eMedicine Specialties > Endocrinology > Diabetes Mellitus

Diabetes Mellitus, Type 2: Treatment & Medication

Author: Kenneth Patrick L Ligaray, MD, Fellow, Department of Endocrinology, Diabetes and Metabolism, St Louis University
Coauthor(s): William L Isley, MD, Senior Associate Consultant, Associate Professor of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic of Rochester
Contributor Information and Disclosures

Updated: Oct 28, 2009

Treatment

Medical Care

The goals in caring for patients with diabetes mellitus include the elimination of symptoms; microvascular (ie, eye and kidney disease) risk reduction through control of glycemia and blood pressure (BP); macrovascular (ie, coronary, cerebrovascular, peripheral vascular) risk reduction through control of lipids and hypertension, smoking cessation, and aspirin therapy; and metabolic risk reduction through control of glycemia. Such care requires appropriate goal setting, regular complications monitoring, dietary and exercise modifications, medications, appropriate self-monitoring of blood glucose (SMBG), and laboratory assessment. Focus on glucose alone does not provide adequate treatment for patients with diabetes mellitus. Treatment involves multiple goals (ie, glycemia, lipids, BP).

Glycemic goals

Implications of the UKPDS: The UKPDS was a landmark study for the care of patients with type 2 diabetes mellitus, confirming the importance of glycemic control in reducing the risk for microvascular complications and refuting previous data implicating increased macrovascular disease risk with sulfonylureas or insulin. Major findings of the study are displayed in the images below (see also Images 6-8). Significant implications include the following:
- Microvascular complications (predominantly the need for laser photocoagulation on retinal lesions) are reduced by 25% when median HbA1c is 7% compared with 7.9%.
- A continuous relationship exists between glycemia and microvascular complications, with a 35% reduction in risk for each 1% decrement in HbA1c. A glycemic threshold (above the upper limit of normal for HbA1c) below which risk for microvascular disease is eliminated does not appear to exist.
- Glycemic control has minimal effect on macrovascular disease risk. Excess macrovascular risk appears to be related to conventional risk factors such as dyslipidemia and hypertension.
- Sulfonylureas and insulin therapy do not increase macrovascular disease risk.¹⁷
- Metformin reduces macrovascular risk in patients who are obese.¹⁸
- Vigorous BP control reduces microvascular and macrovascular events.¹⁹ Beta blockers and angiotensin-converting enzyme (ACE) inhibitors appear to be equally efficacious.
Glycemic goal setting and achieving glycemic goals: The DCCT and UKPDS provide ample evidence that glycemic control is paramount in reducing microvascular complications. Unless the risk outweighs the benefit, an HbA1c target of less than 7% is appropriate. Some organizations (eg, the American Association of Clinical Endocrinologists, the International Diabetes Federation) recommend a glycemic target of HbA1c less than 6.5%.
- The author thinks that practitioners should aim for the lowest possible HbA1c that does not cause undue harm. The limiting factor is almost always risk for hypoglycemia. Unfortunately, some practitioners and their patients pursue a particular HbA1c value despite uncertain benefit (eg, patients with advanced complications) or unacceptable risk (eg, hypoglycemia unawareness, elderly patients, patients with other major systemic disease with significant risk for side effects [eg, coma, seizures, falling and breaking a hip]). Situations with an unfavorable risk-benefit ratio for intensive blood glucose lowering include advanced age, significant concomitant disease, and advanced complications.
- Decisions about glycemic management are generally made on the basis of HbA1c measurements performed quarterly (possibly less often in patients with adequate control through lifestyle measures alone) and the results of SMBG. If a total GHb measurement is used, the actual number is 1-2% higher, but the laboratory should provide a correlation with actual HbA1c values.^{17,18,19,20,21}

Major findings from the primary glucose study in the United Kingdom Prospective Diabetes Study (UKPDS).

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Major findings from the primary glucose study in the United Kingdom Prospective Diabetes Study (UKPDS).

Results from metformin substudy in the United Kingdom Prospective Diabetes Study (UKPDS).

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Results from metformin substudy in the United Kingdom Prospective Diabetes Study (UKPDS).

Findings from the blood pressure substudy in the United Kingdom Prospective Diabetes Study (UKPDS).

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Findings from the blood pressure substudy in the United Kingdom Prospective Diabetes Study (UKPDS).

Complications monitoring

The American Diabetes Association recommends initiation of complications monitoring at the time of diagnosis of diabetes mellitus.²² This regimen should include yearly dilated eye examinations, yearly microalbumin checks, and foot examinations at each visit.

Self-monitoring of blood glucose

Daily SMBG is important for patients treated with insulin or insulin secretagogues to monitor for and prevent hypoglycemia and optimize the treatment regimen. The optimal frequency of SMBG for patients with type 2 diabetes is unresolved, but it should be sufficient to facilitate reaching glucose goals. The author often utilizes no or minimal SMBG in patients using lifestyle changes alone or agents that do not cause hypoglycemia (eg, metformin, glitazones, glucosidase inhibitors).

Laboratory monitoring

Because diabetes mellitus is a multisystem disease, focusing solely on blood sugar is inadequate. The image below lists appropriate laboratory parameters in the global assessment of patients with type 2 diabetes mellitus (see also Image 9). Obviously, patients with abnormalities need more frequent monitoring to guide therapeutic interventions. Drug-specific monitoring is also necessary (eg, serum creatinine for metformin, serum transaminases for glitazones).

