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Management of blood glucose in type 2 diabetes mellitus

Management of Blood Glucose
in Type 2 Diabetes Mellitus
CYNTHIA M. RIPSIN, MD, MS, MPH; HELEN KANG, MD; and RANDALL J. URBAN, MD
University of Texas Medical Branch, Galveston, Texas
Evidence-based guidelines for the treatment of type 2 diabetes mellitus focus on three areas: intensive lifestyle inter-
vention that includes at least 150 minutes per week of physical activity, weight loss with an initial goal of 7 percent of
baseline weight, and a low-fat, reduced-calorie diet; aggressive management of cardiovascular risk factors (i.e., hyper-
tension, dyslipidemia, and microalbuminuria) with the use of aspirin, statins, and angiotensin-converting enzyme
inhibitors; and normalization of blood glucose levels (hemoglobin A1C level less than 7 percent). Insulin resistance,
decreased insulin secretion, and increased hepatic glucose output are the hallmarks of type 2 diabetes, and each class
of medication targets one or more of these defects. Metformin, which decreases hepatic glucose output and sensitizes
peripheral tissues to insulin, has been shown to decrease mortality rates in patients with type 2 diabetes and is consid-
ered a first-line agent. Other medications include sulfonylureas and nonsulfonylurea secretagogues, alpha glucosidase
inhibitors, and thiazolidinediones. Insulin can be used acutely in patients newly diagnosed with type 2 diabetes to
normalize blood glucose, or it can be added to a regimen of oral medication to improve glycemic control. Except in
patients taking multiple insulin injections, home monitoring of blood glucose levels has questionable utility, espe-
cially in relatively well-controlled patients. Its use should be tailored to the needs of the individual patient. (Am Fam
Physician.
2009;79(1):29-36, 42. Copyright 2009 American Academy of Family Physicians.)
T Patient information:
A handout on lifestyle changes to manage type 2 diabetes, written by the authors of this article, is provided on page 42.
Type 2 diabetes mellitus, the sixth of cardiovascular disease risk factors, and leading cause of death in the management of blood glucose levels.7
United States, is directly respon-
sible for more than 73,000 deaths LIFESTYLE CHANGES
annually and is a contributing factor in more Lifestyle modification can help patients lose than 220,000 deaths.1 It is the leading cause weight and reduces the incidence of type of kidney failure and new cases of blind- 2 diabetes in at-risk patients.8 One large ness in adults,1 and it is a significant cause study compared usual care with an inten-of lost workforce productivity.2 More than sive lifestyle intervention.6 Although only 20 million Americans have diabetes; 6 mil- lion of these are undiagnosed.1 Ethnic and maintained the weight loss goal of 7 percent racial minorities are disproportionately of baseline body weight, the incidence of affected.1 Derangement of glucose homeo- type 2 diabetes was reduced by 58 percent. stasis and the eventual development of To prevent one new case of diabetes in three diabetes is a multifactorial process involv- years, 6.9 persons would need to undergo ing genetics, ethnic and racial heritage, intensive lifestyle intervention.6 Lifestyle and environmental factors. Although the changes were much more effective than met-precise interplay of these factors is not yet formin (Glucophage) therapy. In a review fully understood, long-term trials have of 14 trials testing exercise interventions in provided evidence to support aggressive participants with type 2 diabetes , hemoglo-efforts to prevent and manage this disease bin A1C levels were reduced by 0.6 percent, (Table 1).3-6 and triglyceride levels and visceral adiposity were decreased independent of weight loss.9 Management of Type 2 Diabetes
These results underscore the importance of Evidence-based guidelines for the compre- reinforcing lifestyle goals with every patient hensive management of diabetes focus pri- at every visit, even if weight loss falls short marily on lifestyle changes, management of expectations. Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright 2009 American Academy of Family Physicians. For the private, noncommercial s@aafp.org for copyright question A
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Type 2 Diabetes
SORT: KEY RECOMMENDATIONS FOR PRACTICE
Patients with impaired glucose tolerance should MANAGEMENT OF CARDIOVASCULAR
be provided with counseling and instruction for DISEASE RISK FACTORS
Multifactorial interventions to manage car- Metformin (Glucophage) is the only medication diovascular disease risk factors (i.e., blood proven to reduce mortality rates in patients with pressure, cholesterol, microalbuminuria) in patients with type 2 diabetes have been Acarbose (Precose) seems to reduce the risk of shown in well-designed clinical trials to When adding insulin to a regimen of oral decrease mortality rates.10 Daily low-dose medication, oral agents should be continued aspirin is recommended for patients with initially. Long-acting insulin should be used initially, type 2 diabetes and coronary artery disease typically at a dosage of 10 units per day or 0.17 to (CAD), those older than 40 years, and those 0.5 units per kg per day, and titrated in increments of two units approximately every three days.
