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A 63-year-old Hispanic woman with type 2 diabetes (T2DM) has been under your care for ten years and she was diagnosed with T2DM six years ago. In addition to long-standing hypertension and hypercholesteremia, she has a BMI (body-mass index) of 31 kg/m2 as well as a family history of cardiovascular disease.
However, she has never had a cardiovascular event and does not report any cardiac symptoms.
She monitors her fasting glucose level twice a week and her morning fasting glucose levels have ranged between 140 and 160 mg/dl. She is taking metformin (1,000 mg b.i.d.) and extended-release glipizide (10 mg b.i.d.). You have been seeing her every six months since her diagnosis of T2DM six years ago. Her hypertension has been successfully controlled with hydrochlorothiazide (25 mg daily) and lisinopril (20 mg daily) and her hypercholesteremia with simvastatin (20 mg daily). Additionally, she takes aspirin (81 mg daily).
The patient has struggled to manage her weight and has been counseled about lifestyle changes. She has lost weight on various diets (~ 10-15 pounds), however each time she regains all of the weight lost. She tries to walk 30 minutes three times a week. Her BMI has fluctuated between 30 and 32 kg/m2 for the past decade.
A recent blood test showed her HbA1c level to be 8.0%. Her other laboratory tests have consistently shown normal results for liver, renal, and thyroid function. Physical examination shows normal blood pressure (118/78 mmHg) as well as normal cardiorespiratory, abdominal, and neurologic findings.
The patient has health insurance through her employer, which includes prescription drug coverage. Concerned about her inability to reach her glycemic goal (HbA1c of 7.0%), she seeks advice about whether a change in medications might help her manage her T2DM more effectively.
Treatment Options
Which one of the following treatment options do you think would be most appropriate for this patient?
1. Add a thiazolidinedione (TZD)
2. Add a glucagon-like peptide-1 (GLP-1) agonist
3. Add insulin
Continue to Management Options
Thiazolidinedione (TZD)
Zachary T. Bloomgarden, MD
Mount Sinai School of Medicine
New York, NY
We are given a common clinical situation: a patient with longstanding diabetes failing to maintain glycemic control on the combination of maximal effective doses of metformin and a sulfonylurea. A number of lines of reasoning can be advanced to suggest benefit of thiazolidinedione (TZD) treatment in this setting. The TZDs are effective glucose-lowering agents, affecting fasting glucose and HbA1c in a reproducible fashion. Although their onset of action is slower than that of most other agents used to treat type 2 diabetes, they induce durable glucose-lowering, certainly relative to sulfonylureas. Essentially all TZD studies show achieved HbA1c levels maintained over 2-6 year periods, while it has been particularly noted with sulfonylureas (SU) the nadir in A1c is seen within six months, with most or all of the glucose-lowering effect occurring over the subsequent two to five years. There is, furthermore, a suggestion of improvement in beta cell function in patients receiving TZDs, as shown by a reduced proinsulin-insulin ratio and, in animal models, evidence of lowered beta cell function.
The mechanism of action of the thiazolidinediones involves improvement in a fundamental defect of type 2 diabetes, that of reduction in insulin sensitivity. This may involve reduction in adipocyte release of free fatty acids or of insulin resistance-causing cytokines, but has a number of noteworthy non-glycemic benefits. Both rosiglitazone and pioglitazone increase HDL cholesterol, and pioglitazone lowers triglyceride levels, and both agents reduce markers of inflammation, reduce hepatic steatosis, and may have benefit in preventing CNS insulin resistance-related cognitive dysfunction.
There are also a number of practical reasons to consider these agents appropriate next steps in the management of the patient described. It is highly likely that a thiazolidinedione will be approved by the patient’s health insurance pharmacy reimbursement plan, a factor of not inconsiderable importance in the present healthcare environment. The drugs are orally administered either once or twice daily, and hence patient instruction time is minimized and adherence improved. We should note that we have been asked to add an agent to an existing sulfonylurea plus metformin regimen, which means that key putative benefits of incretin-mediated treatment—avoiding hypoglycemia and weight gain—will probably not be seen, despite our concept of incretin-based treatments causing only glucose-stimulated insulin release. Because these agents potentiate the insulin-secretory effect of SUs, they typically cannot prevent such side effects in patients receiving these agents.