Laboratory monitoring guidelines for patients with type 2 diabetes mellitus.

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Laboratory monitoring guidelines for patients with type 2 diabetes mellitus.

Intercurrent medical illness

Patients with intercurrent illness become more insulin resistant because of the effects of increased counter-regulatory (ie, anti-insulin) hormones. Therefore, despite decreased nutritional intake, glycemia may worsen. Patients on oral agents may need transient therapy with insulin to achieve adequate glycemic control. In patients who require insulin, scheduled doses of insulin, as opposed to sliding scale insulin, are far more effective in achieving glycemic control.^23,24 If patients taking metformin have any illness that leads to dehydration or hypoperfusion, the drug should be temporarily discontinued because of a possible increased risk of lactic acidosis.

Critical illness

Standard practice in intensively ill patients has been to provide tight glycemic control through intensive insulin therapy. Research evidence, however, has called this practice into question. A meta-analysis found that in critically ill adult patients, tight glucose control is associated with an increased risk of hypoglycemia but not with significantly reduced hospital mortality.²⁵ A large, international, randomized trial among adults treated in an intensive care unit (ICU) found that intensive glucose control (target, 81-108 mg/dL) resulted in higher mortality than did a blood glucose target of 180 mg/dL or less.²⁶

Results of the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction [DIGAMI] trial) suggested improved outcomes in patients with type 2 diabetes with acute myocardial infarction or stroke who receive constant intravenous insulin during the acute phase of the event to maintain blood glucose values of approximately 100-150 mg/dL.²⁷ However, these results were not confirmed in the follow-up trial, DIGAMI-2.²⁸

In the case of cardiac ischemia, the beneficial effects of insulin therapy may be due to reduction in free fatty acids.

Surgery

Surgical patients may experience worsening of glycemia for reasons similar to those listed above for intercurrent medical illness. Patients on oral agents may need transient therapy with insulin to maintain blood glucose at approximately 100-180 mg/dL. In patients who require insulin, scheduled doses of insulin, as opposed to sliding scale insulin, are far more effective in controlling glucose. Intensive glucose control in surgical ICU patients appears to reduce risk of septicemia, but as with other critically ill patients, this may come at the cost of increased risk of hypoglycemia.²⁵

For patients who can eat soon after surgery: The time-honored approach of administering half the usual morning dose of neutral protamine Hagedorn (NPH) insulin with 5% dextrose in the IV is acceptable, with resumption of scheduled insulin (perhaps at reduced doses) within the first 1-2 days. Patients receiving insulin glargine can often receive their usual dose if they are given intravenous glucose during surgery with appropriate intraoperative and postoperative monitoring of glucose. Oral antidiabetic agents can be restarted when the patient is stable and eating. Insulin secretagogues should be used with caution in the hospital since food intake may be interrupted by diagnostic tests and procedures. Metformin may have to be started at a lower dose and gradually titrated to full dose due to gastrointestinal side effects. Since glitazones have such a long biologic effect, their omission in the hospital is usuallyinconsequential. The role of incretins in the hospital has not yet been defined.
For patients who require more prolonged periods without oral nutrition and for major surgery, such as coronary artery bypass grafting and major abdominal surgery: Constant infusion intravenous insulin is preferred. Discontinue metformin temporarily after any major surgery until the patient is clearly hemodynamically stable and normal renal function is documented. The practice of discontinuing metformin for at least 48 hours in this situation until proof of normal renal function is established is sound.

Pregnancy

The increased prevalence of type 2 diabetes mellitus in women of reproductive age has brought new prominence to the need for prepregnancy planning in this population. Insulin is the only generally accepted pharmacologic therapy for women with diabetes mellitus who are contemplating pregnancy.²⁹ For women with diabetes mellitus controlled by lifestyle measures alone, conversion to insulin as soon as the pregnancy is confirmed is appropriate. For women with polycystic ovary disease who are receiving insulin sensitizer therapy and who subsequently ovulate and become pregnant, conversion to insulin is often mandatory as soon as pregnancy is confirmed. Metformin is used during pregnancy in other countries, but not in the United States.

Insulin is the only acceptable pharmacologic therapy during pregnancy for women with established diabetes mellitus. (Glyburide has been used for gestational diabetes mellitus patients late in the second and third trimesters, but this is not appropriate therapy for pregnant patients with established diabetes. Its safety during early gestation is not established.) For a complete discussion of this topic, see Diabetes Mellitus and Pregnancy.

Hypertension

The role of hypertension in increasing microvascular and macrovascular risk in patients with diabetes mellitus has been confirmed in the UKPDS and Hypertension Optimal Treatment (HOT) trials.^30,31 The American Diabetes Association suggests that the BP goal be less than 130/80 mm Hg. In patients with greater than 1 g/d proteinuria and renal insufficiency, a more aggressive therapeutic goal (ie, 125/75 mm Hg) is advocated. While ACE inhibitors, angiotensin receptor blockers (ARB), diuretics, beta blockers, and calcium channel blocker are all considered acceptable initial therapy, the author prefers inhibitors of the renin-angiotensin system (ie, ACE inhibitors, ARB) because of their proven renal protection effects in patients with diabetes. Many patients require multiple agents. Diuretics or calcium channel blockers frequently are useful as second and third agents.