who have additional risk factors for cardio-vascular disease (e.g., family history of car- A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited- diovascular disease, hypertension, smoking, quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual dyslipidemia, albuminuria).7 Statins are rec- practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml. ommended for patients with type 2 diabe-tes and CAD, and for patients with diabetes Table 1. Major Trials That Form the Basis for Treatment Rationale for Type 2 Diabetes Mellitus
Sulfonylureas, insulin, or dietary intervention Metformin (Glucophage) or dietary intervention Secondary analysis compared metformin with addition of metformin to sulfonylureas when participants failed treatment with sulfonylureas Metformin, placebo, or intensive lifestyle intervention, which included 150 minutes of weekly exercise and a goal of 7 percent fasting glucose level of 95 to 125 mg per dL (5.30 to 6.95 mmol per L), and glucose level of 140 to 199 mg per dL (7.75 to 11.05 mmol per L) two hours post-glucose load BMI = body mass index; CI = confidence interval; UKPDS = United Kingdom Prospective Diabetes Study. Information from references 3 through 6. 30 American Family Physician
Volume 79, Number 1 V January 1, 2009 Type 2 Diabetes
without CAD who are older than 40 years and have one but the studies are so heterogeneous that the expected A1C other cardiovascular disease risk factor.7 Angiotensin- reduction attributed to any class of medication should converting enzyme inhibitors and angiotensin receptor be interpreted with caution.15,16 For example, six trials blockers are mainstays of treatment for patients with that evaluated sulfonylureas for an average of 16 weeks micro- or macroalbuminuria.7 reported mean A1C reductions of 1.8 percent (range, 1 to 2.5 percent),15 whereas the 10-year United Kingdom MANAGEMENT OF BLOOD GLUCOSE LEVELS
Prospective Diabetes Study reported an A1C reduction of Insulin resistance, decreased insulin secretion, and 0.9 percent with sulfonylureas.3 This suggests that short-increased hepatic glucose output are the hallmarks of term studies may not accurately reflect long-term results. type 2 diabetes. Medications target one or more of these It is also critical to remember that the goal of treatment defects (Table 2).11-13 Average absolute reductions in A1C is not only to reduce A1C levels, but also to prevent pre-for each class of medication range from 0.5 to 1.0 percent mature mortality and morbidity. Not all agents have been for exenatide (Byetta), pramlintide (Symlin), and alpha- glucosidase inhibitors to 1 to 2.5 percent for sulfonylureas Insulin Secretagogues. Sulfonuylurea insulin secre- and metformin.14 Reviews have reported that mono- tagogues (e.g., glipizide [Glucotrol], glimepiride therapy with any oral hypoglycemic agent is superior to [Amaryl]) and nonsulfonylurea insulin secretagogues dietary management or placebo in reducing A1C values, (e.g. nateglinide [Starlix]) increase insulin secretion by closing potassium channels on the surface of pancreatic beta cells.11 Hypoglycemia can occur with any insulin secretagogue. Sulfo-nylureas can cause weight gain; this effect is less common with nonsulfonylurea secre-tagogues. A recent review concluded that cardiovascular disease events are neither increased nor decreased with the use of sul- Blood pressure and lipid control greatly fonylureas.17 There is insufficient evidence reduce cardiovascular mortality rates in to make any conclusions about the effects of nonsulfonylurea secretagogues on cardiovas- Tight blood glucose control reduces retinal Biguanides. Metformin decreases hepatic glucose output and, to a lesser extent, sensi- tizes peripheral tissues to insulin.11 A review representing more than 36,000 patient-years Metformin should be the drug of choice in patients with type 2 diabetes, particularly of metformin use found no increase in