hyperglycemia in adults with type 2 diabetes mellitus.

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Author: Deborah J Wexler, MD, MSc Section Editor: David M Nathan, MD Deputy Editor: Katya Rubinow, MD Contributor Disclosures. All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jan This topic last updated: Dec 23, TREATMENT GOALS Glycemic management — Target glycated hemoglobin A1C levels in patients with type 2 diabetes should be tailored to the individual, balancing the anticipated reduction in microvascular complications over time with the immediate risks of hypoglycemia and other adverse effects of therapy.

Summary of glucose-lowering interventions. UK Prospective Diabetes Study UKPDS Group. Lancet ; Holman RR, Paul SK, Bethel MA, et al. N Engl J Med ; Hayward RA, Reaven PD, Wiitala WL, et al.

Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.

Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. Rawshani A, Rawshani A, Franzén S, et al.

Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. Kazemian P, Shebl FM, McCann N, et al. Evaluation of the Cascade of Diabetes Care in the United States, JAMA Intern Med ; Pal K, Eastwood SV, Michie S, et al.

Computer-based diabetes self-management interventions for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev ; :CD Saffari M, Ghanizadeh G, Koenig HG. Health education via mobile text messaging for glycemic control in adults with type 2 diabetes: a systematic review and meta-analysis.

Prim Care Diabetes ; Liang X, Wang Q, Yang X, et al. Effect of mobile phone intervention for diabetes on glycaemic control: a meta-analysis. Diabet Med ; Henry RR, Scheaffer L, Olefsky JM. Glycemic effects of intensive caloric restriction and isocaloric refeeding in noninsulin-dependent diabetes mellitus.

J Clin Endocrinol Metab ; Utzschneider KM, Carr DB, Barsness SM, et al. Diet-induced weight loss is associated with an improvement in beta-cell function in older men. Wing RR, Blair EH, Bononi P, et al. Caloric restriction per se is a significant factor in improvements in glycemic control and insulin sensitivity during weight loss in obese NIDDM patients.

Diabetes Care ; Lean ME, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes DiRECT : an open-label, cluster-randomised trial. Delahanty LM. The look AHEAD study: implications for clinical practice go beyond the headlines. J Acad Nutr Diet ; Evert AB, Dennison M, Gardner CD, et al.

Nutrition Therapy for Adults With Diabetes or Prediabetes: A Consensus Report. Lean MEJ, Leslie WS, Barnes AC, et al. Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial.

Lancet Diabetes Endocrinol ; Niskanen LK, Uusitupa MI, Sarlund H, et al. Five-year follow-up study on plasma insulin levels in newly diagnosed NIDDM patients and nondiabetic subjects. Norris SL, Zhang X, Avenell A, et al.

Long-term effectiveness of lifestyle and behavioral weight loss interventions in adults with type 2 diabetes: a meta-analysis. Am J Med ; United Kingdom Prospective Diabetes Study UKPDS. BMJ ; Umpierre D, Ribeiro PA, Kramer CK, et al.

Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: a systematic review and meta-analysis. JAMA ; Jeon CY, Lokken RP, Hu FB, van Dam RM. Physical activity of moderate intensity and risk of type 2 diabetes: a systematic review.

Egan AM, Mahmood WA, Fenton R, et al. Barriers to exercise in obese patients with type 2 diabetes. QJM ; American Diabetes Association Professional Practice Committee. Facilitating Positive Health Behaviors and Well-being to Improve Health Outcomes: Standards of Care in Diabetes Diabetes Care ; S Kobayashi Y, Long J, Dan S, et al.

Strength training is more effective than aerobic exercise for improving glycaemic control and body composition in people with normal-weight type 2 diabetes: a randomised controlled trial.

Diabetologia ; Look AHEAD Research Group, Wing RR, Bolin P, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.