Dyslipidemia

Dyslipidemia, particularly high triglycerides and low HDL-C, is more common in patients with type 2 diabetes mellitus. Data from statin trials show that event reduction is achievable in secondary prevention (ie, patients with diabetes and known coronary heart disease (CHD) and LDL-C elevation). Fibrates may reduce CHD events in patients with isolated low HDL-C. Primary prevention studies have also now shown that statin therapy reduces CHD events. Whether therapy aimed more at triglyceride reduction and HDL-C elevation (ie, fibrates, niacin) is effective in CHD event reduction in primary prevention remains to be determined. The American Diabetes Association guidelines for therapy of LDL-C are presented in the image below (see also Image 10).³²

American Diabetes Association guidelines for low-density lipoprotein cholesterol in diabetes mellitus type 2.

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American Diabetes Association guidelines for low-density lipoprotein cholesterol in diabetes mellitus type 2.

Surgical Care

Bariatric surgery has been shown to improve diabetes control and, in some situations, normalize glucose tolerance in morbidly obese patients. It is certainly a reasonable alternative in carefully selected patients if an experienced team (providing appropriate preoperative evaluation as well as technical surgical expertise) is available.

Consultations

Primary care providers can care for patients with type 2 diabetes mellitus adequately. The multiple facets of disease treatment (eg, nutrition, exercise, smoking cessation, medications, complications monitoring) and data management (eg, glucose levels, BP, lipids, complications monitoring) must be continually addressed. Inability to achieve adequate glycemic (or BP or lipid) control usually should be a clear indication to consult a diabetes specialist. When a patient has developed advanced complications, a diabetes specialist cannot be expected to be able to lessen the burden of these complications.

Diet

For most patients, the best diet is one consisting of the foods that they are currently eating. Attempts to calibrate a precise macronutrient composition of the diet to control diabetes, while time-honored, are generally not supported by the research. Caloric restriction is of first importance. After that, individual preference is reasonable. Modest restriction of saturated fats and simple sugars is also reasonable. However, some patients have remarkable short-term success with high-fat, low-carbohydrate diets of various sorts. Therefore, the author always stresses weight management in general and is flexible regarding the precise diet that the patient consumes. Also, the practitioner should advocate a diet using foods that are within the financial reach and cultural milieu of the patient.

Esposito et al compared the effects of a low-carbohydrate, Mediterranean-style diet with those of a low-fat diet in patients with newly diagnosed type 2 diabetes mellitus.³³ In a single-center, randomized trial, 215 overweight patients with newly diagnosed type 2 diabetes mellitus who had never been treated with antihyperglycemic drugs and whose hemoglobin A1c levels were less than 11% were assigned to either a Mediterranean-style diet (<50% of daily calories from carbohydrates) or a low-fat diet (<30% of daily calories from fat).

After 4 years, participants assigned to the Mediterranean-style diet had lost more weight and had demonstrated more improvement in some measures of glycemic control and coronary risk than had participants consuming the low-fat diet; 44% of patients in the Mediterranean-style diet group required antihyperglycemic drug therapy, compared with 70% of those in the low-fat diet group.

Activity

Most patients with type 2 diabetes mellitus can benefit from increased activity. Aerobic exercise improves insulin sensitivity and may improve glycemia markedly in some patients.

The patient should choose an activity that she or he is likely to continue. Walking is accessible to most patients in terms of time and financial expenditure.
A previously sedentary patient should start activities slowly.
Older patients, patients with long-standing disease, patients with multiple risk factors, and patients with previous evidence of atherosclerotic disease should have a cardiovascular evaluation, probably including an imaging study, prior to beginning a significant exercise regimen.
Risk for vascular complications and cardiovascular mortality in patients with diabetes mellitus is increased by poor glucose control. Loimaala et al investigated the efficacy of a long-term exercise training program on metabolic control and arterial stiffness in patients with type 2 diabetes mellitus. The study indicated that in comparison with standard treatment, long-term endurance and strength training improve metabolic control of diabetes mellitus. However, although significant cardiovascular risk reduction occurred in the study, conduit arterial elasticity did not improve.³⁴

Medication

Pharmacologic therapy has changed dramatically in the last 10 years. New drug classes and new drugs effectively treat type 2 diabetes mellitus, allowing glycemic control previously beyond the reach of medical therapy. Traditionally, diet modification has been the cornerstone of diabetes management. Weight loss is more likely to control glycemia in patients with recent onset of the disease than in patients who are significantly insulinopenic. Medications that induce weight loss, such as orlistat, may be effective in highly selected patients but are not generally indicated in the treatment of the average patient with type 2 diabetes mellitus. At presentation, patients who are symptomatic may require transient treatment with insulin to reduce glucose toxicity (which may reduce beta cell insulin secretion and worsen insulin resistance) or an insulin secretagogue to rapidly relieve symptoms such as polyuria and polydipsia.

Patients with HbA1c less than 8% are usually treated initially with single oral agents. Patients with initial HbA1c greater than 9-10% may benefit from initial therapy with 2 oral agents.

Various categories of therapeutic agents effectively treat type 2 diabetes mellitus. Comparisons of studies looking at glycemic efficacy of individual agents are highly affected by 2 study conditions: level of glycemia prior to treatment and percent of study population previously untreated with drugs. These 2 factors make comparison of drug studies quite difficult, because all agents are more effective in a population of patients with poor glycemic control at baseline (a large decrease in glucose concentrations occurs, but the treatment often leaves the patients with poorly controlled glucose levels) and in patients who previously were diabetes-drug naive.

Sulfonylureas

Sulfonylureas are time-honored insulin secretagogues (ie, oral hypoglycemic agents) and probably have the greatest efficacy for glycemic lowering of any of the oral agents. The UKPDS confirmed their safety after years of suspicion from the University Group Diabetes Program (UGDP).