fatal or nonfatal lactic acidosis.18 However, cur- related death (P = .017) with use rent guidelines recommend that metformin should not be used in patients with chronic or acute renal insufficiency, and should be discontinued when creatinine levels reach 1.4 mg per dL (120 μmol per L) in women or 1.5 mg per dL (130 μmol per L) in men. Met- Metformin: 7.8 cases per 100 person-years formin has been shown to decrease progres- Lifestyle: 4.8 cases per 100 person-years sion from impaired glucose tolerance to type 2 diabetes.6 To prevent one new case in three years, 13.9 persons would have to be treated with metformin.6 It is the only hypoglyce- mic agent shown to reduce mortality rates in patients with type 2 diabetes.5 increase insulin sensitivity in peripheral tis-sues and, to a lesser extent, decrease hepatic January 1, 2009 V Volume 79, Number 1 American Family Physician 31
Type 2 Diabetes
Table 2. Medications Used to Manage Blood Glucose in Patients with Type 2 Diabetes Mellitus
lin; injectable medica-tion; reduce insulin dose by 50 percent when initiating therapy procedure if serum creatinine levels are unchanged) congestive heart failure (New York Heart Association class III or IV); use with caution in patients with edema CYP = cytochrome P450; NA = not applicable. *— Relative cost is based on average wholesale price for one-month supply; range of cost of all diabetic agents divided into quartiles ($ = lowest cost, $$$$ = highest cost).—Not yet approved by the U.S Food and Drug Administration. §—Brand no longer available in the United States. Information from references 11 through 13. Approach to the Patient with Type 2 Diabetes Mellitus
Impaired fasting glucose (100 to 125 mg
Type 2 diabetes mellitus
Impaired glucose tolerance (two-hour
Lifestyle intervention:
Fasting blood glucose > 250 mg per dL Reinforce at every visit
Lifestyle intervention:
Lifestyle intervention:
Reinforce at every visit
Reinforce at every visit
Begin insulin therapy
10 units per day or 0.2 units per kg per day; increase by 2 units every three days Add short-acting pre-meal insulin as needed Control not achieved with oral medications Exenatide (Byetta; approved for use with Sitagliptin (Januvia; approved for use with Figure 1. Algorithm for management of type 2 diabetes mellitus.
Information from references 7, 14, and 24. glucose production.11 These agents will not cause hypo- of four trials concluded that the risk of MI and heart glycemia when used as monotherapy. A recent review of failure are significantly increased, but overall cardiovas- 18 trials concluded that rosiglitazone (Avandia) is associ- cular mortality rates are unaffected.13 The latter review ated with an increased risk of myocardial infarction (MI) was limited to trials with one or more years of follow-up, and death from cardiovascular causes.12 Another review whereas the former review included trials with shorter January 1, 2009 V Volume 79, Number 1 American Family Physician 33
Type 2 Diabetes
Table 3. Insulin and Insulin Analogues
Rapid-acting insulin
Intermediate-acting insulin
Smoother curve than NPH; administered once or twice daily; available in pen form; can be kept without refrigeration for up to 42 days Mixed insulin
Mixed insulin preparations may hinder tight glycemic control because the ratio of the two preparations cannot be altered follow-up periods. In a meta-analysis of 19 controlled expert opinion and have not been conclusively evalu-trials, pioglitazone (Actos) was associated with a reduc- ated14,24 (Figure 1).7,14,24 The goal is to maintain blood glu- tion in a composite end point of death, MI, and stroke.19 cose levels as close to normal as possible without risking The incidence of serious heart failure was increased by significant hypoglycemia. The American Diabetes Asso-40 percent, but there was no change in cardiovascular ciation recommends an A1C goal of less than 7 percent.7 disease mortality rates.