Clinical Considerations
The decision to add a TZD in this woman must be considered in light of her long-term struggle with weight. These agents cause fluid retention in all patients, to some extent explaining the weight gain associated with their use. Because of this, TZDs should be used with caution in persons with peripheral vascular disease, both venous and arterial, and are relatively contraindicated in those with systemic fluid-retaining states. It is not widely appreciated, however, that SU and insulin are associated with comparable weight gain. Furthermore, the weight gain we might expect from adding a TZD is somewhat attentuated by prior initiation of metformin. Because weight gain seen with TZDs appears largely to occur in subcutaneous fat deposits, moreover, these agents favorably affect the ratio of visceral to subcutaneous fat, which may lessen the adverse impact of increased body weight. A concept now being explored is the use of submaximal doses of TZDs to further reduce weight gain, as well fluid retention.
Adding TZDs also raises hypoglycemia risk—essentially a potentiating effect of the TZD on inappropriate insulin secretion induced by SU, typically in the late-afternoon or night. The clinician should therefore instruct this patient in self-monitoring of blood glucose and should explain the likely times of potential events to prevent severe hypoglycemia; reducing the SU dose when initiating TZD treatment may also be useful. Because the degree of glucose-lowering seen with TZDs will increase over the first 2-4 months of therapy, this entire period requires careful observation.
The clinician should also consider this patient’s osteoporosis and fracture risk before prescribing a TZD . It is now recognized that type 2 diabetes is associated with increased skeletal fracture rates, particularly in the hip and foot, despite the effect of obesity in increasing bone mass. The TZDs reduce bone mass in animal models, an effect appearing to involve reduced recruitment of bone precursors to osteoblasts, and the agents are associated with increased fracture rates in clinical studies, particularly affecting long bones, although it is by no means certain that hip and vertebral fracture rates do not increase as well.
A spirited argument continues about potential adverse cardiac effects. Both pioglitazone and rosiglitazone worsen congestive heart failure and increase LDL cholesterol levels, although both have also been shown to have antiatherosclerotic effects in ultrasound studies of the carotid and coronary arteries, and in persons who have undergone percutaneous coronary intervention. Some meta analyses have shown that rosiglitazone in particular is associated with increased rates of myocardial infarction. A US Food and Drug Administration Panel began addressing this controversy in July 2010.
Summary
The durable glucose lowering and improved insulin sensitivity associated with the TZDS, as well as their several noteworthy nonglycemic effects, make them attractive options as additions to the treatment regimen of this patient. The wise clinician, however, must also be cognizant of potential adverse effects and contraindications, particularly if this patient, known to be at risk for cardiovascular disease, has any signs of peripheral vascular disease or systemic fluid retention. The clinician should also assess this 63-year-old for fracture risk, since a woman at even moderately high risk of fracture might better be given a different agent.
See below for References and Disclosures.
References
Suggested Reading
1. Bloomgarden ZT. Thiazolidinediones. Diabetes Care. 2005;28:488-493.
2. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773-795.
3. Derosa G, Maffioli P. Effects of thiazolidinediones and sulfonylureas in patients with diabetes. Diabetes Technol Ther. 2010;12:491-501.
4. Bloomgarden ZT. Diabetes treatment. Diabetes Care. 2009;32:e25-30.
5. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457-71.
6. Bloomgarden ZT. The Avandia debate. Diabetes Care. 2007;30:2401-2408
7. Bodmer M, Meier C, Krähenbühl S, Jick SS, Meier CR. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. Diabetes Care. 2008;31:2086-2091
8. Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S, Wiley C, Selvin E, Wilson R, Bass EB, Brancati FL. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007;147:386-399
9. Phung OJ, Scholle JM, Talwar M, Coleman CI. Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA. 2010;303:1410-1418.