Meglitinides

Meglitinides are much more short-acting insulin secretagogues than sulfonylureas, with preprandial dosing potentially achieving more physiologic insulin release and less risk for hypoglycemia. Their glycemic efficacy is possibly less than sulfonylureas.

Biguanides

Biguanides are old agents that reduce hepatic glucose production and may have a minor effect on glucose utilization in the periphery (ie, antihyperglycemics, hepatic insulin sensitizers). Insulin must be present for biguanides to work. Phenformin was taken off the market in the United States in the 1970s because of its risk of causing lactic acidosis and associated mortality (rate of approximately 50%). Metformin has proved effective and safe.³⁵

A nested case-control analysis found that, as with other oral antidiabetic drugs, lactic acidosis during metformin use is very rare and is associated with concurrent comorbidity; moreover, hypoglycemic episodes are substantially less common among patients taking metformin than they are among those taking sulfonylureas.³⁶ In addition, metformin is the only oral diabetes drug that reliably facilitates modest weight loss. In the UKPDS, it was found to be successful at reducing macrovascular disease endpoints in patients who were obese.³⁷ The results with concomitant sulfonylureas in a heterogeneous population were conflicting,³⁸ but overall, this drug probably improves macrovascular risk.

Kooy et al found improvements in body weight, glycemic control, and insulin requirements when metformin was added to insulin in patients with type 2 diabetes mellitus. No improvement of an aggregate of microvascular and macrovascular morbidity and mortality was observed; however, risk reduction of macrovascular disease was evident after a follow-up period of 4.3 years. These sustained beneficial effects indicated that, unless contraindicated, metformin treatment should be continued after the introduction of insulin in patients with type 2 diabetes mellitus.³⁹

Pradhan et al did not find an association between improving glycemic control with metformin or insulin and reducing inflammatory biomarker levels in patients with recent-onset type 2 diabetes mellitus.⁴⁰ Patients were randomized to 1 of 4 groups: placebo, placebo plus insulin glargine, metformin only, and metformin and insulin glargine. HbA1c and glucose levels were reduced with active treatment compared with placebo, but no difference in levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) was shown between study participants who received insulin or metformin and those who did not.

Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors prolong the absorption of carbohydrates. Their induction of flatulence greatly limits their use. These agents should be titrated slowly to reduce gastrointestinal intolerance. Their effect on glycemic control is modest, affecting primarily postprandial glycemic excursions.

Thiazolidinediones (glitazones)

Glitazones are a newer class of drugs that reduce insulin resistance in the periphery (ie, sensitize muscle and fat to the actions of insulin) and perhaps to a small degree in the liver (ie, insulin sensitizers, antihyperglycemics). They activate peroxisome proliferator–activated receptor (PPAR) gamma, a nuclear transcription factor that is important in fat cell differentiation and fatty acid metabolism. Their major action is probably actually fat redistribution. These drugs may have beta cell preservation properties. Their glycemic efficacy is moderate, between alpha-glucosidase inhibitors and sulfonylureas. They are the most expensive oral agents.

Glitazones require the presence of insulin to work. They generally decrease triglycerides and increase HDL-C, but they increase LDL-C (perhaps large buoyant LDL, which may be less atherogenic). While these drugs have many desirable effects on inflammation and the vasculature, edema and weight gain may be problematic adverse effects in patients taking glitazones, especially when administered with insulin or insulin secretagogues. These effects may induce or worsen congestive heart failure in patients with left ventricular compromise and occasionally in patients with normal left ventricular function. These agents have not been tested in patients with New York Heart Association class III or IV heart failure. A recently recognized possible side effect of these agents is macular edema. Recent animal work suggests that concomitant therapy with the diuretic amiloride may reduce fluid retention related to glitazone therapy.

The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) trial assessed the effect of pioglitazone titrated to 45 mg/d versus placebo added to existing diabetes therapy on macrovascular outcomes. No statistically significant difference was noted between the 2 groups at 3 years. A later developed main secondary endpoint (all-cause mortality, nonfatal myocardial infarction, and stroke) not mentioned in the original study design was reduced 16% (p=0.027).⁴¹ Treated patients gained 4 kg on average and had a much higher rate of heart failure and edema than patients treated with placebo. The author views this study as primarily a confirmation of concerns over weight gain, edema, and congestive heart failure with these drugs and thinks their potential antiatherosclerotic effects are still unproven.

The US Food and Drug Administration (FDA) issued an alert on May 21, 2007 to patients and health care professionals of rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths following the online publication of a meta-analysis.

A study indicates that in women with type 2 diabetes, long-term (ie, 1 y or longer) use of glitazones doubles the risk of fracture.⁴² In this investigation, glitazones did not significantly increase fracture risk among men with type 2 diabetes.

Incretin-mimetic

The incretin-mimetic agent exenatide has a novel mechanism of action. Mimicking the endogenous incretin, glucagonlike peptide-1 (GLP-1), it stimulates glucose-dependent insulin release (as opposed to oral insulin secretagogues, which may cause non–glucose-dependent insulin release and hypoglycemia), reduces glucagon, and slows gastric emptying. Studies have used exenatide in addition to metformin and/or a sulfonylurea. Patients may attain modest weight loss. Animal data suggest that this drug prevents beta cell apoptosis and may in time restore beta cell mass. This latter property, if proven in humans, would have tremendous therapeutic potential.

