Hyperglycemia from gluconeogenesis causes a solute diuresis resulting in the manifestations of uncontrolled diabetes mellitus: polyuria, polydipsia and volume loss leading to hypovolemia, hypotension, organ hypoperfusion and tachycardia.

Although hyperosmolar hyperglycemic syndrome typically occurs in the elderly, it may occur at any age. Often, the patient is not known to have diabetes, or the disease has been managed by diet, oral hypoglycemic agents or small amounts of insulin.

Patients with the syndrome may present with a depressed mental status. In one series including uncontrolled diabetic patients, 2 45 percent of patients with an effective osmolarity of greater than mOsm per L were comatose on presentation.

Patients with the syndrome have a history of days to weeks of thirst, polyuria and, frequently in the background, a condition such as stroke or renal insufficiency.

Weight loss, weakness, visual disturbances and leg cramps are common symptoms. The physical examination demonstrates profound dehydration, poor tissue turgor, soft, sunken eyeballs, cool extremities and, at times, a rapid thready pulse.

On presentation, these patients have glucosuria and minimal or no ketonuria or ketonemia. Mild metabolic acidosis with an increased anion gap is present in up to one half of patients with hyperosmolar hyperglycemic syndrome. Nausea, vomiting and abdominal pain occur less frequently in pataients with hyperosmolar hyperglycemia than in those with diabetic ketoacidosis.

Occasionally, patients with the syndrome have constipation and anorexia. Gastric stasis and ileus occur less often than in patients with classic diabetic ketoacidosis. Abdominal pain or tenderness, nausea and vomiting, lack of bowel sounds and ileus in patients with uncontrolled diabetes may obscure intra-abdominal pathologic processes that require urgent attention.

Therefore, historical information and response to therapy are of critical importance. The development of findings secondary to uncontrolled diabetes follows the onset of symptoms rather than precedes it, and the symptoms usually improve markedly following the infusion of fluids and insulin.

Fatty infiltration of the liver, associated with abnormal liver function tests, may be another cause of abdominal pain and tenderness in patients with uncontrolled diabetes. Liver function tests are abnormal in up to one third of patients with uncontrolled diabetes. Approximately 20 to 25 percent of patients who have hyperosmolar hyperglycemic syndrome present in a coma.

In one series, 2 most of the comatose patients had an effective osmolarity of greater than mOsm per L. The absence of hyperosmolarity and hypoglycemia in an obtunded patient with diabetes suggests a cause other than diabetic decompensation.

Patients with diabetes and hyperosmolarity may present with neurologic abnormalities that rarely occur in patients with nonhyperosmolar diabetic ketoacidosis.

These abnormalities include seizures, transient hemiparesis and other focal neurologic findings leading to the erroneous impression of stroke. Patients with hyperosmolarity who have adequate urine output and blood pressure on hospital admission may become oliguric and hypotensive after insulin lowers their glucose level and osmolarity to to mg per dL Once the glucosuric osmotic load dissipates, urine output falls to oliguric levels until total body water and intravascular volume are restored.

In patients with uncontrolled diabetes, fluid losses range from to mL per kg. In patients with hyperosmolar hyperglycemia, the mean fluid loss is approximately 9 L.

A calculation of effective osmolarity can serve as a guide in determining the type of fluid replacement to use. A rough approximation of the measured value can be obtained as follows:. In some calculations, the serum potassium level is omitted. It is the effective osmolarity that is critical to the pathogenesis of the hyperosmolar state and the determination of the osmotic content of replacement solutions.

The distinction between osmolarity, which is the concentration of an osmolar solution, and tonicity, which is the osmotic pressure of a solution, must be made. Tonicity more appropriately reflects what is referred to as the effective osmolarity 11 Table 1.

If the effective osmolarity exceeds mOsm per L, significant hyperosmolarity exists, and this value guides the tonicity of the replacement solution used. The volume and rate of fluid replacement are determined by renal and cardiac function, as well as evidence of hypovolemia.

Typically, replacement volumes are 1, mL in the first hour 15 to 30 mL per kg per hour , 1, mL in the second and possibly third hours, and to mL in the fourth hour and possibly beyond. For the physician, the key to fluid management is vigilant monitoring and adjustment of response on a continuous basis.