Pillay J, Armstrong MJ, Butalia S, et al. Behavioral Programs for Type 2 Diabetes Mellitus: A Systematic Review and Network Meta-analysis. Ann Intern Med ; Johansen MY, MacDonald CS, Hansen KB, et al. Effect of an Intensive Lifestyle Intervention on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

Lingvay I, Sumithran P, Cohen RV, le Roux CW. Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation.

Look AHEAD Research Group, Pi-Sunyer X, Blackburn G, et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial.

Arterburn DE, O'Connor PJ. A look ahead at the future of diabetes prevention and treatment. Look AHEAD Research Group, Gregg EW, Jakicic JM, et al. Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial.

Look AHEAD Research Group. Eight-year weight losses with an intensive lifestyle intervention: the look AHEAD study. Obesity Silver Spring ; Look AHEAD Research Group, Wing RR.

Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial.

Arch Intern Med ; Gregg EW, Chen H, Wagenknecht LE, et al. Association of an intensive lifestyle intervention with remission of type 2 diabetes. Jakicic JM, Egan CM, Fabricatore AN, et al. Four-year change in cardiorespiratory fitness and influence on glycemic control in adults with type 2 diabetes in a randomized trial: the Look AHEAD Trial.

Kuna ST, Reboussin DM, Borradaile KE, et al. Long-term effect of weight loss on obstructive sleep apnea severity in obese patients with type 2 diabetes.

Sleep ; Wing RR, Bond DS, Gendrano IN 3rd, et al. Effect of intensive lifestyle intervention on sexual dysfunction in women with type 2 diabetes: results from an ancillary Look AHEAD study. For example, if bedtime NPH is used, it should be adjusted based on fasting glucose levels.

More frequent self-monitoring should be implemented during insulin dose adjustment and when changes in daily activities traveling, changes in diet or exercise pattern or acute illness makes insulin adjustments necessary. The dose of basal or long-acting insulin may be adjusted every three to four days until fasting glucose targets are achieved.

Once an insulin regimen is stable, less frequent glucose monitoring may suffice. See "Insulin therapy in type 2 diabetes mellitus", section on 'Titrating dose'. Related Pathway s : Diabetes: Initiation and titration of insulin therapy in non-pregnant adults with type 2 DM.

For patients who continue to have poor glycemic management on basal insulin after titration, diet and exercise patterns should be reviewed. Potential next steps include adding rapid-acting insulin before the largest meal and then two or three meals if needed , adding a GLP-1 receptor agonist, or changing to premixed insulin twice daily figure 5.

Several premixed combinations of basal and prandial insulin or basal insulin and a GLP-1 receptor agonist are available. See "Insulin therapy in type 2 diabetes mellitus", section on 'Designing an insulin regimen' and "General principles of insulin therapy in diabetes mellitus" and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".

Use of an intensive insulin regimen with multiple daily injections MDI; similar to that used in type 1 diabetes may be necessary in insulin-deficient type 2 diabetes. Patients with type 2 diabetes on MDI or with insulin deficiency may benefit from devices used more commonly in type 1 diabetes such as insulin pumps or continuous glucose monitors.

See "Continuous subcutaneous insulin infusion insulin pump " and "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'CGM systems'.

MDI results in higher serum insulin concentrations and better glycemic management than that achieved with either an oral drug or basal insulin therapy alone [ 7 ]. MDI in type 2 diabetes may require large doses of insulin to overcome insulin resistance and can be associated with substantial weight gain averaging 8.

Patients with type 2 diabetes with generalized obesity or with central overweight, often with nonalcoholic fatty liver disease, frequently require insulin doses in the range of 65 to units per day or much higher.

Although the total daily dose of insulin may be high, the insulin dose per kilogram is less remarkable. High daily insulin requirements may prompt consideration of use of concentrated insulins, such as U glargine or U regular insulin.

Concentrated insulin formulations deliver more potent insulins in smaller volumes, which is less cumbersome for patients and facilitates improved insulin absorption. See "General principles of insulin therapy in diabetes mellitus", section on 'U regular insulin' and "General principles of insulin therapy in diabetes mellitus", section on 'Basal insulin analogs'.