Exenatide has greater ease of titration (only 2 possible doses, with most patients progressing to the higher dose) than does insulin. However, exenatide is more expensive than high-dose glitazone therapy and requires twice-daily injections. A long-acting formulation that is given once weekly has been developed and has been found to provide significantly greater improvement in glycemic control than does the twice-daily formulation⁴³; it currently awaits FDA approval.

Bunck et al investigated the effects of 1 year's therapy with either exenatide or insulin glargine in metformin-treated patients with type 2 diabetes (with 36 patients in the exenatide group and 33 patients in the insulin glargine group).⁴⁴ This was followed by an off-drug period on hyperglycemic clamp-derived measures of beta cell function, glycemic control, and body weight.

The investigators measured patient improvement by using changes in glucose-stimulated and arginine-stimulated C-peptide secretion as markers. Exenatide provided significantly greater improvement in beta cell function during the 52-week treatment period than did insulin glargine (p <0.0001). A1c was similarly reduced by exenatide and insulin glargine. Beta cell function and glycemic control returned to pretreatment values following discontinuation of exenatide or insulin glargine, suggesting that long-term treatment is required to maintain the beneficial effects of these drugs.

Dipeptidyl peptidase IV inhibitors

The newest addition to available oral hypoglycemic agents is the dipeptidyl peptidase IV (DPP-4) inhibitor, sitagliptin, which gained FDA approval in October 2006. DPP-4 degrades numerous biologically active peptides, including the endogenous incretins GLP-1 and glucose-dependent insulinotropic peptide (GIP). Sitagliptin can be used as a monotherapy or in combination with metformin or a glitazone. It is given once daily and is weight neutral. Saxagliptin was FDA-approved July 2009. Another DPP-4 inhibitor, vildagliptin, is currently under review at the FDA.

Insulin

Ultimately, many patients with type 2 diabetes mellitus become markedly insulinopenic. The only therapy that corrects this defect is insulin. Because most patients are insulin resistant, small changes in insulin dosage may make no difference in glycemia in some patients. Furthermore, because insulin resistance is variable from patient to patient, therapy must be individualized in each patient.

A range of insulin preparations, individual and premixed, is currently available. The AHRQ has reviewed the use of premixed insulin analogues in patients with type 2 diabetes mellitus; conclusions for which the strength of evidence was high are as follows⁴⁵:

For lowering postprandial glucose, premixed insulin analogues are more effective than either long-acting insulin analogues alone or premixed NPH/regular human insulin 70/30.
For lowering HbA1c, premixed insulin analogues are as effective as premixed NPH/regular human insulin 70/30 and more effective than long-acting insulin analogues.
The frequency of hypoglycemia reported with premixed insulin analogues is similar to that with premixed human insulin and higher than that with oral antidiabetic agents.

On July 1, 2009, the FDA issued an early communication to health care practitioners regarding 4 recently published observational studies that described the possible association of insulin glargine (Lantus), a long-acting human insulin analogue approved for once-daily dosing, with an increased risk of cancer.⁴⁶

The observational studies evaluated large patient databases, and all reported some association between insulin glargine and other insulin products with various types of cancer. The duration of the observational studies was shorter than that considered to be necessary to evaluate for drug-related cancers. Additionally, findings were inconsistent within and across the studies, and patient characteristics differed across treatment groups. These issues raise further questions about the risk that actually exists, and therefore warrants further evaluation.
The FDA states that patients should not stop taking their insulin without consulting their physician. An ongoing review by the FDA will continue to update the medical community and consumers with additional information as it emerges. Statements from the American Diabetes Association and the European Association for the Study of Diabetes called the findings conflicting and inconclusive and cautioned against overreaction.

The first inhaled insulin (Exubera) was approved by the FDA in January 2006 as a rapid-acting prandial insulin. It did not produce better glycemic control than did conventionally injected insulins and required a mildly cumbersome device, skill to deliver an accurate dose (up to a few minutes to deliver 1 dose), and pulmonary function monitoring due to concerns about lung toxicity over time. Exubera was withdrawn from the market in October 2007; this was done not because of safety concerns but because too few patients were using the product for its continued sale to be economically feasible.

Medication strategy

A great deal of debate exists regarding the best initial oral therapy for patients with type 2 diabetes mellitus. The Agency for Healthcare Research and Quality (AHRQ) reviewed the published evidence (which came from short-term studies but was applicable to long-term use) regarding the comparative effectiveness of oral diabetes medications; the agency found little evidence to support predictions as to whether a particular medication is more likely to be effective in a given patient subgroup or to cause adverse effects in a particular patient.

The AHRQ concluded that when used as a monotherapy, most oral diabetes medications (with the exception of the less-effective nateglinide and alpha-glucosidase inhibitors) produce similar reductions in HbA1c, and that older medications (eg, metformin, second-generation sulfonylureas) can reasonably be used before newer ones (eg, glitazones, meglitinides), especially when cost is a factor.⁴⁷

Based on the results of the UKPDS and safety record, patients who are obese (120% ideal body weight) should be started on metformin initially, titrated to at least 2000 mg/d administered in divided doses (during or after meals to reduce gastrointestinal side effects). Patients who are markedly symptomatic may be treated with an insulin secretagogue initially to rapidly alleviate symptoms and then perhaps switched to other agents. Patients with near-normal weight may be treated with sulfonylureas or metformin initially. Short-acting insulin secretagogues (eg, repaglinide, nateglinide) can be used in patients unusually predisposed to hypoglycemia.