Glycemic control requires the patient to have cognitive, Alpha-Glucosidase Inhibitors. Alpha-glucosidase inhibi- visual, and motor skills to monitor and manage blood tors act at the brush border in the small intestine, inactivat- glucose levels, and identifying and minimizing barriers ing the enzyme that breaks down complex carbohydrates, for effective self-management is an important first step slowing absorption, and flattening the postprandial gly- to setting individualized goals. There are no evidence- cemic curve.11 Acarbose (Precose) reduces the risk of car- based recommendations for the frequency of home diovascular disease events, including acute MI, in patients blood glucose monitoring except for patients adminis- with impaired glucose tolerance or type 2 diabetes.17,20,21 tering multiple daily injections of insulin; several studies Incretin Mimetics and Incretin Enhancers. Incretin hor- have questioned the usefulness of home monitoring.25,26 mones stimulate glucose-dependent insulin secretion, In patients with relatively well-controlled diabetes, home decrease glucagon secretion, slow gastric emptying, and monitoring has not been associated with clinically sig-decrease appetite.11 Exenatide lowers blood glucose levels nificant improvements in A1C levels.25,26 Monitoring can and stimulates weight loss, perhaps by slowing gastric be a useful tool in adjusting medications in the three-emptying and producing satiety.11,22 Sitagliptin (Januvia) month intervals between A1C measurement, but it is has no effect on body weight.23 There are no data on the also expensive and time-consuming, and it should be effects of these medications on cardiovascular events.17 individualized to meet the needs of each patient.
Amylin Analogues. Pramlintide is an amylin analogue indicated for use in patients with type 1 diabetes; it is INITIAL MANAGEMENT
rarely used to manage type 2 diabetes.11 When pram-
The first step in managing type 2 diabetes is to normalize lintide is initiated, the insulin dosage should be reduced fasting glucose levels, with weekly or monthly adjustments by 50 percent to avoid potentially severe hypoglycemia. in the regimen.14 Metformin is a first-line consideration. There is insufficient evidence to make conclusions about Gastrointestinal symptoms associated with its use can the effects of pramlintide on cardiovascular disease.17 be minimized by beginning with a low dose and titrat-ing slowly. Additional agents include sulfonylureas, Approach to the Patient
nonsulfonylurea secretagogues, thiazolidinediones, and Algorithms for the management of blood glucose con- alpha-glucosidase inhibitors. Any of these agents can tain elements derived from large, well-designed clinical be combined with another. Once fasting blood glucose trials, but the algorithms themselves are compiled from approaches near-normal levels, postprandial glucose is 34 American Family Physician
Volume 79, Number 1 V January 1, 2009 Type 2 Diabetes
Creating a Sliding-Scale Insulin Regimen
Sample patient
failure. However, progressive failure of the Rapid-acting insulin: 10 units before breakfast, beta cells often occurs even with proper diet, 8 units before lunch, and 12 units before dinner exercise, and oral medications, so patients should be counseled that insulin is simply another management tool. Although insulin is typically introduced when glucose control is no longer possible with oral agents, it can also be used when contraindications to oral This means 10 g of carbohydrates will be medications exist. Newly diagnosed patients covered by 1 unit of rapid-acting insulin also can benefit from acute insulin use. Pro- units of insulin needed to cover the meal and the longed hyperglycemia can cause glucose tox- icity, a potentially reversible impairment in Blood glucose before breakfast = 190 mg per dL glucose-stimulated insulin secretion. This glucose. Add these numbers to get the total units of can be corrected with aggressive insulin therapy, then oral medications can be added 3 units of rapid-acting insulin required to correct as insulin is tapered or discontinued. Expert opinion suggests that insulin therapy should Current glucose – target glucose = 190 – 100 = 90 be initiated if the fasting blood glucose level is consistently greater than 250 mg per dL (13.90 mmol per L), or if random testing Patient plans to eat 50 g of carbohydrates at breakfast; shows levels greater than 300 mg per dL24 5 units of insulin is needed to cover the meal (16.65 mmol per L; Figure 17,14,24).
tion regimen, oral agents should initially Rapid-acting insulin needed for this meal: 3 + 5 = 8 units be continued. Long-acting insulin should be used initially, typically at a dosage of If the patient cannot count calories, estimate the amount of carbohydrates per 10 units per day or 0.17 to 0.5 units per kg meal (e.g., 60 g per meal). Then 6 units of insulin is required per meal to cover carbohydrates (C:I = 10; calculated above) per day, and titrated in increments of two units approximately every three days14,24 Premeal glucose = 70 to 100 mg per dL (3.90 to 5.55 mmol per L); no additional (Table 3). Rapid-acting or premixed prepa- insulin is needed to correct. Patient should take 6 units to cover meal.
rations can be added if fasting blood glu- Premeal glucose = 101 to 130 mg per dL (5.60 to 7.20 mmol per L); 1 unit of insulin cose levels are persistently high or if A1C is needed to correct (CF = 30; calculated above). Patient should take 7 units total.