Volume replacement is critical in determining survival and in correcting hyperglycemic hyperosmolarity. One study 12 of patients with diabetic ketoacidosis documented that hydration alone without any insulin administration reduced hyperglycemia, hyperosmolarity, acidosis and insulin counterregulatory hormone levels.

Generally, however, insulin is also administered. Guidelines for fluid replacement in hyperglycemic hyperosmolarity are provided in Table 2. Early in treatment, a decrease in the plasma glucose level serves as an index of the adequacy of rehydration and the restoration of renal perfusion.

Failure of the plasma glucose level to decline by 75 to mg per dL 4. The physician must be wary of uncontrolled diabetes in patients with renal failure. These patients may present with marked hyperglycemia and elevated BUN and creatinine levels. If renal failure is not recognized and rapid fluid replacement is instituted, the likely consequences are congestive heart failure and pulmonary edema.

In patients with hyperglycemia and renal failure, insulin administration may be all that is necessary. Insulin reduces elevated serum potassium levels. As the glucose level falls, water freed from its osmotic hold moves out of the extracellular fluid into the intracellular space intracellular fluid , thereby decreasing the manifestations of circulatory congestion.

Sudden loss of diabetic control in the presence of renal failure may cause pulmonary edema and life-threatening hyperkalemia. Both of these conditions can be reversed by insulin alone. Electrolyte deficits in patients with uncontrolled diabetes are in the following ranges: sodium, 7 to 13 mEq per kg; chloride, 3 to 7 mEq per kg; potassium, 5 to 15 mEq per kg; phosphate as phosphorus , 70 to mmol; calcium, 50 to mEq; and magnesium, 50 to mEq.

A variety of physiologic multielectrolyte solutions e. Loss of sodium occurs because of osmotic diuresis and the absence of insulin, which is essential for distal tubular sodium reabsorption. Because sodium losses are proportionally less than water losses, hypernatremia may occur.

In the absence of insulin, glucose is largely confined to the extracellular fluid compartment. The osmotic action of glucose causes water to flow out of the intra-cellular fluid into the extracellular fluid compartment, with consequent dilution of extra-cellular sodium. One group of investigators 17 demonstrated that the measured serum sodium concentration in the presence of hyperglycemia may be corrected by adding 2.

Total body potassium depletion is the rule in uncontrolled diabetes and related chronic catabolic states e. As with phosphate and magnesium, the degree of total body potassium depletion is often unrecognized or underestimated because of the initially elevated serum concentrations until correction of the underlying catabolic state is undertaken.

At this time, as potassium returns to its intracellular site along with magnesium and phosphate under the influence of insulin and renewed protein synthesis, the deficiency may become chemically and, occasionally, clinically overt unless supplements are administered during the early phases of therapy.

Recommendations for potassium administration in adults are provided in Table 2. The use of potassium acetate, potassium phosphate or a mixture of the two avoids administration of excess chloride.

The objective of potassium replacement is to maintain normokalemia. The total body deficits of potassium cannot and should not be replaced acutely.

Full correction of the potassium level requires days to weeks of steady anabolism. Even in the presence of renal insufficiency, early potassium replacement may be indicated because, with the exception of urinary loss, all other factors that drive the serum potassium level down in the treated patient are occurring.

Caution must be exercised in patients with diabetic nephropathy who may have renal tubular acidosis associated with hyperaldosteronism and hyporeninemia and resultant hyperkalemia.

Once insulin is administered, potassium moves intracellularly because of either insulin stimulation of sodium-potassium adenosine triphosphatase or insulin-induced synthesis of phosphate esters intracellularly.

These anions attract potassium into the cells. Thus, to replace intracellular losses, potassium should be given with an anion that distributes in the intracellular fluid i. The benefits and risks of phosphate repletion in patients with uncontrolled diabetes have been investigated primarily in patients with acute diabetic ketoacidosis.

Chronic catabolic states, including hyperosmolar diabetes, are likely to be associated with more severe total body phosphate depletion and its unmasking during treatment, as originally noted in the refeeding syndrome. Although phosphate replacement makes physiologic sense, no controlled data demonstrate that it alters the outcome or contributes to survival in patients with uncontrolled diabetes unless severe reductions in the serum phosphate level i.