10. Gerstein HC, Ratner RE, Cannon CP, Serruys PW, García-García HM, van Es GA, Kolatkar NS, Kravitz BG, Miller DM, Huang C, Fitzgerald PJ, Nesto RW; APPROACH Study Group. Effect of rosiglitazone on progression of coronary atherosclerosis in patients with type 2 diabetes mellitus and coronary artery disease: the assessment on the prevention of progression by rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history trial. Circulation. 2010;121:1176-1187.
11. Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, Jure H, De Larochellière R, Staniloae CS, Mavromatis K, Saw J, Hu B, Lincoff AM, Tuzcu EM; PERISCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299:1561-1573.
12. Schwartz AV, Sellmeyer DE, Vittinghoff E, Palermo L, Lecka-Czernik B, Feingold KR, Strotmeyer ES, Resnick HE, Carbone L, Beamer BA, Park SW, Lane NE, Harris TB, Cummings SR. Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab. 2006;91:3349-3354.
13. Bloomgarden ZT. Bone disease, gestational diabetes mellitus, and health care. Diabetes Care. 2009;32:e77-83.
Disclosure:
Speaker's Bureau: Merck, Novo Nordisk, GSK
Advisory Panel: Merck, BMS, Astra Zeneca, Boehringer Ingelheim, Biodel
Consultant: Merck, Novartis, Dainippon Sumitomo Pharma America, Forest Laboratories
Stock/Shareholder: Covidien, Bard, Novartis, Roche, Stryker
Glucagon-like peptide-1 (GLP-1)
Carol H. Wysham, MD
Washington State University
Spokane, WA
The management options for this patient, as in all patients, should be individualized. Adding pioglitazone, insulin, or a GLP-1 receptor agonist to combination therapy with metformin and sulfonylurea would similarly lower A1c, so that, without clear head-to-head comparison, the choice should center around what is known about efficacy, safety, and nonglycemic effects of available options. Importantly, the patient’s priorities and potential barriers to adherence should also be considered.
GLP-1 Receptor Agonists
Currently, two GLP-1 receptor agonists are available in the United States: exenatide and liraglutide. Both lower blood glucose levels by multiple mechanisms: stimulating insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, and reducing food intake.[1] Most subjects treated in clinical trials showed improved glycemic control and modest weight loss.[1] The latter benefit is particularly important in our patient. Additionally, GLP-1 receptor agonist therapy is usually associated with improved cardiovascular risk factors, particularly blood pressure and non-HDL cholesterol, largely due to the weight loss.[2]
Considerable animal data also suggest that GLP-1 has positive effects on beta cell function and number (beta cell mass).[1] However, in humans, demonstrating these effects has been elusive. No persistent effect on beta cell function could be demonstrated after one year’s therapy with exenatide.[3] However, after three years, the same investigators demonstrated improved beta cell function four weeks after discontinuing exenatide.[4]
Weighty Considerations
For optimal outcomes, weight loss should be an important therapeutic objective for overweight or obese individuals with diabetes.[5] Over 85% of patients with diabetes are overweight. When diabetes is complicated by overweight/obesity, lifetime risk of developing CVD increases to 90%. Furthermore, a 5 kg weight gain is estimated to increase CVD risk by 30%,[6] whereas similar weight loss is associated with reduced fasting blood glucose, blood pressure, and lipoprotein levels.[5]
Here the GLP-1 agonists may offer a relative benefit over other available options. A recent meta-analysis, for example, concluded that, when added to metformin, exenatide was associated with A1c reduction equivalent to other antihyperglycemic therapies, but with weight loss rather than gain.[7] Given her admission of life-long weight-related struggles, the association of weight gain with pioglitazone or insulin would likely be a significant barrier for our patient. There is evidence that weight gain from medications might negatively affect adherence. Anticipation of a 2.3 kg weight gain has been associated with an anticipated 20% reduction in adherence to taking the medication.[8]
Choosing a GLP-1Receptor Agonist
Which of the two currently available GLP-1 receptor agonists to choose should depend upon therapeutic goals and patient characteristics. These compounds have differing pharmacokinetic properties. Exenatide’s shorter half-life (t½=60-90 min versus liraglutide‘s t½ =10-14 hrs) necessitates twice daily injection, whereas liraglutide can be given once daily.[1] Also, liraglutide’s longer duration of action it more effective than exenatide at lowering fasting plasma glucose (FPG). However, liraglutide appears to be less potent than exenatide in reducing the postprandial glucose excursion.[2] One study suggests that adding exenatide to ongoing treatment with sulfonylurea and metformin might lower our patient’s A1c by about 1.0%.[9] In another similarly designed study, adding liraglutide lowered A1c by 1.2%.[10] Clinical trials comparing these agents with insulin glargine similarly reduced A1c, with 3.4-5 kg difference in body weight after 26 weeks.[10][11] A small study comparing exenatide to insulin glargine showed an even greater difference in weight (7.9 kg) after three years.