Failure of initial therapy usually should result in addition of another class of drug rather than substitution (reserve substitution for intolerance to a drug due to adverse effects). Considerable debate exists regarding second agents added to (or used initially in conjunction with) metformin. The time-honored approach is to add an insulin secretagogue (usually titrated to no more than the half-maximal approved dose to reduce risk for hypoglycemia). However, some experts recommend a glitazone because of the positive effects of these drugs on inflammation and the vasculature. If this strategy is used, a moderate dose of glitazone (as opposed to the highest approved dose) should be used. A therapeutic scheme utilized by the author is listed in the image below (see also Image 11).

Treatment of type 2 diabetes mellitus.

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Treatment of type 2 diabetes mellitus.

Because glitazones not infrequently cause weight gain and edema, the author usually reserves the use of these agents for patients who cannot use metformin, as a result of intolerance or contraindications. Exceptions to this practice might include patients of relatively normal weight who have marked insulin resistance, such as patients of Asian heritage. If an insulin secretagogue is being taken by the patient prior to the addition of a second agent, the patient should be warned about the possibility that hypoglycemia will be induced when another agent is added. In such cases, the dose of the insulin secretagogue, not the newly added agent, should be reduced.

If 2 drugs are unsuccessful, the practitioner may consider adding a third class of oral agents. An alternative would be to add bedtime insulin, usually NPH or glargine, to the initial oral agent or 2-drug combination, or add the new injectable drug exenatide. The expense and side effect profile of glitazones make the oral triple therapy approach less of an option for the author. The new approach of adding exenatide twice daily to 1 or 2 oral agents (eg, metformin and/or sulfonylureas) is attractive because of its simplicity (ie, only 2 possible doses of exenatide with easy titration compared with insulin), but its expense may be prohibitive. If insulin is used, the insulin dose is titrated to the fasting sugar concentration, which the patient can measure at home (usually with titration to a maximum bedtime insulin dose of approximately 60 units).

Some patients need reduction of their insulin secretagogue to prevent daytime hypoglycemia as the bedtime insulin is initiated or increased and the fasting glucose concentration is decreased. If exenatide is used, the author monitors fasting and postprandial sugars, expecting a marked flattening of the postprandial rise in glucose concentrations.

Measurement of glucose patterns in patients with type 2 diabetes, particularly those who have central obesity and hepatic steatosis, often reveals that the highest preprandial glucose level of the day is before breakfast (because of disordered hepatic glucose production overnight), with a "stair-step" decrease during the day (after the usual postmeal rise). These higher-than-desired morning glucose values do not necessarily dictate abandonment of the current therapeutic regimen, provided that the HbA1c level is at target. For patients who primarily have fasting hyperglycemia, bedtime insulin is the easiest way to correct this abnormality.

When the previous approaches are unsuccessful, the patient should be switched to conventional twice-daily or multiple daily dose insulin with or without an insulin sensitizer. The author prefers metformin in this scenario if there are no problems with tolerability or contraindications. If a glitazone is used, a moderate dose should be administered to minimize fluid retention and weight gain.

A necessary condition for twice-daily insulin to succeed is a regimented lifestyle, with mealtimes regularly spaced and insulin injections taken at essentially the same time every day, including weekends and holidays. Lack of regularity in the schedule is self-defeating for this approach to therapy. The author limits the use of premixed insulin to patients who might have trouble mixing their insulins. The author also prefers premixes containing regular insulin if the premix is administered to maintain better midday coverage. Premixes with rapid-acting medications can be used if the midday meal is small. All insulin injections should be administered in the abdomen.

A systematic review found that glycemic control with premixed insulin analogues (ie, mixtures of rapid-acting and intermediate-acting insulin analogues) is similar to that of premixed human insulin.⁴⁸

Conventional multiple daily dosing of insulin gives the patient the greatest flexibility. In this approach, insulin glargine or twice-daily insulin detemir is generally given as the basal insulin, and rapid-acting insulin (eg, aspart, glulisine, lispro) are administered just before each meal. The basal component can be administered any time of day as long as it is given at the same time each day. Interpreting glucose patterns is probably easiest if the basal insulin is administered at or near bedtime. The basal insulin can then be titrated to the morning sugar, and the bolus premeal insulin can be titrated to the next premeal sugar and, in some cases, a postprandial (2 h) value.

For patients trying to achieve near euglycemia, premeal glucose values of 80-120 mg/dL are the goal, with the patient going to sleep at night with a value at least 100 mg/dL. In patients with less stringent glycemic goals (eg, because of advanced age, advanced complications, severe concomitant disease), preprandial glucose values of 100-140 mg/dL are desired. Because of the limitations of therapies, essentially no patient is able to achieve these goals all the time if, in fact, insulin is needed to treat their disease.

Unlike in long-standing type 1 diabetes mellitus, patients with type 2 diabetes mellitus usually maintain adequate warning symptoms and signs of hypoglycemia. This situation greatly facilitates hypoglycemic therapy (ie, insulin secretagogues, insulin) in patients with type 2 diabetes.

Glycemic control is a function of not only of fasting and preprandial glucose values but also of postprandial glycemic excursions. Emphasis on postprandial glucose measurements has been fueled to some degree by the availability of short-acting insulin secretagogues, very–short-acting insulin, and alpha-glucosidase inhibitors, all of which target postprandial glycemia. While postprandial glucose levels are a better predictor of macrovascular disease risk early in the course of loss of glucose tolerance, it remains to be seen whether targeting after-meal glucose excursions has more of an effect on the risk of complications than do more conventional strategies.