The only risk of giving phosphate is the occasional development of hypocalcemic tetany described in diabetic ketoacidosis, 22 but this condition does not occur when magnesium is supplemented. As many as 40 percent of outpatients with diabetes and 90 percent of patients with uncontrolled diabetes after 12 hours of therapy are hypomagnesemic.

These manifestations include ECG changes, arrhythmias, muscle weakness, convulsions, stupor, confusion and agitation. As is true of the serum potassium level, the serum magnesium concentration is an unreliable marker of total body stores of this predominantly intracellular cation.

Many patients have elevated serum magnesium levels on presentation, and hypomagnesemia may not be evident for hours. Serum magnesium levels and body stores parallel and mirror those of potassium in hyperosmolar hyperglycemic syndrome. Unless precluded by renal failure of hypermagnesemia, the routine administration of magnesium to patients with uncontrolled diabetes is safe and physiologically appropriate.

Because many patients with diabetes and hyperosmolar hyperglycemic syndrome fit the criteria for catabolic malnourishment, they are at risk for development of the refeeding syndrome. Concern, primarily focused on the potential for cerebral edema, has been expressed about the effects of rapid fluid administration, the use of hypotonic fluids to treat hyperglycemic hyperosmolarity and the dangers of rapid reduction of the effective osmolarity to mOsm per L or the glucose level to to mg per dL Cerebral edema occurs almost exclusively in young patients who have nonhyperosmolar diabetes with diabetic ketoacidosis.

This complication is exceedingly rare in adult patients with hyperosmolar hyperglycemic syndrome. In the United States, diabetic ketoacidosis and hyperosmolar diabetes are responsible for thousands of deaths every year, whereas fatal cerebral edema in adults almost never occurs.

Many more patients with uncontrolled diabetes die as a result of undertreatment than overtreatment. Any recommendation to reduce the rate of correction of hyperglycemia risks increasing the mortality rate and should be viewed with alarm.

Rapid correction of hyperosmolarity to an effective osmolarity of mOsm per L and the plasma glucose level to to mg per dL Thereafter, a much slower rate of correction toward normal is warranted.

Insulin has a direct antinatriuretic effect on the kidney. Vascular occlusions i. With aggressive rehydration, the incidence of these complications may be reduced to 2 percent. Improving the management results for hyperosmolar hyperglycemic syndrome requires an effective preventive strategy.

Patients with hyperosmolar diabetes tend to be elderly and to have type 2 diabetes. Often, these patients live alone, and social isolation is a precipitant in one third to one half of hyperosmolar diabetes episodes.

If the patient displays any change in mental status or symptoms of loss of diabetic control, this person is instructed to contact the patient's physician immediately. Nursing home residents are prone to develop dehydration, hyperosmolarity and hyperglycemia.

Thus, education of nursing home staff in the prevention and detection of diabetes-related problems is also essential. Fishbein H, Palumbo PJ. Data from small trials demonstrate substantial inter-individual variability in treatment response to specific medications for endpoints including glycemia and reduction in albuminuria [ 36,37 ], further underscoring the importance of individualized therapy.

Established cardiovascular or kidney disease — For patients with existing ASCVD, HF, or albuminuric DKD, a glucose-lowering medication with evidence of cardiac or kidney benefit should be added to metformin algorithm 2.

SGLT2 inhibitors with cardiovascular benefit empagliflozin or canagliflozin are good alternatives. See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.

In the setting of declining eGFR, the main reason to prescribe an SGLT2 inhibitor is to reduce progression of DKD. However, cardiac and kidney benefits have been shown in patients with eGFR below this threshold.

See "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'. In the absence of randomized trials directly comparing cardiovascular outcomes of the GLP-1 receptor agonists and SGLT2 inhibitors, the following findings and those from network meta-analyses [ 38,39 ] largely support our approach outlined above:.

See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects'. Patients at high CVD risk but without a prior event might benefit, but the data are less definitive [ 45 ].

Similarly, patients without severely increased albuminuria derive some benefit, but the absolute benefits are greater among those with severely increased albuminuria. For the other primary outcome a composite of hospitalization for myocardial infarction or stroke , there was a small benefit with SGLT2 inhibitors in patients with a history of CVD rate difference There was no difference in CVD outcomes between the two classes in those without a history of CVD.