While use of concentrated insulins is often effective for glycemic management, the worsening obesity associated with high-dose insulin can result in progressively increasing insulin requirements. This phenomenon may then lead to reconsideration of addition of an insulin-sparing agent eg, GLP-1 receptor agonist or thiazolidinedione or bariatric surgery.

See 'Bariatric metabolic surgery' below and "Medical nutrition therapy for type 2 diabetes mellitus". The vast majority of these CVD safety studies were placebo-controlled and enrolled all or a majority of patients with pre-existing CVD or at high cardiovascular risk, representing a minority of the type 2 diabetes population.

The long-term benefits and risks of using one agent over another in the absence of diagnosed CVD or high atherosclerotic CVD ASCVD risk are less clear. Thus, the results of these trials are most applicable to patients similar to the trial population and not to all patients with type 2 diabetes [ 2,60 ].

Cardiovascular benefit has been demonstrated for some of these medications when taken in combination with metformin , but benefit has not been definitively established in drug-naïve patients at low to moderate cardiovascular risk.

See 'Without established cardiovascular or kidney disease' above. The cardiovascular effects of each diabetes drug when data are available is reviewed in the individual topics. See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Sulfonylureas and meglitinides in the treatment of 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' and "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Dipeptidyl peptidase 4 DPP-4 inhibitors for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Insulin therapy in type 2 diabetes mellitus".

They can reduce A1C values slightly 0. They act predominantly by lowering glucose concentrations after meals but may be poorly tolerated because of flatulence and other gastrointestinal GI side effects. However, if they are started at a low dose 25 mg before meals and slowly increased, they can be effective in people who follow high-carbohydrate diets.

See "Alpha-glucosidase inhibitors for treatment of diabetes mellitus". Pramlintide is only approved for use in patients also taking prandial insulin, and therefore, it is not generally used in patients with type 2 diabetes.

It also has frequent GI side effects. See "Amylin analogs for the treatment of diabetes mellitus". In , another inhaled insulin preparation was approved by the US Food and Drug Administration FDA.

Inhaled insulin causes a very rapid rise in serum insulin concentration similar to that after subcutaneous rapid-acting insulins and faster than that after subcutaneous regular insulin. It is designed to be used to manage postprandial glucose levels.

Inhaled insulin may cause a transient cough with each inhalation, and it requires pulmonary monitoring. It is used infrequently in patients with type 2 diabetes. See "Inhaled insulin therapy in diabetes mellitus". Colesevelam's mechanism of action to improve glycemia is uncertain [ 64 ]. One possibility is that bile acid sequestrants act in the GI tract to reduce glucose absorption.

In a meta-analysis of five short-term trials 16 to 26 weeks in patients with type 2 diabetes inadequately treated with oral agents or insulin, the addition of colesevelam compared with placebo modestly reduced A1C levels mean difference 0.

The meta-analysis was limited by the high or unclear risk of bias in the individual trials. Side effects can include constipation, nausea, and dyspepsia. In contrast to its effects on LDL cholesterol, colesevelam increases triglyceride concentrations by approximately 20 percent [ 66,67 ].

The clinical implications of this increase are unknown. See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Apolipoprotein C-III'.

Given the modest glucose-lowering effectiveness, expense, and limited clinical experience, we typically do not recommend colesevelam to improve glycemic management in patients with type 2 diabetes. See "Management of hyperprolactinemia", section on 'Overview of dopamine agonists'. A quick-release formulation of bromocriptine has been approved by the FDA for the treatment of type 2 diabetes mellitus [ 68 ].

In short-term clinical trials in patients with type 2 diabetes mellitus, bromocriptine up to 4. Common side effects include nausea, vomiting, dizziness, and headache [ 70 ]. The mechanism of action in reducing blood sugar is unknown. Given its modest glucose-lowering effect, very frequent GI side effects, and the availability of more effective drugs, we do not recommend bromocriptine for the treatment of type 2 diabetes.