Side Effects
The major side effects of GLP-1 receptor agonists are gastrointestinal: nausea, vomiting, diarrhea, and reflux. Nausea occurs most frequently upon initiation and titration and generally improves within a few weeks. Frequency and severity of nausea appear to be less with liraglutide..[2] Mild hypoglycemia has been reported in about 28% of subjects when either exenatide or liraglutide is added onto treatment including a sulfonylurea.[9][11] To minimize this risk, lowering the dose or discontinuing the sulfonylurea is appropriate, particularly in patients with A1c < 8%.
Pancreatitis has been described in post-marketing reports with exenatide[12] and in the clinical trial program with liraglutide.[13] However, analysis of a large health system database failed to demonstrate increased pancreatitis with exenatide compared to other antihyperglycemic therapies.[14] Recently, exenatide’s label has been changed to include warnings about use in patients with renal disease, due to dehydration risk associated with vomiting.[12] Preclinical studies with liraglutide demonstrated excess thyroid c-cell hyperplasia and carcinoma in rodents, but not in non-human primates.[15] Additionally, calcitonin levels have not increased in human studies with liraglutide, suggesting differing interspecies effects of GLP-1 receptor stimulation of c-cells.[15]
Clinical Considerations
I would discuss risks and benefits of all three options with our patient and allow her to participate in the decision. This exercise would let her to choose a therapy compatible with her lifestyle and help her meet personal goals. It takes only a few minutes and, in my experience, more than 75% of patients choose a GLP-1 receptor agonist. Given the convenience of once daily injection and the lower incidence of nausea, I would likely choose liraglutide for this patient. I would demonstrate the use of the pen and injection technique while she is in the office. To maximize the weight benefit of GLP- 1 receptor agonist therapy, I would also strongly recommend she see a registered dietician or, at least, participate in a formal weight loss program, such as Weight Watchers. Upon initiating liraglutide treatment, I would ask her to hold the sulfonylurea until the liraglutide dose is stable. If glycemic goals remain unmet, the sulfonylurea can be reintroduced, generally at the lowest effective dose.
Summary
Compared to insulin glargine or pioglitazone, GLP-1 receptor agonists have similar potential to improve our patient’s glucose levels. These agents are available as easy-to-use pens and, unlike the other options presented, our patient will likely experience satiety and weight loss. In my experience GLP-1 agonists are very well received by patients. Once the overall glycemic and non-glycemic effects (especially weight loss potential) are described to patients, the need for injection does not present itself as a barrier.
See below for References and Disclosures.
References
1. Drucker D, Nauck M. The incretin system: glucagons-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. The Lancet 2006; 368:1696-1705.
2. Buse J, Rosenstock J, Sesti G et al. Liraglutide once a day vs exenatide BID for type 2 diabetes: a 26 week randomized, parallel group, multinational, open-label trial (LEAD-6). The Lancet 2009;374:39-47.
3. Bunck M, Diamant M, Corner A et al. One year treatment with exenatide improves B-cell function, compared with insulin glargine in metformin treated patients. Diab Care 2009;32:762-768.
4. Bunck M, Corner A, Elizasson B et al. Three-year exenatide therapy, followed by a 4 week off-drug period, had sustainable effect on B-call disposition index in metformin treated patients with type 2 diabetes. Abstract 728-P. Presented at the 70th Annual Sessions of the American Diabetes Association. 2010.