GLP-1 receptor agonists are an alternative since glycemic benefit is independent of kidney function. In addition, GLP-1 receptor agonists have been shown to slow the rate of decline in eGFR and prevent worsening of albuminuria, albeit to a lesser degree than SGLT2 inhibitors.

GLP-1 receptor agonists should be titrated slowly, with monitoring for GI side effects, which could precipitate dehydration and acute kidney injury AKI. See "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", section on 'Microvascular outcomes'.

We avoid use of SGLT2 inhibitors in patients with frequent genitourinary yeast infections or bacterial urinary tract 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 use disorder because of increased risk for each while using these agents.

SGLT2 inhibitors should be held for procedures, 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'.

In general, we tolerate higher glycemic targets, and, if medication is required, we prefer a short-acting, low-dose sulfonylurea eg, glipizide , repaglinide , linagliptin , or cautious use of a GLP-1 receptor agonist or insulin. See "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic kidney disease or end-stage kidney disease", section on 'Treatment' and "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Use in chronic kidney disease' and "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Clinical use of meglitinides'.

Without established cardiovascular or kidney disease — For most patients without established ASCVD or kidney disease who have persistent hyperglycemia while taking metformin mg per day or a lower maximally tolerated dose , we suggest a GLP-1 receptor agonist or basal insulin based on the results of the GRADE trial, a comparative effectiveness study of commonly used classes of glucose lowering medications algorithm 2 [ 10,54 ].

In the GRADE trial, choice of a second glucose-lowering medication was evaluated in patients with type 2 diabetes A1C 6. Participants with hyperglycemia despite taking maximum tolerated doses of metformin were randomly assigned to treatment with U glargine, liraglutide , glimepiride , or sitagliptin.

Over a mean follow-up of five years, all four medications lowered A1C levels. The proportion of individuals with severe hypoglycemia was highest in the glimepiride group 2. Liraglutide had the highest frequency of gastrointestinal side effects.

The treatment groups did not differ in the rate of the prespecified secondary micro- or macrovascular outcomes, including moderately or severely increased albuminuria, reduced kidney function, peripheral neuropathy, major adverse cardiovascular events MACE , hospitalization for HF, cardiovascular mortality, or overall mortality [ 54,55 ].

However, there was a small reduction in the incidence of any CVD defined as first incidence of MACE, hospitalization for unstable angina or HF, or revascularization in any arterial bed with liraglutide 6. The GRADE trial was designed and implemented prior to the availability of SGLT2 inhibitors.

SGLT2 inhibitors have lower glycemic efficacy compared with basal insulin and GLP-1 receptor agonists [ 20 ]. The cardiovascular benefit of SGLT2 inhibitors has not been demonstrated in those at low cardiovascular risk.

Shorter-term trial data also support selection of the dual-acting GLP-1 and GIP receptor agonist tirzepatide as a second glucose-lowering agent, particularly in individuals for whom substantial body weight loss is a treatment goal. Trial data for tirzepatide are reviewed separately.

The choice of an alternative glucose-lowering medication is guided by efficacy, patient comorbidities, preferences, side effects, and cost algorithm 2. These benefits are offset by risks of hypoglycemia and modest weight gain.

Sulfonylureas can be used safely and effectively with dose adjustment, even in people at risk of hypoglycemia, but this requires a bit more attention. We prefer a shorter-duration sulfonylurea or one with relatively lower risk for hypoglycemia eg, glipizide , glimepiride , since longer-acting glyburide is associated with a higher risk of hypoglycemia, especially in older or frail patients.

In addition, there are good data providing reassurance of the cardiovascular safety of these sulfonylureas. See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.

The glycemic efficacy of sulfonylureas in combination with other oral agents is illustrated by the findings of a meta-analysis of trials in which sulfonylureas were added to oral agents predominantly metformin or thiazolidinediones [ 56 ].

Compared with placebo, the addition of sulfonylureas to oral diabetes treatment lowered A1C by 1. The clinical use, side effects, and concerns about the cardiovascular safety of sulfonylureas are reviewed separately. See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus".

SGLT2 inhibitors are associated with modest weight loss. With both medication classes, weight loss effects are stronger when the medication is combined with sustained efforts at dietary modification.

In patients with diabetes mellitus and biopsy-proven NASH, pioglitazone has been shown to improve fibrosis as well as inflammation and steatosis. GLPbased therapies also appear to improve liver biopsy evidence of NASH.