BARIATRIC METABOLIC SURGERY — In patients with type 2 diabetes and obesity, bariatric and metabolic surgical procedures that result in sustained, major weight loss have been shown to lead to at least temporary remission of diabetes in a substantial fraction of patients.

Bariatric surgical procedures are targeted at weight loss in the setting of obesity; the term "metabolic surgery" is used when a major goal of surgery is to improve diabetes or other metabolic diseases eg, nonalcoholic fatty liver disease. Patient selection — Surgical treatment of obesity is an option to treat type 2 diabetes in appropriate surgical candidates with [ 71 ]:.

Surgical treatment has also been endorsed in patients with type 2 diabetes with BMI 30 to Given the increasing availability of potent GLPbased therapies and lack of comparative effectiveness data for bariatric surgery and these potent agents, we review these options with our patients and engage in shared decision-making.

See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Diabetes education' and "Bariatric surgery for management of obesity: Indications and preoperative preparation", section on 'Indications'. Outcomes — Unblinded trials have compared bariatric surgery with medical therapy for the treatment of type 2 diabetes see "Outcomes of bariatric surgery", section on 'Diabetes mellitus'.

However, relapse of diabetes usually occurs over time, with 35 to 50 percent of patients who initially achieved diabetes remission after surgery experiencing a recurrence [ 72,75 ]. Nevertheless, bariatric surgery improves glycemia substantially and significantly more than medication therapy, and most patients have marked improvement in glycemic management for at least 5 to 15 years after surgery.

The effects of bariatric surgery on diabetes-related complications are reviewed in detail elsewhere. See "Outcomes of bariatric surgery", section on 'Diabetic complications'.

Risks and concerns — Despite these impressive metabolic results, concerns remain about acute postoperative complications including the need for reoperations and rehospitalizations and rare, but potentially severe, adverse events; the long-term success rates in maintaining weight loss [ 71,80,81 ]; and the reproducibility of the results in patients with an extensive history of diabetes or with different surgical teams [ 82 ].

Some weight regain is typical within two to three years of bariatric procedures, and different procedures result in different levels of weight loss and corresponding reductions in glycemia.

Bariatric surgical procedures are reviewed in detail elsewhere. See "Bariatric procedures for the management of severe obesity: Descriptions" and "Bariatric surgery for management of obesity: Indications and preoperative preparation" and "Bariatric operations: Early fewer than 30 days morbidity and mortality".

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: Diabetic kidney disease". 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 10 th to 12 th 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.

This decision is based on glycated hemoglobin A1C assay results calculator 1 typically performed every three to six months after initial therapy. After a successful initial response to lifestyle intervention and oral therapy, the majority of patients do not maintain target A1C levels during the subsequent three to five years.

See 'Indications for a second agent' above. Options include glucagon-like peptide 1 GLP-1 receptor agonists, a dual-acting GLP-1 and glucose-dependent insulinotropic polypeptide GIP receptor agonist tirzepatide , sodium-glucose co-transporter 2 SGLT2 inhibitors, short-acting sulfonylureas eg, glipizide , glimepiride , repaglinide if sulfonylurea not chosen as initial therapy , insulin, dipeptidyl peptidase 4 DPP-4 inhibitors, and pioglitazone figure 1 and table 2.

For patients with persistent hyperglycemia while taking a maximally tolerated dose of metformin, the choice of a second medication should be individualized based on efficacy, risk for hypoglycemia, the patient's comorbid conditions, impact on weight, side effects, and cost. These agents have been shown to have the best glycemic efficacy algorithm 1.

Gastrointestinal GI side effects, contraindications, and cost may limit their use. To select a medication, we use shared decision-making with a focus on beneficial and adverse effects within the context of the degree of hyperglycemia as well as a patient's comorbidities and preferences algorithm 2.

See 'Established cardiovascular or kidney disease' above. The majority of patients in the cardiovascular and renal outcomes trials had established cardiovascular disease CVD or diabetic kidney disease DKD with severely increased albuminuria, and therefore, these are the primary indications for one of these drugs.