Intuitively, one would assume that therapies that normalize preprandial and postprandial glycemia (or that come close to normalizing them) would be optimal. Whether such a strategy can be achieved without untoward adverse effects and with further reductions in microvascular and macrovascular disease risk (compared to regimens used in the UKPDS) with newly available therapies is open to question. Practically speaking, most patients are fully occupied trying to do conventional glucose monitoring and insulin dose adjustment.

An outline of the therapeutic approach generally used by the author is presented in the first 2 images below (see also Images 11, 13). An idealized scheme for glucose and insulin patterns is presented in the third image below (see also Image 14). The author finds that keeping such an idealized scheme in mind is helpful in treating and educating patients, even if the patient is trying to replicate it with less-intensive insulin therapy.

Treatment of type 2 diabetes mellitus.

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Treatment of type 2 diabetes mellitus.

Simplified scheme for using insulin in treating patients with type 2 diabetes mellitus.

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Simplified scheme for using insulin in treating patients with type 2 diabetes mellitus.

Simplified scheme of idealized blood glucose values and multiple dose insulin therapy in type 2 diabetes mellitus.

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C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Meglitinides

Short-acting insulin secretagogues with preprandial dosing, potentially achieving more physiologic insulin release and less risk for hypoglycemia.

Repaglinide (Prandin)

Probably most useful in patients at increased risk for hypoglycemia who still need an insulin secretagogue. Better control of postprandial glycemic excursions also may be achieved with repaglinide. FDA approved for monotherapy and in conjunction with metformin or glitazones.

Adult

0.5-4 mg PO up to qid ac; not to exceed 16 mg qd

Pediatric

Not established

CYP3A4 inhibitors (eg, clarithromycin, ketoconazole, miconazole, erythromycin) decrease metabolism, thus increasing serum levels and effects; NSAIDs, sulfonamides, chloramphenicol, probenecid, warfarin, MAOIs, or beta-blockers produce increased hypoglycemic effects; thiazides, hydantoins, oral contraceptives, estrogens, corticosteroids, phenothiazines, thyroid products, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid produce decreased hypoglycemic effects; increases alcohol-related disulfiram reactions; increases warfarin effects

Documented hypersensitivity; diabetic ketoacidosis; type 1 diabetes mellitus

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients predisposed to hypoglycemia, such as patients with liver disease and elderly patients; trauma, infection, surgery, and stress may require use of insulin

Nateglinide (Starlix)

Mimics endogenous insulin patterns, restores early insulin secretion, and controls mealtime glucose surges. Indicated as monotherapy for type 2 diabetes or combination therapy with metformin or glitazones.
Available as 60-, 120-, and 180-mg tablets.

Adult

Usual dose: 120 mg PO 1-30 min ac
Elderly patients or patients at higher risk of hypoglycemia: May use 60 mg ac

Pediatric

Not established

NSAIDs, MAOIs, and beta-blockers produce increased hypoglycemic effects; thiazides, hydantoins, corticosteroids, thyroid products, and sympathomimetics produce decreased hypoglycemic effects

15-30 mg PO qd; may increase; not to exceed 45 mg/d (15-mg dose often of little efficacy)

Pediatric

Not established

May reduce plasma concentrations of contraceptives containing ethinyl estradiol and norethindrone; laboratory studies suggest ketoconazole may inhibit metabolism of pioglitazone (monitor blood glucose levels closely); pioglitazone in combination with insulin or oral hypoglycemics (eg, sulfonylureas) may increase risk for hypoglycemia

Documented hypersensitivity; active liver disease; ketoacidosis; type 1 diabetes mellitus; class III or IV CHF; macular edema

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Alpha-glucosidase inhibitors

These agents delay sugar absorption and help prevent postprandial glucose surges.

Acarbose (Precose)

First alpha-glucosidase inhibitor approved by FDA. Absorbed to small degree, so liver function abnormalities can occur rarely. Can be used as monotherapy or in combination with other treatment modalities. Its modest effect on glycemia and high degree of GI adverse effects (flatulence) limit use.

Adult

12.5 mg PO qd with first bite of meal, titrate dose slowly to 25-50 mg PO tid with first bite of meal; may administer 100 mg tid in patients >60 kg

Pediatric

Not established

Decreases absorption and bioavailability of digoxin, propranolol, and ranitidine; digestive enzymes reduce effects; diuretics (ie, thiazide), corticosteroids, phenothiazines, thyroid, estrogen, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, isoniazid, intestinal absorbents, and digestive enzymes produce decreased hypoglycemic effects

See individual drug component

Glyburide/metformin drug combination (Glucovance)

Indicated for initial therapy or second line. Targets dual physiologic defects, but main utility may be one of convenience.

Adult

Available as 1.25-mg glyburide/250-mg metformin tab, 2.5-mg glyburide/500-mg metformin tab, and 5-mg glyburide/500-mg metformin tab; not to exceed 20 mg glyburide and 2000 mg metformin PO; glyburide in these pills may be more bioavailable than conventional glyburide tab

Pediatric

Not established

Administer in thigh, abdomen, or upper arm; may cause hypoglycemia, nausea, vomiting, diarrhea, jittery feeling, dizziness, headache, or dyspepsia; may develop antibodies to protein contents

Insulin agents

Stimulate proper utilization of glucose by the cells and reduce blood sugar levels.