5. American Diabetes Association. Standards of Medical Care in Diabetes – 2010. Diab Care2010;33(suppl 1): S11-S61.
6. Anderson JW, Kendall CW and Jenkins DJ. Importance of weight management in type 2 diabetes: review with meta-analysis of clinical studies. J Am Coll Nutr. 2003;22:331-339.
7. Phung OJ, Scholle JM, Talwar M et al. Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 Diabetes. .JAMA 2010; 303: 1410-1418.
8. Hauber A et al. Treatment preferences and medication adherence of people with type 2 diabetes using oral glucose medications. Diab. Med 2009;26:416-424.
9. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005;28:1083-1091.
10. Russell-Jones D, Vaag A, Schmitz O et al. Liraglutide vs insulin glargine and placebo in combination with metormin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5): randomized controlled trial. Diabetologia 2009;52:2046-2055.
11. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2005;143:559-569.
12. Lovshin JA, Drucker DJ. Incretin-based therapies for type 2 diabetes mellitus. Nat Rev Endocrinol 2009;5:262-269.
13. Parks M, Rosebraugh C. Weighing risks and benefits of liraglutide – the FDA’s review of a new antidiabetic therapy. New Engl J Med 2010;362:744-745.
14. Noel RA, Braun DK, Patterson RE et al. Increased risk of acute pancreatitis in patients with type 2 diabetes: a retrospective cohort study. Diab Care 2009;32:834-838
15. Knudsen LB, Madsen LW, Andersen S et al. Glucagon-like peptide-1 receptor agonists activate thyroid c-cells causing calcitonin release and c-cell proliferation. Endocrinology 2010;151:1473-1486.
Disclosure:
Carol Wysham has received honoraria for acting as a speaker for Amilyn Pharmaceuticals, Eli Lilly and Novo Nordisk.
Insulin Therapy
Charles F. Shaefer, MD, FACP, FCCP
Medical College of Georgia
Augusta, GA
This patient presents in a very typical fashion, appropriately treated for T2DM for six years but now failing to maintain an HbA1C goal of < 7%. It is reasonable to surmise that she is experiencing a gradual worsening of control due to inexorable beta cell failure.[1] The ADOPT trial demonstrates that even with the best of oral agents, glycemic control gradually worsens over time.[2]
A number of factors impact the health of the beta cell,[3] and it is ultimately loss of beta cell function and the resultant relative (or absolute) insulin deficiency that leads to loss of glycemic control.[1]At the time of T2DM diagnosis as much as 80% of beta cell function may be lost.[4] UKPDS showed that T2DM patients with a similar treatment regimen as this lady experience a progressive need for insulin over time in order to achieve the intensive treatment goal HbA1C. In fact, by about year six into the study, most UKPDS intensive treatment arm patients required insulin to reach goal HbA1c.[5] It is therefore plausible that progressive decline in beta cell function now sets the stage for insulin requirement in our lady.
Goal: Mimicking Physiology Cost Effectively
Our goal for this patient is to attempt to mimic physiology as closely as possible by providing therapy to replace what is missing without creating untoward side effects such as hypoglycemia, treatment-associated weight gain, or other treatment-related adverse outcomes.[6] And this objective should be met in the most cost-effective manner possible.
To obtain guidance for therapeutic decision making in a world of abundant diabetes therapies, it helps to systematize the decision making process. First, what is the basic clinical problem facing us? Secondly, are there any clues available that might give greater understanding of the basic problem? Third, what underlying physiologic condition(s) seem to be causing this problem? Finally, what tools do we have that most specifically address the problem at hand? The more closely the fix matches the underlying fault, the fewer treatment-associated issues like hypoglycemia and weight gain should come into play as we establish HbA1C control.