These studies are reviewed in detail separately. See "Management of nonalcoholic fatty liver disease in adults", section on 'Patients with NASH and diabetes'. The potential benefits of these drugs must be balanced with their associated adverse effects.

In particular, pioglitazone is not typically a first-choice agent due to adverse effects, including increased risk of weight gain, fluid retention, HF, fractures, and the potential increased risk of bladder cancer. It may play a role in the treatment of selected patients with severe insulin resistance, NASH or nonalcoholic fatty liver disease , at low risk of fracture.

Adverse effects of pioglitazone may be minimized by using 15 to 30 mg rather than the 45 mg highest dose. See "Management of nonalcoholic fatty liver disease in adults", section on 'Patients with NASH and diabetes' and "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Safety' and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Adverse effects'.

Trials comparing other combinations are reviewed separately in the individual topics. See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Glycemic efficacy' and "Dipeptidyl peptidase 4 DPP-4 inhibitors for the treatment of type 2 diabetes mellitus", section on 'Glycemic efficacy' and "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Glycemic efficacy'.

Dual agent failure — For patients who have deterioration of glycemic management on dual therapy, the options include:.

Although guidelines suggest combining SGLT2 inhibitors and GLP-1 receptor agonists [ 1 ], we do not usually add an SGLT2 inhibitor to GLP-1 receptor agonist therapy for hyperglycemia alone given the absence of data showing additive cardiovascular and kidney benefit and increased patient burden cost, polypharmacy, adverse effects.

The choice of additional therapy should be individualized, as discussed above for patients with monotherapy failure, based on efficacy, glycemic target, risk of hypoglycemia, the patient's underlying comorbidities, impact on weight, side effects, and cost.

See 'Monotherapy failure' above. In patients on sulfonylureas and metformin who are starting insulin therapy, sulfonylureas are generally discontinued, while metformin is continued. In patients on a DPP-4 inhibitor who are starting a GLP-1 receptor agonist or dual-acting GLP-1 and GIP receptor agonist, the DPP-4 inhibitor should be discontinued.

Insulin dose requirements can decrease precipitously with the addition of these medications, requiring patient education and close follow-up with insulin dose adjustment in the short term to reduce the risk of hypoglycemia. 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'.

In a meta-analysis of randomized trials evaluating the addition of a third agent in patients inadequately managed with two agents predominantly metformin and a sulfonylurea or metformin and a thiazolidinedione , triple-agent combinations reduced A1C to a greater extent than two agents [ 58 ].

In trials lasting 52 to 54 weeks, the addition of thiazolidinediones, GLP-1 receptor agonists, or SGLT2 inhibitors to metformin and sulfonylurea reduced A1C to a similar extent, and tirzepatide imparted even greater A1C reduction. However, these trials did not directly compare the third-line agents with each other.

Moreover, only the GRADE study was of sufficient duration to determine long-term glycemic effects. For patients who are not well managed on two oral agents, switching to insulin may be less expensive than adding a third oral or injectable agent, depending on which insulin and which third oral or injectable agent is selected.

Insulin initiation and intensification — If a decision has been made to add insulin to oral hypoglycemic therapy in patients with type 2 diabetes, a single daily dose of either insulin NPH or detemir given at bedtime or insulin glargine or degludec given in the morning or at bedtime is a reasonable initial regimen [ 1 ].

Metformin , GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors can be continued when insulin is added, whereas sulfonylureas and pioglitazone are usually discontinued due to reduced efficacy in comparison with other combinations and to adverse effects [ 59 ].

Patients should measure blood glucose at appropriate times, and usually once to twice per day, depending on the insulin used and timing of administration.

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 ; Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Shah BR, Hux JE, Laupacis A, et al.

Asymptomatic, not catabolic — The majority of patients with newly diagnosed type 2 diabetes are asymptomatic, without symptoms of catabolism eg, without polyuria, polydipsia, or unintentional weight loss.

Hyperglycemia may be noted on routine laboratory examination or detected by screening. Metformin — In the absence of specific contraindications, we suggest metformin as initial therapy for patients with newly diagnosed type 2 diabetes who are asymptomatic. We begin with mg once daily with the evening meal and, if tolerated, add a second mg dose with breakfast.