Patients at high CVD risk but without a prior event might benefit, but the data are less supportive. Similarly, patients without severely increased albuminuria have some benefit, but the absolute benefits are greater among those with severely increased albuminuria.

The choice of an alternative glucose-lowering medication is guided by efficacy, patient comorbidities, preferences, side effects, and cost. algorithm 2. See 'Dual agent failure' above. For most patients who do not achieve target A1C with initial dual therapy, we suggest starting insulin or a GLP-1 receptor agonist Grade 2B if neither already chosen as a second agent.

In patients on sulfonylureas and metformin who are starting insulin therapy, sulfonylureas are generally tapered and discontinued, while metformin is continued. In patients on DPP-4 inhibitors who are starting a GLP-1 receptor agonist or dual-acting GLP-1 and GIP receptor agonist, the DPP-4 inhibitor is discontinued, while metformin is continued.

See 'Dual agent failure' above and 'Insulin initiation and intensification' above. Related Pathway s : Diabetes: Initial therapy for non-pregnant adults with type 2 DM.

An alternative is two oral agents and a GLP-1 receptor agonist or dual-acting GLP-1 and GIP receptor agonist, particularly for patients in whom weight loss or avoidance of hypoglycemia is a primary consideration. These GLPbased therapies should not be combined with DPP-4 inhibitors.

Another option for patients close to glycemic goals is three oral agents eg, metformin , sulfonylurea plus: DPP-4 inhibitor, SGLT2 inhibitor, or pioglitazone. Although guidelines suggest combining SGLT2 inhibitors and GLP-1 receptor agonists, we do not usually add an SGLT2 inhibitor to GLP-1 receptor agonist therapy for management of hyperglycemia alone, given the absence of data showing additive cardiovascular and kidney benefit and increased patient burden cost, polypharmacy, adverse effects.

Bariatric surgery may also be an option in patients with lower BMI 30 to Patients seeking bariatric surgery should be counseled to develop coping skills, eliminate maladaptive behavior, and understand the risks and benefits of the surgery. See 'Bariatric metabolic surgery' above and "Bariatric surgery for management of obesity: Indications and preoperative preparation", section on 'Preoperative counseling'.

Why UpToDate? Product Editorial Subscription Options Subscribe Sign in. Learn how UpToDate can help you. Select the option that best describes you. View Topic. Font Size Small Normal Large. Management of persistent hyperglycemia in type 2 diabetes mellitus. Formulary drug information for this topic.

No drug references linked in this topic. Find in topic Formulary Print Share. View in. Language Chinese English. Author: Deborah J Wexler, MD, MSc Section Editor: David M Nathan, MD Deputy Editor: Katya Rubinow, MD Contributor Disclosures. All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jan This topic last updated: Jan 11, Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes Diabetes Care ; S Davies MJ, Aroda VR, Collins BS, et al.

Management of hyperglycaemia in type 2 diabetes, A consensus report by the American Diabetes Association ADA and the European Association for the Study of Diabetes EASD.

Diabetologia ; Kirkman MS, Briscoe VJ, Clark N, et al. Diabetes in older adults. Diabetes Care ; Wei N, Zheng H, Nathan DM. Empirically establishing blood glucose targets to achieve HbA1c goals.

American Diabetes Association Professional Practice Committee. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes UKPDS UK Prospective Diabetes Study UKPDS Group.

Lancet ; United Kingdom Prospective Diabetes Study UKPDS. BMJ ; prospective diabetes study Overview of 6 years' therapy of type II diabetes: a progressive disease. Prospective Diabetes Study Group.

Diabetes ; Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies UKPDS JAMA ; GRADE Study Research Group, Nathan DM, Lachin JM, et al.

Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes. N Engl J Med ; Bressler P, DeFronzo RA. Drugs and diabetes.

Diabetes Reviews ; In the face of significant hyperglycemia i. People who have evidence of metabolic decompensation e. 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.