Our patient’s basic clinical problem is worsening glycemic control despite taking two oral anti-diabetic agents (OADs). Several features of her presentation provide useful additional information. We know her HbA1C (8%) must decrease more than 1% to reach goal HbA1C (and she is already on the two most powerful OADs). We know she is Hispanic, a group with often difficult to control diabetes. And we know that there are substantial elevations in her fasting blood sugar, likely a significant contributor to her HbA1C.[7] Progressive beta cell failure and worsening relative insulin deficiency are the physiologic fault. And the treatment, added to her oral agents, which will most specifically address the failure of beta cells to produce adequate insulin, is insulin itself. And basal insulin therapy specifically targets a major issue of her case: consistently elevated fasting sugars. No other single therapeutic option so directly addresses the unmet needs expressed in this case.
Ineffectiveness of Alternatives
Prior to looking more specifically at the agent we chose for our fix, let’s look at why we didn’t select some other therapies. Why not add more oral agents? In a word–ineffectiveness! Yale et al. showed that the addition of a third oral (TZD) to metformin + sulfonylurea failed to achieve goal HbA1C at one year in 86% of patients.[8] And the addition of a TZD is a very expensive proposition. DPP-4 inhibitors are useful new oral agents, but they are not likely to lower the HbA1C beyond 0.8% and are quite expensive.[9],[10] The use of DPP-4 inhibitors with sulfonylurea worsens hypoglycemia,[11] but without the SU our patient’s HbA1C would likely climb even higher.
A very common situation after a patient fails on one or two oral agents is the choice of adding incretin therapy or basal insulin.[12] For our patient, exenatide or liraglutide, GLP-1R agonists, could result in adequate HbA1C reduction to achieve our goal of < 7%, and weight loss would be expected. Liraglutide, which is given once a day, would impose no more injection burden than we are considering by adding basal insulin. Additionally, AACE (American Association of Clinical Endocrinologists) guidelines support incretin therapy at all stages of T2DM.[13] Major drawbacks to incretin therapy, however, are frequently nausea and cost. Over 20% of patients are likely to experience nausea .[14] While our lady is insured, pharmaceutical benefit plans may make incretin therapies costly or difficult to obtain with prior approval processes. Also, these are relatively new agents with much less clinical exposure than insulin. There are theoretical concerns regarding safety (pancreatitis and thyroid tumors) that might make our patient reluctant to use these agents as well.[15]
Advantages of Basal Analog Insulin
Insulin has the capacity to lower our patient’s HbA1C to goal. Additionally, basal insulin therapy specifically addresses the issue of FBS elevation, which is a factor in this case. And, analog basal insulins detemir and glargine are less likely to cause hypoglycemia and weight gain than NPH;[16],[17] and cause no more hypoglycemia or weight gain than seen with addition of more oral agents.[18] The 4-T trial showed detemir is preferable to commonly used 70/30 premixed analog insulin (at HbA1C’s < 9.5%) for glycemic control due to less hypoglycemia and less weight gain.[19] While many early studies showed need for detemir twice daily in some patients,[19] recent studies show good efficacy with a single daily dose.[20] Therefore, basal analog insulin added to her oral anti-diabetic agents as a convenient once daily injection meets the needs of our patient while being more cost-effective than adding incretin or TZD therapy.[21]
I most frequently start basal analog insulin at 10 U subcutaneously per day and upward titrate by one additional unit per day until an FBS range of 100-110 mg/dl is achieved,[18] requiring self-monitoring of blood glucose at least once daily. Knowing the difficulty of managing diabetes in the Hispanic population, I would re-evaluate her often, at a minimum 3-4 times annually, and strive to be attuned to cultural issues that impact her control. She has shown some capacity to take control of her situation: she walks regularly and has been successful from time to time with weight loss. She should do very well with a comprehensive management plan including not only her provider, but also regular interaction with Certified Diabetes Educators (CDE’s), nutritionists, and a support group as part of a team approach to empower her to take control of her diabetes.
Conclusion
Currently, more than 90% of T2DM is managed by the primary care community.[22] It should be within the scope of expertise for every primary care provider to recognize the need for and institute basal insulin therapy, when appropriate. When there is failure to maintain goal HbA1C with one or two oral agents, basal analog insulin is a well-studied, effective and cost-efficient way to advance therapy with a minimum of treatment-related side-effects or safety issues.