The dose can be increased slowly one tablet every one to two weeks as tolerated to reach a total dose of mg per day. See 'When to start' above and "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Dosing'. Metformin is the preferred initial therapy because of glycemic efficacy see 'Glycemic efficacy' below , promotion of modest weight loss, very low incidence of hypoglycemia, general tolerability, and favorable cost [ 47 ].

Metformin does not have adverse cardiovascular effects, and it appears to decrease cardiovascular events [ ]. See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Cardiovascular effects'.

Metformin is far less expensive and has more clinical practice experience than glucagon-like peptide 1 GLP-1 receptor agonists and sodium-glucose cotransporter 2 SGLT2 inhibitors. Although some guidelines and experts endorse the initial use of these alternative agents as monotherapy or in combination with metformin [ 48,52 ], we prefer initiating a single agent typically metformin and then sequentially adding additional glucose-lowering agents as needed, rather than starting with combination therapy.

In the clinical trials that demonstrated the protective effects of GLP-1 receptor agonists and SGLT2 inhibitors, these agents were added to background metformin therapy in most participants. Further, the cardiorenal benefits of GLP-1 receptor agonists and SGLT2 inhibitors have not been demonstrated in drug-naïve patients without established CVD or at low cardiovascular risk or without severely increased albuminuria.

Although each diabetes medication is associated with adverse events, metformin is associated with less weight gain and fewer episodes of hypoglycemia compared with sulfonylureas, and with less edema, heart failure HF , and weight gain compared with thiazolidinediones.

See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.

Although virtually all recommendations for initial pharmacologic therapy outside of China, where alpha-glucosidase inhibitors are recommended as an alternate first-line monotherapy [ 53 ] endorse use of metformin , there are, in fact, relatively few relevant direct comparative effectiveness data available.

Contraindications to or intolerance of metformin — For patients who have gastrointestinal intolerance of metformin , slower titration, ensuring that the patient is taking the medication with food, or switching to an extended-release formulation may improve tolerability.

For patients who still cannot tolerate metformin or have contraindications to it, we choose an alternative glucose-lowering medication guided initially by patient comorbidities, and in particular, the presence of atherosclerotic CVD ASCVD or albuminuric chronic kidney disease.

See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Contraindications'. When compared with placebo, the GLP-1 receptor agonists liraglutide , semaglutide , and dulaglutide demonstrated favorable atherosclerotic cardiovascular and kidney outcomes [ ].

The SGLT2 inhibitors empagliflozin , canagliflozin , and dapagliflozin have also demonstrated benefit, especially for HF hospitalization, risk of kidney disease progression, and mortality [ ]. 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. 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.

As examples:. SGLT2 inhibitors with cardiovascular benefit empagliflozin or canagliflozin are good alternatives, especially in the presence of HF. Given the high cost of these classes of medications, formulary coverage often determines the choice of the first medication within the class.

See "Glucagon-like peptide 1-based therapies for 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 'Microvascular outcomes'. Choice of agent is primarily dictated by provider preference, insurance formulary restrictions, eGFR, and cost.

In the setting of declining eGFR, the main reason to prescribe SGLT2 inhibitors is to reduce progression of DKD. However, kidney and cardiac benefits have been shown in patients with eGFR below this threshold. Dosing in the setting of DKD is reviewed in detail elsewhere.

See "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'. An alternative or an additional agent may be necessary to achieve glycemic goals. GLP-1 receptor agonists are an alternative in patients with DKD as their glycemic effect is not related to eGFR.

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 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 ; It happens when sugar stays in your bloodstream instead of being used as energy. For people with type 1 diabetes, blood sugar control over the long term is important.

Insulin is a hormone made by the pancreas that lets your body use the sugar glucose in your blood, which comes primarily from carbohydrates in the food that you eat. Hyperglycemia happens when your body has too little insulin to use the sugar in your blood.

People with T1D can have episodes of hyperglycemia every day. Although this can be frustrating, it rarely creates a medical emergency. Not taking enough insulin can lead to hyperglycemia like missing a dose or not taking enough insulin for the carbs you ate.

Also, every day around 4 to 5 am, your body releases hormones as it is getting ready to wake up. These hormones can work against insulin and cause high blood sugar. If you notice any of these symptoms, you should check your blood sugar. If your blood sugar is very high, you should also test for ketones in either your blood or urine.