Premeal glucose = 131 to 160 mg per dL (7.25 to 8.90 mmol per L); 2 units of has plateaued at about 7.5 percent, which insulin is needed to correct. Patient should take 8 units total.
indicates that postprandial glucose lev-els are high. Adding more basal insu-lin in this setting usually will not help Figure 2. Steps to create a sliding scale for the use of rapid-acting insu-
patients reach their target levels.24 Sliding- lin. (CF = correction factor; C:I = carbohydrate-to-insulin ratio; TDDI = scale doses can be set by counting carbo- hydrate grams or by a preset scale (Figure addressed by increasing the dose of the current medi- 2). For the latter method, one suggested regimen is to cations or by adding additional agents. Once maximal give 90 percent of the basal dose of insulin in long-act-benefit is achieved from first-line medications, other ing form and the remainder in rapid-acting form at the agents, such as exenatide (approved for use with metformin largest meal, then adjust the dose as necessary.24 Insulin or sulfonylureas) and sitagliptin (approved for use with is used almost exclusively in pregnancy because of the metformin or thiazolidinediones), can be considered.
concern of teratogenicity with oral medications.
INITIATING INSULIN THERAPY
CHILDREN AND OLDER ADULTS
Less than 40 percent of patients with diabetes success- As the prevalence of obesity in children has increased, fully achieve an A1C level of less than 7 percent.24 One type 2 diabetes has also become more common. Metfor-reason for this is the reluctance of patients and physi- min is approved for use in children 10 years and older cians to start insulin therapy, perceiving it as a treatment and sustained-release preparations are approved for use January 1, 2009 V Volume 79, Number 1 American Family Physician 35
Type 2 Diabetes
in persons 17 years and older who cannot maintain gly- 6. Knowler WC, Barrett-Connor E, Fowler SE, et al., for the Diabetes Pre- vention Program Research Group. Reduction in the incidence of type cemic control with diet and exercise.7,27 2 diabetes with lifestyle intervention or metformin. N Engl J Med. The increased prevalence of comorbid conditions in older adults requires careful consideration of medica- 7. American Diabetes Association. Clinical practice recommendations tions. Serum creatinine levels are not always a reliable 2007. Diabetes Care. 2007;30(suppl 1):S1-S103.
predictor of renal insufficiency in the elderly, so metfor- 8. Norris SL, Zhang X, Avenell A, et al. Long-term, non-pharmacologic weight loss interventions for adults with type 2 diabetes. Cochrane min should be used with caution. The high prevalence of Database Syst Rev. 2005;(2):CD004095.
heart failure in this population limits the use of thiazoli- 9. Thomas DE, Elliott EJ, Naughton GA. Exercise for type 2 diabetes mel- dinediones. Older patients are likely to benefit more from litus. Cochrane Database Syst Rev. 2006;(3):CD002968.
aggressive management of known cardiovascular disease 10. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multi- factorial intervention and cardiovascular disease in patients with type 2 risk factors such as hypertension than by tight glycemic diabetes. N Engl J Med. 2003;348(5):383-393.
control, which can increase symptomatic hypoglycemia.7 11. Goodman LS, Gilman AZ, Brunton LL. Goodman & Gilman’s The Pharmaco- logical Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2005.
12. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events The Authors
with rosiglitazone: a meta-analysis. JAMA. 2007;298(10):1189-1195.