See below for References and Disclosures.
References
1. Leahy JL. Natural history of beta-cell dysfunction in NIDDM. Diabetes Care1990;13:992-1010.
2. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G, for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-2443.
3. Kahn SE. The importance of ß-Cell failure in the development and progression of type 2 diabetes. J. Clin. Endocrinol. Metab 2001; 86: 4047-4058.
4. DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773-795.
5. UKPDS Group. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853.
6. Riddle MC, Ambrosius WT, Brillon DJ, Buse JB, Byington RB, Cohen RM, Goff, Jr. DC, Malozowski S, Margolis KL, Probstfield JL, Schnall A, Seaquist ER, and for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Investigators. Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 201;33:983-990.
7. Monnier L, Lapinski Hand Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c.Diabetes Care 2003;26:881-885.
8. Yale JF, Valiquett TR, Ghazzi MN, Owens-Grillo JK, Whitcomb RW, Foyt HL, and for the Troglitazone Triple-Therapy Study Group. The effect of a thiazolidinedione drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus poorly controlled with sulfonylurea and metformin: a multicenter, randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;134:737-745.
9. Scott R, Loeys T, Davies MJ, Engel SS, for the Sitagliptin Study 801 Group. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2008;10:959-969.
10. DeFronzo RA, Hissa MN, Garber AJ, Gross JL, Duan RY, Ravichandran S, Chen RS, and for the Saxagliptin 014 Study Group. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care 2009 ;32:1649-1655.
11. Package insert for sitagliptin and saxagliptin, September 2010.
12. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193–203.
13. Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, Handelman Y, Horton ES, Lebovitz H, Levy P, Moghissi E, and Schwartz SS. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract 2009;15:540-559.
14. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, Zychma M, Blonde L. LEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009;374:39– 47.
15. Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, and Buse JB. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care 2010;33:428-433.
16. Riddle MC, Rosenstock J, and Gerich J. The. Treat-to-Target Trial: Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26:3080-3086.
17. Hermansen K, Davies M, Derezinski T, Ravn GM, Clauson P, and Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir With NPH insulin as add_on therapy to oral glucose-lowering drugs in insulin-naive people With type 2 diabetes. Diabetes Care 2006;291269-1274.
18. Gerstein HC, Yale JF, Harris SB, Issa M, Stewart JA, Dempsey E. A randomized trial of adding insulin glargine vs. avoidance of insulin in people with Type 2 diabetes on either no oral glucose-lowering agents or submaximal doses of metformin and/or sulphonylureas. The Canadian INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) Study. Diabet Med 2006; 23:736-742.
19. Holman RR, Farmer AJ, Davies MJ, Levy JC, Darbyshire JL, M.A., Keenan JF, B.A., and Paul SK, for the 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med 2009; 361:1736-1747.
20. King, AB. Once-daily insulin detemir is comparable to once-daily insulin glargine in providing glycaemic control over 24 h in patients with type 2 diabetes: a double-blind, randomized, crossover study. Diabetes, Obesity and Metabolism 2009;11:69–71.
21. Shaefer, CF. Unpublished data. Cost Analysis of 90 day diabetes therapy. June 2010.
22. Hirsch, IB. Oral communication. ADA 68th Scientific Sessions, Chicago, IL, 2007.
Disclosure:
Charles Shaefer has received honoraria as a speaker for Sanofi-Aventis, Novo Nordisk, Amylin, Eli Lilly, Bristol Myers Squibb, AstraZeneca, Novartis, Abbott Labs, Forest Pharmaceuticals, Daiichi Sankyo, and Pfizer. He has acted as a consultant for Sanofi-Aventis, Amylin, and Eli Lilly.
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Posted 1/25/13 by Pearline Kopf
I'm not sure why but this weblog is loading very slow for me. Is anyone else having this problem or is it a issue on my end? I'll check back later on and see if the problem still exists. Pearline Kopf
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I'm not sure why but this weblog is loading very slow for me. Is anyone else having this problem or is it a issue on my end? I'll check back later on and see if the problem still exists. Pearline Kopf
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