It is normal for patients with T1D to get hyperglycemia, and most of the time this is simply treated with insulin. This produces chemicals called ketones, which make your blood more acidic. DKA is dangerous. Too much acid in your blood can make you pass out diabetic coma or even cause death.

If you notice these or any of the other signs of hyperglycemia listed above, you are at risk of or may already have DKA. You can use a urine test strip or blood ketone meter and ketone test strip to test for ketones at home.

Testing either urine or blood is important, but when possible, a blood test is preferred because it gives you and your care team more precise information about your ketone levels. Because urine may have been in the bladder for some time, the results from these tests may show levels that are either higher or lower than the ketone levels that are actually circulating in your body.

It is also very important to know that urine test trips degrade over time, so if you are using this method, you need to look at expiration dates carefully. At-home urine test strips will change color to show the level of ketones in the urine.

The following ranges are generally used:. You should call your diabetes care team immediately if your urine test results show you that you have moderate or large levels of ketones or your blood ketone test shows 1.

You should go to the emergency room if you have high levels of ketones and have vomited at least twice in the last 4 hours. The first thing you should do to treat hyperglycemia is take insulin. If you take insulin by syringe or pen, and your blood sugar has not responded within 2 hours, you can take a second dose using the same correction dose.

Remember that insulin takes 20 to 30 minutes to work and will continue to work for 4 to 5 hours. If you get hyperglycemia often, talk with your doctor. They might adjust your medication or suggest you talk with a dietitian about meals and exercise.

Also, a CGM can help you keep track of changes in your blood sugar throughout the day. Your body releases stress hormones when you are sick, which can cause hyperglycemia. Keep taking your insulin and other diabetes medications, even if you are throwing up. They might also want you to call if:.

Managing blood sugar during and after physical activity is important and is something that a lot of people with T1D have questions about.

JDRF has a number of resources available for people with T1D and their families, many of which can be found here. If you are using an insulin pump, talk to your diabetes team about how to best manage hyperglycemia.

In general, be sure to check your pump first. Make sure all parts are connected and working correctly. Check your bolus history and temporary basal rate.

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.

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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.

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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.

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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.

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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.

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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.

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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.

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Long-term effect of weight loss on obstructive sleep apnea severity in obese patients with type 2 diabetes.

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Stress management improves long-term glycemic control in type 2 diabetes. Ismail K, Winkley K, Rabe-Hesketh S. Systematic review and meta-analysis of randomised controlled trials of psychological interventions to improve glycaemic control in patients with type 2 diabetes.

Safren SA, Gonzalez JS, Wexler DJ, et al. Check if you need prescription refills. Your health care provider can renew your prescriptions while you're at the appointment.

For hyperglycemia, questions you may want to ask include: How often do I need to monitor my blood sugar? What is my target range? How do diet and exercise affect my blood sugar? When do I test for ketones? How can I prevent high blood sugar? Do I need to worry about low blood sugar?

What are the symptoms I need to watch for? Will I need follow-up care? Sick-day planning Illness or infections can cause your blood sugar to rise, so it's important to plan for these situations.

Questions to ask include: How often should I monitor my blood sugar when I'm sick? Does my insulin injection or oral diabetes pill dose change when I'm sick?

When should I test for ketones? What if I can't eat or drink? When should I seek medical help? By Mayo Clinic Staff.

Aug 20, Show References. Hyperglycemia high blood glucose. American Diabetes Association. Accessed July 6, What is diabetes?

National Institute of Diabetes and Digestive and Kidney Diseases. Wexler DJ. Management of persistent hyperglycemia in type 2 diabetes mellitus. Hirsch IB, et al. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis.

Managing diabetes. Inzucchi SE, et al. Glycemic control and vascular complications in type 2 diabetes mellitus. Comprehensive medical evaluation and assessment of comorbidities: Standards of Medical Care in Diabetes — Diabetes Care.

The big picture: Checking your blood glucose. Castro MR expert opinion. Mayo Clinic, Rochester, Minn. July 7, Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment.

Take care of your diabetes during sick days and special times. Accessed July 7, Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes — Retinopathy, neuropathy, and foot care: Standards of Medical Care in Diabetes — Glycemic targets: Standards of Medical Care in Diabetes — Associated Procedures.

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