CYNTHIA M. RIPSIN, MD, MS, MPH, is an assistant professor of family 13. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocar- medicine at the University of Texas Medical Branch in Galveston. She dial infarction and death from cardiovascular causes [published cor- received her medical degree from Eastern Virginia Medical School, Nor- rection appears in N Engl J Med. 2007;357(1):100]. N Engl J Med. folk, and her master’s degree in public health from the University of Min- nesota School of Public Health, Minneapolis. Dr. Ripsin completed her 14. Nathan DM, Buse JB, Davidson MB, et al. Management of hypergly- residency at Portsmouth (Va.) Family Medicine Residency Program.
cemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy [published correction appears in Diabetes Care. HELEN KANG, MD, is currently in private practice. At the time this article 2006;49(11):2816-2818]. Diabetes Care. 2006;29(8):1963-1972.
was written, she was a fellow in endocrinology and metabolism at the 15. Kimmel B, Inzucchi SE. Oral agents for type 2 diabetes: an update. Clin University of Texas Medical Branch. She received her medical degree from Chicago (Ill.) Medical School and completed an internal medicine resi- 16. Bolen S, Feldman L, Vassy J, et al. Systematic review: comparative effec- dency at the University of Texas Medical Branch.
tiveness and safety of oral medications for type 2 diabetes mellitus [published correction appears in Ann Intern Med. 2007;147(12):887]. RANDALL J. URBAN, MD, is a professor of internal medicine and the Ann Intern Med. 2007;147(6):386-399.
Edward Randall and Edward Randall Jr. Distinguished Chair in Inter- 17. Uwaifo GI, Ratner RE. Differential effects of oral hypoglycemic nal Medicine at the University of Texas Medical Branch. He received his agents on glucose control and cardiovascular risk. Am J Cardiol. medical degree from Texas A&M College of Medicine, College Station. Dr. Urban completed an internal medicine residency at the Mayo Clinic in Rochester, Minn., and a fellowship in endocrinology and metabolism at 18. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic the University of Virginia School of Medicine, Charlottesville. review and meta-analysis. Arch Intern Med. 2003;163(21):2594-2602.
Address correspondence to Cynthia M. Ripsin, MD, MS, MPH, Dept. of 19. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of Family Medicine, University of Texas Medical Branch, 301 University cardiovascular events in patients with type 2 diabetes mellitus: a meta- Blvd., Galveston, TX 77555 (e-mail: cmripsin@utmb.edu). Reprints are analysis of randomized trials. JAMA. 2007;298(10):1180-1188.
20. Chiasson JL. Acarbose for the prevention of diabetes, hypertension, and cardiovascular disease in subjects with impaired glucose tolerance: the Author disclosure: Nothing to disclose.
STOP-NIDDM Trial. Endocr Pract. 2006;12(suppl 1):25-30.
21. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laasko M, for REFERENCES
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sheet—United States, 2005. http://www.cdc.gov/diabetes/pubs/pdf/ 22. AHFS Drug Information. Exenatide (systemic). http://www.ashp.org/ ndfs_2005.pdf. Accessed October 9, 2008. mngrphs/essentials/a305021e.htm. Accessed October 9, 2008. 2. Goetzel RZ, Hawkins K, Ozminkowski RJ, Wang S. The health and pro- 23. AHFS Drug Information. Sitagliptin phosphate. http://www.ashp.org/ ductivity cost burden of the “top 10” physical and mental health condi- mngrphs/AHFS/a307001.htm. Accessed October 9, 2008.
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24. Hirsch IB, Bergenstal RM, Parkin CG, Wright E Jr, Buse JB. A real-world approach to insulin therapy in primary care practice. Clin Diabetes. 3. Intensive blood-glucose control with sulphonylureas or insulin com- pared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) [published correction appears in Lan- 25. Farmer A, Wade A, Goyder E, et al. Impact of self monitoring of blood cet. 1999;354(9178):602]. Lancet. 1998;352(9131):837-853.
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26. Welschen LM, Bloemendal E, Nijpels G, et al. Self-monitoring of blood 5. Effect of intensive blood-glucose control with metformin on compli- glucose in patients with type 2 diabetes who are not using insulin: a cations in overweight patients with type 2 diabetes (UKPDS 34) [pub- systematic review. Diabetes Care. 2005;28(6):1510-1517.
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org/mngrphs/AHFS/a396005.htm. Accessed October 9, 2008.
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