Types of insulin. Premixed insulins can be assumed to have a combination of the onset, peak, and duration of the individual components.

[ CLOSE WINDOW ]

Types of insulin. Premixed insulins can be assumed to have a combination of the onset, peak, and duration of the individual components.

Simplified scheme for using insulin in treating patients with type 2 diabetes mellitus.

[ CLOSE WINDOW ]

Simplified scheme for using insulin in treating patients with type 2 diabetes mellitus.

Simplified scheme of idealized blood glucose values and multiple dose insulin therapy in type 2 diabetes mellitus.

[ CLOSE WINDOW ]

Simplified scheme of idealized blood glucose values and multiple dose insulin therapy in type 2 diabetes mellitus.

Insulin (Humulin multiple types, Novolin multiple types, Lantus, Apidra)

Insulin is a vital therapy in many patients with type 2 diabetes mellitus because the pancreas ultimately fails to produce enough insulin, even in the setting of insulin secretagogues, to maintain glycemic control. Types of insulin and their characteristics are listed in the first image above (see also Image 12). Therapy is largely empiric, with multiple choices available to achieve glycemic control (see second image above and Image 13). Idealized glucose and insulin patterns with MDI (multiple daily injections) are shown in the third image above (see also Image 14). The DIGAMI trial and the UKPDS largely have exonerated insulin therapy as atherogenic in patients with type 2 diabetes mellitus.
Aspart, glargine, glulisine, and lispro are all insulin analogs (modifications of the insulin molecule to change absorption characteristics, dissociation in subcutaneous tissue, and time course of action). All but glargine are rapid-acting insulins.

Adult

Insulin injections should generally be taken in the abdomen; insulin analogs may be administered in the limbs if absolutely necessary; pen devices facilitate convenience and may improve compliance but increase expense
Bedtime NPH or glargine: approximately 10-15 U initial dose, titrate to fasting glucose; not to exceed 60 U bid
Insulin: initiate with approximately 0.5 U/kg with two thirds in morning and two thirds as NPH, titrate by SMBG results; for this therapy to be successful, the injections and meals should be taken at about the same time every day
Multiple daily injections: 50% as basal insulin (glargine or ultralente) and preprandial insulin (aspart, glulisine, or lispro) 20% ac breakfast, 15% ac lunch, and 15% ac supper; titrate by SMBG results; add metformin or glitazone if total insulin dose >1-2 U/kg; rapid-acting insulins should be injected immediately ac; regular insulin should be injected 20-30 min ac; the timing of other insulin preparations is variable
Premixed insulins: Novolin and Humulin 70/30 with 70% NPH and 30% regular insulin; NovoMix 70/30 with NPH-like profile 70% and 30% aspart; Humalog mix 75/25 with NPH-like profile 75% and 25% lispro

Pediatric

Administer as in adults

Acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid products, estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine, phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin may decrease hypoglycemic effects; calcium, ACE inhibitors, alcohol, tetracyclines, beta-blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone may increase hypoglycemic effects

Overview: Diabetes Mellitus, Type 2

Differential Diagnoses & Workup: Diabetes Mellitus, Type 2

Treatment & Medication: Diabetes Mellitus, Type 2

Follow-up: Diabetes Mellitus, Type 2

Multimedia: Diabetes Mellitus, Type 2

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Keywords

diabetes mellitus, diabetes, insulin, glucose, blood sugar, metformin, diabetes type 2, diabetic, diabetes 2, hyperglycemia, diabetes diet, diabetes treatment, mellitus, diabetes mellitus type 2, diabetic ketoacidosis, diabetes symptoms, ketoacidosis, diabetes diagnosis, high blood sugar, type 2 diabetes mellitus, type II diabetes mellitus, DM, DM type 2, adult-onset diabetes mellitus, maturity-onset diabetes mellitus, non–insulin-dependent diabetes mellitus, NIDDM, maturity-onset diabetes of the young, MODY, microvascular complications, macrovascular complications, lack of endogenous insulin, pancreatic beta-cellfailure, insulinresistance,elevated free fatty acids, obesity, metabolic complications, insulin deficiency, end-stage renal disease, ESRD, nontraumatic lower limb amputations, diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, polyuria, polydipsia, polyphagia, blurred vision, lower extremity paresthesias, yeast infections, hypertension, high triglycerides,polycystic ovary disease, Cushing syndrome, acromegaly, pheochromocytoma, incretins, dipeptidyl-peptidase inhibitor-IV, DPP-4 inhibitor, gestational diabetes mellitus

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Contributor Information and Disclosures

Author

Kenneth Patrick L Ligaray, MD, Fellow, Department of Endocrinology, Diabetes and Metabolism, St Louis University
Kenneth Patrick L Ligaray, MD is a member of the following medical societies: American Association of Clinical Endocrinologists and Endocrine Society
Disclosure: Nothing to disclose.

Coauthor(s)

William L Isley, MD, Senior Associate Consultant, Associate Professor of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic of Rochester
William L Isley, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Diabetes Association, American Federation for Medical Research, Endocrine Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Medical Editor

David S Schade, MD, Chief, Division of Endocrinology and Metabolism, Professor, Department of Internal Medicine, University of New Mexico School of Medicine and Health Sciences Center
David S Schade, MD is a member of the following medical societies: American College of Physicians, American Diabetes Association, American Federation for Medical Research, Endocrine Society, New Mexico Medical Society, New York Academy of Sciences, and Society for Experimental Biology and Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Don S Schalch, MD, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics
Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

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